CN-122005445-A - Nanometer Realgar temperature-sensitive gel preparation for intratumoral injection and preparation method and application thereof

CN122005445ACN 122005445 ACN122005445 ACN 122005445ACN-122005445-A

Abstract

The invention discloses a nanometer Realgar temperature-sensitive gel preparation for intratumoral injection and a preparation method and application thereof. The preparation method comprises the steps of S1, obtaining nano-realgar suspension with the mass concentration of 0.1% -5%, S2, adding a dispersing agent into the nano-realgar suspension, carrying out ultrasonic mixing under ice bath, and then carrying out vacuum freeze-drying to obtain nano-realgar freeze-dried powder, wherein the mass of the dispersing agent is 0.01% -0.2% of the mass of the nano-realgar suspension, S3, obtaining a temperature-sensitive gel matrix, adding the nano-realgar freeze-dried powder into the temperature-sensitive gel matrix, and carrying out ice bath ultrasonic treatment to obtain the nano-realgar temperature-sensitive gel preparation, wherein the mass of the nano-realgar freeze-dried powder is 0.1% -5% of the mass of the temperature-sensitive gel matrix. The method provided by the invention has simple equipment, low cost and suitability for industrialization, and the preparation can realize slow release of drugs in local tumor, has long action time, and avoids the problems of low bioavailability and systemic toxicity of the realgar.

Inventors

YANG HONGYI
ZHANG HUIYU
SHI YUBING
YUAN RUIHUA
TAN JUANJUAN
WANG HAIFANG

Assignees

陕西中医药大学

Dates

Publication Date: 20260512
Application Date: 20260403

Claims (10)

1. The preparation method of the nano-Realgar temperature-sensitive gel preparation for intratumoral injection is characterized by comprising the following steps: s1, obtaining a nano-realgar suspension, wherein the mass concentration of nano-realgar in the nano-realgar suspension is 0.1% -5%, and the particle size of the nano-realgar is less than 1 mu m; S2, adding a dispersing agent into the nano-realgar suspension, carrying out ultrasonic mixing in ice bath, and then carrying out vacuum freeze-drying to obtain nano-realgar freeze-dried powder, wherein the mass of the dispersing agent is 0.01% -0.2% of the mass of the nano-realgar suspension; S3, obtaining a temperature-sensitive gel matrix, adding the nano-realgar freeze-dried powder into the temperature-sensitive gel matrix, and carrying out ice bath ultrasound to obtain a nano-realgar temperature-sensitive gel preparation, wherein the mass of the nano-realgar freeze-dried powder is 0.1% -5% of the mass of the temperature-sensitive gel matrix.
2. The method for preparing the nano-realgar temperature-sensitive gel preparation for intratumoral injection according to claim 1, wherein in the step S1, the step of obtaining nano-realgar suspension comprises the following steps: Adding sterile ultrapure water into the realgar raw material, and carrying out ultrasonic treatment for 20-40 min to obtain a primary suspension; and (3) carrying out suction filtration on the primary suspension by adopting a vacuum pump with the vacuum degree not less than-85 kPa and a1 mu m filter membrane, and collecting filtrate to obtain the nano-realgar suspension.
3. The method for preparing the nano-Realgar temperature-sensitive gel preparation for intratumoral injection according to claim 1, wherein in the step S2, the dispersing agent is one or more of pharmaceutical grade polyvinylpyrrolidone, hydroxypropyl-beta-cyclodextrin or sodium hydroxymethyl cellulose.
4. The preparation method of the nanometer Realgar temperature-sensitive gel preparation for intratumoral injection according to claim 3, which is characterized in that the step S2 further comprises the steps of carrying out ultraviolet sterilization on the nanometer Realgar freeze-dried powder for 20-60 min, carrying out aseptic sealed package on the sterilized nanometer Realgar freeze-dried powder, and preserving in a dark place.
5. The method for preparing the nano-Realgar temperature-sensitive gel preparation for intratumoral injection according to claim 1, wherein in step S3, the step of obtaining the temperature-sensitive gel matrix comprises the following steps: Adding poloxamer 407 powder into sterile ultrapure water precooled to 2-4 ℃, and stirring until the poloxamer 407 powder is dissolved to obtain a temperature-sensitive gel matrix, wherein the mass of the poloxamer 407 powder is 10-30% of the mass of the temperature-sensitive gel matrix.
6. The method for preparing the nano-Realgar temperature-sensitive gel preparation for intratumoral injection according to claim 1, wherein the content of arsenic disulfide in the nano-Realgar is not less than 95%.
7. A nano-realgar temperature-sensitive gel preparation for intratumoral injection, which is characterized by being prepared by the preparation method of any one of claims 1-6.
8. The use of the nanometer Realgar temperature-sensitive gel preparation for intratumoral injection of claim 7 in preparing antitumor drugs.
9. The use according to claim 8, wherein the anti-tumor drug is an anti-solid tumor drug.
10. The use according to claim 9, wherein the antineoplastic agent is an anti-lung cancer agent, an anti-breast cancer agent, an anti-liver cancer agent or an anti-pancreatic cancer agent.

Description

Nanometer Realgar temperature-sensitive gel preparation for intratumoral injection and preparation method and application thereof Technical Field The invention belongs to the technical field of temperature-sensitive gel preparations for injection, and particularly relates to a nano-realgar temperature-sensitive gel preparation for intratumoral injection as well as a preparation method and application thereof. Background Cancer is a major malignant disease seriously threatening human life health in the global scope, and is also an important public health problem restricting the life expectancy of people, wherein lung cancer always occupies the first cause of death of cancer in the global scope, both morbidity and mortality are high, and clinical diagnosis and treatment pressure is extremely high. At present, the clinical treatment of lung cancer takes surgical excision, radiotherapy, chemical drug treatment, molecular targeting treatment and immune checkpoint inhibitor treatment as core means, and although the treatment scheme is gradually diversified and individualized, various mainstream therapies have the limitation that the traditional chemotherapy drugs lack tumor targeting and are easy to induce multi-drug resistance, and meanwhile, the traditional chemotherapy drugs are accompanied by serious bone marrow suppression, gastrointestinal damage, liver and kidney function damage and other systemic toxic and side effects, and the molecular targeting and immune treatment have stronger pertinence, but are applicable to limited crowds, often accompanied by immune-related adverse reactions, gastrointestinal reactions, skin toxicity and the like, and part of patients have poor tolerance. The toxic and side effects not only severely restrict the improvement of clinical treatment effect, but also greatly reduce the life quality of patients and even cause treatment interruption. Therefore, the development of a novel therapeutic scheme with definite curative effect, controllable toxic and side effects and direct anti-tumor and organism immunoregulation dual effects becomes an urgent need in the clinical diagnosis and treatment field of lung cancer. The traditional Chinese medicine has obvious clinical value in the aspects of improving clinical symptoms of lung cancer patients, improving body immunity, relieving toxic and side effects of radiotherapy and chemotherapy, delaying disease progression, prolonging life and the like by virtue of the unique advantages of overall regulation and diagnosis and treatment. Realgar is used as classical traditional mineral Chinese medicine, which is listed in Shennong Ben Cao Jing as a Chinese medicinal product, and the classic of the traditional Chinese medicine is recorded, so that the Realgar is a common medicinal material of an oral and external prescription, and has long medicinal history and definite curative effect after thousands of years of clinical practice. Modern pharmacology and clinical researches prove that the realgar has the main active ingredient of arsenic disulfide (As 2S2), is a specific drug for clinically treating acute promyelocytic leukemia, and has good proliferation inhibition and apoptosis induction effects on various solid tumor cells such As lung cancer, breast cancer, liver cancer and the like. However, the realgar has extremely poor water solubility, so that the bioavailability in vivo is low, the effective treatment concentration is difficult to reach at the tumor part, meanwhile, the arsenic-containing component of the realgar has potential systemic toxicity risk, and if the realgar is directly taken, the accumulation injury of organs such as liver and kidney is easily caused, so that the two core problems greatly restrict the large-scale application of the realgar in the clinical treatment of the solid tumor. Aiming at the technical bottlenecks of indissolvable realgar and poor toxicity controllability, the research in the current medicine field focuses on the development of novel targeted drug delivery preparations, aims at realizing the accurate enrichment and long-acting retention of drugs in tumor tissues through preparation means, furthest improving the local anti-tumor drug effect, reducing the toxic and side damage to normal organism tissues and providing a feasible path for clinical anti-tumor application of realgar. With the increasing maturation of local tumor administration technology, intratumoral injection preparation becomes a research hot spot in the field of tumor treatment due to the advantages of strong targeting and low systemic exposure, and the research and development and application of related antitumor preparation are increasing. The related art is mainly focused on the fields of biological agents and chemical medicines, and Chinese patent publication No. CN114867491A provides a recombinant MVA virus for intratumoral and/or intravenous administration to treat cancers, and the antitumor effect is realized through the mediati