KR-102963105-B1 - Carboplatin complex and drug preparations thereof

Abstract

The present invention provides a carboplatin complex and a drug formulation thereof, wherein the carboplatin complex is a complex formed by combining carboplatin and 1,1-cyclobutanedicarboxylic acid through two hydrogen bonds, and said two hydrogen bonds are formed between the carboxyl group oxygen of the carboplatin molecule and the carboxyl group hydrogen of the 1,1-cyclobutanedicarboxylic acid molecule. The present invention further provides the application of said carboplatin complex in antitumor drugs, antibacterial drugs, antifungal drugs, or antiviral drugs, and a method for quality control of said carboplatin complex.

Inventors

• 쩡, 지양치양

Assignees

• 어드밴클 바이오테크놀로지 서비스 센터 (샹하이)

Dates

Publication Date

20260508

Application Date

20200826

Priority Date

20190827

Claims (16)

1. In a method for preparing a carboplatin complex, the carboplatin complex is a complex formed by combining carboplatin and 1,1-cyclobutanedicarboxylic acid through two hydrogen bonds, wherein the two hydrogen bonds are formed between the carboxyl group oxygen of a carboplatin molecule and the carboxyl group hydrogen of a 1,1-cyclobutanedicarboxylic acid molecule, and The structure of the above carboplatin complex is as follows: Method for manufacturing a carboplatin complex: The above manufacturing method is, A step of preparing a supersaturated aqueous solution by mixing carboplatin and 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1.5-3, wherein the operation of mixing and preparing the solution is performed at 65℃±10℃ for a time of 0.5 hours or more; A method for preparing a carboplatin complex comprising the step of obtaining a crystal of the above carboplatin complex.
2. A method for preparing a carboplatin complex according to claim 1, wherein the carboplatin complex is provided from a self-assembled product of carboplatin and 1,1-cyclobutanedicarboxylic acid, and the carboplatin complex has a mass content of 95% or more in the self-assembled product.
3. In paragraph 1, In the differential scanning calorimetry measurement results, the carboplatin complex forms a phase transition peak starting from 197.8±2℃; or, In the measurement results of X-ray powder diffraction analysis, the absence of a diffraction peak when 2θ is 11.55±0.2°; or, A method for preparing a carboplatin complex, wherein, in the differential scanning calorimetry measurement results, the carboplatin complex forms a phase transition peak from 197.8±2℃; and in the X-ray powder diffraction analysis measurement results, there is no diffraction peak when 2θ is 11.55±0.2°.
4. In a method for manufacturing a drug formulation, the drug formulation comprises a carboplatin complex manufactured by the method according to claim 1 as an active ingredient, and The above drug preparation is an antitumor agent, an antibacterial agent, an antifungal agent, or an antiviral agent, and the method of manufacturing the above drug preparation is, A step of preparing crystals of the carboplatin complex according to the manufacturing method of claim 1, and obtaining carboplatin complex powder by grinding and drying; A method for manufacturing a drug formulation comprising the step of manufacturing the above carboplatin complex powder into a formulation.
5. In claim 4, the step of dissolving the carboplatin complex powder in sterilized water, stirring and dissolving at 45℃±5℃, and leaving at room temperature for at least 1 hour to obtain a mother liquor; A step of filtering and sterilizing the above mother liquid at room temperature and then individually packaging it as a water injection; or, A method for manufacturing a drug formulation, further comprising the step of preparing the above mother liquid into a freeze-dried powder injectable, a solid oral formulation, a gel formulation, or a spray formulation.
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Description

Carboplatin complex and drug preparations thereof The present invention relates to platinum derivatives, specifically to carboplatin complexes bonded via hydrogen bonding on the basis of carboplatin molecules, and also to platinum drug formulations obtained based on said carboplatin complexes. The discovery of the antitumor efficacy of cis-dichlorodiamine platinum initiated research and applications of platinum-based anticancer drugs, and research into platinum-based anticancer drugs has recently become one of the hotspots in the field of tumor treatment. Cisplatin, containing cis-dichlorodiamine platinum as its active ingredient, is the first platinum-based anticancer drug in humans; it is a cell-nonspecific drug, and research results indicate that cisplatinum can bind to DNA and induce cross-linking, thereby disrupting DNA function and inhibiting cellular DNA replication. In clinical applications, cisplatinum exhibits a broader antitumor spectrum and is used for head and neck squamous cell carcinoma, ovarian cancer, embryonic cancer, spermatogonium carcinoma, lung cancer, thyroid cancer, lymphosarcoma, and reticular cell sarcoma. While it demonstrates statistically superior tumor therapeutic effects based on big data, it has also exhibited serious toxicity and side effects in clinical practice. Meanwhile, due to drug resistance in chemotherapy drugs, the discovery of alternative agents is necessary. Carboplatin is a second-generation platinum-based anticancer drug obtained by modifying the molecular structure of cisplatin. It is a new platinum compound produced by simultaneously replacing two chlorine atoms of the cisplatin molecule with a single 1,1-cyclobutanedicarboxylic acid molecule, and it maintains antitumor properties while partially overcoming the toxicity and side effects of cisplatin. According to clinical applications, while the biochemical properties of carboplatin are similar to those of cisplatin, nephrotoxicity, ototoxicity, neurotoxicity, and especially gastrointestinal reactions are significantly lower than those of cisplatin. Consequently, it has become a broad-spectrum anticancer drug that has received significant attention for over a decade. Like cisplatin, carboplatin belongs to the category of cell cycle non-specific drugs. It primarily acts on the N7 and O6 atoms of guanine in DNA to induce cross-linking between and within DNA strands, thereby disrupting DNA replication and inducing apoptosis in tumor cells. In addition to cisplatin and carboplatin, various platinum-based anticancer drugs have entered the research and clinical stages. However, in addition to toxicity issues, the stability of these drugs, particularly their stability in aqueous solutions, poses a critical disadvantage for clinical application. Consequently, improvements and modifications to existing drug structures are continuously being made. Meanwhile, drug resistance to chemotherapy drugs is another obstacle affecting tumor treatment; after repeated contact with drugs, tumor cells lose or even lose sensitivity to the medication, resulting in reduced or ineffective therapeutic effects. Once drug resistance develops, the chemotherapy action of the drug is significantly diminished, and continued use leads to treatment failure. Simultaneously, if tumor cells develop resistance to a single anticancer drug, cross-drug resistance also develops against other anticancer drugs with different structures and mechanisms of action. This "Multiple Drug Resistance (MDR)" or cross-drug resistance is the most critical cause of tumor chemotherapy failure, and there is still no ideal clinical strategy for it. Advancements in translational medicine have revealed that mutations in tumor-inducing genes promote tumor development and progression through various signaling pathways, paving the way for targeted tumor therapy. However, targeted therapy inevitably faces the problem of drug resistance after 8 to 14 months of treatment, and resolving this issue remains a challenge for the success of tumor treatment. While continuous research and development and the launch of new drugs are certainly pursuits in the pharmaceutical field, upgrading existing classic anticancer, antiviral, and antimicrobial drugs is also an important idea and direction for improving therapeutic efficacy and expanding indications. Figure 1 is a diagram showing the change in the chemical shift of OH of the carboxyl group as the concentration of carboplatin increases. Figure 2 is a nonlinear fitting diagram of the reciprocal of the chemical shift value of the carboxyl group hydrogen (1/Chemical shift) and the reciprocal of the molar concentration of carboplatin (1/C carboplatin). Figure 3 is a DSC measurement diagram of 1,1-cyclobutanedicarboxylic acid, carboplatin, mixed powder c, freeze-dried powder b, carboplatin 4.0 raw material drug, and freeze-dried powder a. Figure 4 is a DSC measurement diagram of the carboplatin 4.0 raw material drug from Nelot. Figure 5 is an