Cetrorelix Tablet

1. Research and Development Background

The discovery of cetrorelixum stemmed from breakthroughs in basic research on gonadotropin-releasing hormone (GnRH). In 1971, Schally's team successfully isolated and characterized the decapeptide structure of native GnRH, laying the foundation for subsequent analog development. Early clinical practice relied on GnRH agonists, which exhibited an initial hormone flare-up effect and failed to meet the need for rapid LH surge suppression. Meanwhile, first- and second-generation GnRH antagonists were limited clinically by severe adverse effects such as edema and hypersensitivity due to histamine release. Against this background, third-generation GnRH antagonists with high activity and minimal side effects became the core focus of research.

2. Molecular Discovery and Structural Optimization (1988–1990)

In 1988, the team led by Nobel laureate Schally launched the development of novel GnRH antagonists. In 1990, Bokser et al. at Tulane University (USA) first synthesized cetrorelixum, a synthetically modified decapeptide containing five non-natural D-amino acids, which markedly enhanced receptor affinity and metabolic stability. Through multiple rounds of amino acid substitution, the research team completely eliminated histamine release-related side effects while retaining potent competitive antagonistic activity at pituitary GnRH receptors, enabling rapid and reversible suppression of LH and FSH secretion. Preclinical studies confirmed its safe and effective inhibition of gonadotropin secretion in various animal models, paving the way for clinical trials.

4. Developmental Significance and Academic Value

1. Solubility and Acid-Base Properties

Cetrorelix Tablet has low water solubility (approximately 2.0 mg/mL), is freely soluble in DMSO (solubility increases with heating), and slightly soluble in methanol. Formulation optimization with excipients improves in vivo dissolution and absorption stability of the tablets. With a pKa ≈ 9.82, it is a weakly basic polypeptide with optimal stability in the pH range of 5–8. It exists as a zwitterion under neutral conditions, with a plasma protein binding rate of approximately 86%.

2. Stability and Degradation Characteristics

It are sensitive to light, heat, strong acids, and strong bases, requiring refrigerated storage at 2–8°C in a light-protected, sealed container. Both the drug substance and tablets have a shelf life of up to 3 years. Aqueous solutions are stable for 21 days at pH 7.0 and room temperature; rapid hydrolysis occurs under high temperature (100°C) or extreme pH conditions, with approximately 15% degradation within 30 minutes. The D-amino acids in the structure significantly enhance resistance to enzymatic hydrolysis, with tolerance to chymotrypsin, pronase, and other enzymes exceeding 50 hours, far superior to native GnRH and agonists.

3. Chemical Characteristics of the Tablet Formulation

It use the acetate salt as the active ingredient, combined with excipients including microcrystalline cellulose, lactose, and magnesium stearate to ensure uniform content, rapid disintegration, and stable oral absorption. The formulation lacks histamine-releasing side chains, eliminating the hypersensitivity risk of early antagonists. Rapid absorption after oral administration results in bioavailability comparable to injectable formulations, with reversible action and no receptor desensitization, meeting clinical needs for rapid LH surge suppression and flexible cycle regulation.

Sources of Information:Engel J, Reissmann T. Cetrorelixum, a potent LHRH-antagonist: Chemistry, pharmacology and clinical data. Arzneim Forsch. 1999;49(8):697–705.National Medical Products Administration. Drug Registration Standard for Cetrorelixum. 2023.