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A stable parenteral dosage form of cetrorelix acetate

a parenteral and acetate technology, applied in the field of stable parenteral dosage form of cetrorelix acetate, can solve the problems of increased turbidity or cloudiness of the solution, easy chemical degradation of the solution, and expensive and time-consuming process of aqueous solution of peptides such as cetrorelix

Pending Publication Date: 2022-05-19
SUN PHARMA INDS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]Degradation of peptides can lead to generation of other peptides and / or peptide derivatives which may themselves have pharmacological activity. Therefore the objective more particularly was to develop an appropriate method to separate individual impurities and quantify them. The objective was to limit the concentration of such impurities. The inventors discovered a High Performance Liquid Chromatographic (“HPLC”) method which gave separate peaks for several impurities which were here before not reported in the prior art. Whereas the prior art advocated low pH values to decrease the tendency for agglomeration, the inventors found with the use of their HPLC method that in the parenteral dosage form of the present invention, a pH of 3 to 5 was optimal for chemical stability in terms of increases in level of impurities over a period of time and also the aqueous solution of cetrorelix acetate could be prepared at this higher pH without agglomeration problems.

Problems solved by technology

However, aqueous solutions of peptides such as cetrorelix are susceptible to chemical degradation.
They are also prone to aggregation whereby the turbidity or cloudiness of the solution increases on storage.
However, this solution to the problem has clear disadvantages—(1) expensive and time consuming process; (2) product is not ready-to-inject and requires reconstitution before administration; and (3) reconstituted solution is stable only for a short period of time.
The disadvantage of the method is that the degree of resolution of the problem of aggregation is dependent on the gluconic acid concentration and with more gluconic acid the pH decreases.
However, U.S. Pat. No. 7,718,599 did not report the effect of pH on the chemical stability of cetrorelix.
Moreover, there were no formulations where aggregation was not seen during long term storage stability studies.

Method used

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  • A stable parenteral dosage form of cetrorelix acetate
  • A stable parenteral dosage form of cetrorelix acetate
  • A stable parenteral dosage form of cetrorelix acetate

Examples

Experimental program
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Effect test

example 1a

Identification of the Degradation Product

[0100]In order to investigate the degradation of cetrorelix, peptide related substances of cetrorelix were prepared by the known technique of solid phase peptide synthesis. The synthesis involved coupling of one amino acid at a time sequentially starting from c-terminal amino acid on a resin. The synthesis of the peptide chain was carried out using the Fluorenylmethyloxycarboyl (Fmoc) / tButyl (Fmoc / tBu) with N,N′-diisopropyl carbodiimide (DIPC) as the coupling reagent. The Fmoc groups were removed via treatment with 20% piperidine in dimethylformamide. The peptide formed on resin was finally cleaved using trifluoroacetic acid to obtain related substances which were further purified by reverse phase high performance liquid chromatography (RP-HPLC) on a C18 Silica column using a gradient of acetonitrile / water containing 0.1% trifluoroacetic acid. The purified peptide related substances were lyophilized to obtain pure solid form. The structure of...

example 1b

[0106]Cetrorelix and the identified impurities namely, Impurity A, Impurity B, Impurity D and Impurity F from the aqueous solution samples were separated on a reverse phase (C-18) column using gradient technique (Column: X-Select CHS C18, (150×4.6) mm, 2.5p. (by Waters, Ireland, Part No: 186006729), detected and quantified by Ultraviolet spectroscopy at 225 nm wavelength. The mobile phase was run at a flow rate of 0.7 ml / min and 1.0 ml / min. The run time of the chromatogram was 150 minutes.

Mobile Phase Details:

[0107]Mobile Phase A: A mixture of buffer solution as below, with acetonitrile and tetrahydrofuran in the ratio of (700:280:20), degassed by sonication.

Mobile Phase B: A mixture of buffer solution as below, with acetonitrile and tetrahydrofuran in the ratio of (500:480:20), degassed by sonication.

Buffer: 2.5 g of Ammonium dihydrogen orthophsphate and 0.75 g of 1-Octane sulphonic acid sodium salt in 1000 ml water with pH adjusted to 8.0±0.05 using triethylamine.

Diluent: A mixtur...

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PUM

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Abstract

The present invention relates to a stable parenteral dosage form with a ready-to-inject sterile stable aqueous solution of cetrorelix acetate. The invention also relates to an injection device prefilled with the ready-to-inject sterile stable aqueous solution of cetrorelix acetate. The present invention relates a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising a stable parenteral dosage form with a ready-to-inject sterile stable aqueous solution of cetrorelix acetate.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a stable parenteral dosage form with a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate. The invention also relates to an injection device prefilled with the ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate. The present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising a stable parenteral dosage form with a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate.BACKGROUND OF THE INVENTION[0002]Cetrorelix is gonadotropin releasing hormone antagonist (GnRH antagonist) acetyl-D-3-(2′-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3′-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide (C70H92ClN17O14) having the below formula. It is a decapeptide with a terminal acid amide group. It acts by blocking the action of GnRH upon the p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/59A61K9/08
CPCC07K14/59A61K38/00A61K9/08A61K38/09A61K47/12A61K9/0019A61K9/0029A61P15/00A61K38/08G01N2030/027G01N30/16A61P15/02
Inventor JOSHI, JAYDIPTHUMMAR, RAKESHAGRAWAL, SUDEEPBALARAM, SUBHASYADAV, ARUNKUMARTHENNATI, RAJAMANNAR
Owner SUN PHARMA INDS
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