Method for producing sterile suspensions or lyophilisates of poorly soluble basic peptide complexes, pharmaceutical formulations containing the same, and use thereof as medicaments

摘要

Producing a soluble basic peptide complex sterile suspension comprises mixing a sterile solution having a basic peptide complex and carboxylic acid, in solvent and optionally with solubility-increasing additives, adding diluent to the mixture, and depleting solvent, free non-peptide ions, excess carboxylic acid and additives in obtained suspension. Producing (M1) a sterile suspension of at least one slightly soluble basic peptide complex, under aseptic conditions by: (a) mixing a sterile solution comprising a salt or complex of basic peptide and of an aliphatic or aromatic organic carboxylic acid and/or its salts in a solvent or its mixture, optionally with the addition of solubility-increasing and/or agglomeration-suppressing additives; or combining and mixing a sterile solution of a salt or complex of a basic peptide in a solvent or its mixture and a sterile solution of an aliphatic or aromatic organic carboxylic acid and/or its salts in a solvent or its mixture, optionally with the addition of solubility-increasing and/or agglomeration-suppressing additives; (b) generating, by mixing and addition of a diluent or its mixture, a suspension of slightly soluble basic peptide complex of the basic peptide with the carboxylic acid, where the complex precipitates at the latest after addition of the diluent or its mixture; (c) depleting, while mixing in a continuous or stepwise separation process, the solvent or its mixture, free non-peptide ions, excess carboxylic acid and optionally added solubility-increasing and/or agglomeration-suppressing additives in the resulting suspension, with the liquid content of the suspension being reduced and optionally further diluent or its mixture being added; and (d) optionally adding to the slightly soluble basic peptide complex, while mixing the sterile suspension at the time of performing step (c) and/or after performing step (c), pharmaceutical excipients, carriers and/or bulking agents. Independent claims are also included for: (1) producing (M2) sterile lyophilizates of slightly soluble basic peptide complexes by lyophilizing the sterile suspension of the slightly soluble basic peptide complex obtained in (M1(c) or (d)) and optionally adding pharmaceutical excipients, carriers and/or bulking agents to the obtained lyophilizate, or lyophilizing the sterile suspension obtained in (M1(d)); (2) producing (M3) sterile suspensions suitable for parenteral administration of slightly soluble basic peptide complexes by reconstituting the lyophilizate obtained by (M2) with a sterile reconstituting medium, or with water for injection; (3) a sterile suspension (I) obtained by (M1); (4) a sterile lyophilizate (II) obtained by (M2); (5) a pharmaceutical formulation (F1) for parenteral administration, comprising (I); (6) a pharmaceutical composition (C1) comprising an aseptic reaction product of a sterile solution of a cetrorelix salt and organic carboxylic acid or salt in solvent with sterile diluent, where the reaction product is depleted of solvent, free salt ions and free carboxylic acid; (7) a pharmaceutical composition (C2) comprising a slightly soluble cetrorelix salt or complex, where the cetrorelix salt is free of any tracers of ion exchange resin or of any materials embedded in it, and substantially free of solvent, free non-peptide ions, and/or excess carboxylic acid; (8) a slightly soluble cetrorelix salt composition comprising 30 mg of cetrorelix salt, where the composition cumulatively releases greater than 15 mg of the cetrorelix salt in vitroover 160 hours; (9) aseptically manufacturing a cetrorelix salt by: mixing a sterile solution comprising the cetrorelix salt in solvent, organic carboxylic acid or salt, and diluent; or mixing a sterile solution of a cetrorelix salt in a solvent, and sterile solution of an organic carboxylic acid or salt in a second solvent, to form a third solution, and mixing the third solution with a diluent; (10) aseptically manufacturing cetrorelix pamoate by dissolving cetrorelix acetate in water to form a solution, mixing in ethanol to form an ethanol/water solution that is predominantly ethanol, adding, while stirring, disodium embonate to form a cetrorelix embonate solution, sterilizing by filtration, continuously adding sterile water while stirring, to form a suspension of cetrorelix embonate particles, continuously removing liquid using filtration to form a concentrated suspension of cetrorelix embonate particles, adding, while stirring, a sterile mannitol solution, and lyophilizing the concentrated suspension; and (11) an aseptic, cetrorelix pamoate manufacturing apparatus, comprising: container(s) having a cetrorelix pamoate suspension forming chamber and permeate chamber, a filter filterably separating the chambers, and a stirrer placed within the cetrorelix pamoate suspension forming chamber adjacent to the filter; or container(s) having a filter positioned in a bottom portion of the container having a pore size sufficient to substantially retain particles of cetrorelix pamoate, while passing a liquid content of a suspension containing the particles of cetrorelix pamoate, and a mixer positioned adjacent to the filter that, when mixing maintains the retained particles in suspension. ACTIVITY : Cytostatic; Endocrine-Gen.; Antiinferility; Anti-HIV; Neuroprotective; Depilatory; Gynecological; Nootropic; Neuroprotective. No supporting data is given. MECHANISM OF ACTION : LHRH antagonist; LHRH superagonist; Nal-Glu antagonist.