Search

RU-2861681-C2 - NANOPARTICLE COMPOSITION FOR RAPID SUSPENSION AND METHOD FOR PRODUCING THE SAME

RU2861681C2RU 2861681 C2RU2861681 C2RU 2861681C2RU-2861681-C2

Abstract

FIELD: pharmaceutics. SUBSTANCE: disclosed is a nanoparticle composition for treating cancer, containing 2-20 mas.% of an active ingredient, 1-25 mas.% of a protein, 0.005-1 mas.% of sodium chloride as a stabiliser, the remainder being a lyoprotectant, wherein the weight ratio of the protein to the active ingredient is 0.3:1 – 4:1. Also disclosed are a pharmaceutical composition for treating cancer, containing said composition, a method for producing said composition and the use of said nanoparticle composition or pharmaceutical composition for producing a medicament for treating cancer. EFFECT: stability of the compositions during production and after reconstitution, their rapid suspension and reduced foaming. 25 cl, 6 dwg, 11 tbl, 30 ex

Inventors

  • LI, CHUNLEI
  • WANG, YEMING
  • LI, YANHUI
  • LI, Mengmeng
  • LI, YONGFENG
  • LI, JINGJING
  • WANG, CAIXIA
  • WANG, Danqing
  • TIAN, Haiwei
  • WANG, SHIXIA

Dates

Publication Date
20260507
Application Date
20230426
Priority Date
20220427

Claims (20)

  1. 1. A nanoparticle composition for the treatment of cancer, comprising in percentage by weight:
  2. 2-20% of an active ingredient selected from the group consisting of taxanes, macrolides, camptothecins, anthracyclines, colchicine and its derivatives, thiocolchicine dimer, liothyronine, exemestane, flutamide, fulvestrant, romidepsin, semustine and ibuprofen,
  3. 1-25% protein, which is selected from serum albumins,
  4. 0.005-1% particle stabilizer, which is sodium chloride, and
  5. the remaining percentage by weight of a lyoprotectant selected from the group consisting of mannitol, sucrose or any combination thereof,
  6. wherein the mass ratio of protein and active ingredient in the composition is 0.3:1 - 4:1.
  7. 2. The nanoparticle composition of claim 1, wherein the active ingredient is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, lipophilic derivatives of docetaxel, rapamycin and its derivatives, epothilone B and its derivatives, tanespimycin and its derivatives, 10-hydroxycamptothecin, SN38 and its derivatives, aclarubicin and pirarubicin,
  8. Preferably, the active ingredient is paclitaxel or docetaxel.
  9. 3. The nanoparticle composition according to claim 1 or 2, wherein the protein is selected from human serum albumin and bovine serum albumin and is preferably human serum albumin.
  10. 4. The nanoparticle composition according to claim 1 or 2, wherein the lyoprotectant is a combination of mannitol and sucrose in a ratio between them of preferably 10:1 to 1:1, preferably 8:1 to 3:1 and most preferably 5:1.
  11. 5. The nanoparticle composition according to claim 1 or 2, wherein the nanoparticle composition contains, in percentage by weight, 0.005-0.05% or 0.008-0.022% of a particle stabilizer.
  12. 6. The nanoparticle composition according to claim 1 or 2, wherein the nanoparticle composition contains, in percentage by weight, 3-15% or 5-10% of the active ingredient.
  13. 7. The nanoparticle composition of claim 1 or 2, wherein the nanoparticle composition contains, in percentage by weight, 5-20% human serum albumin.
  14. 8. The nanoparticle composition according to claim 1 or 2, wherein the binding rate of the active ingredient to the protein is more than 90%, preferably 94% or more.
  15. 9. The nanoparticle composition of claim 1 or 2, wherein the weight ratio of the protein to the active ingredient in the composition is selected from the group consisting of 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.70:1, 0.8:1, 0.9:1, 0.95:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1, 3.5:1, 4:1 or a range between any two of the above ratios.
  16. 10. The nanoparticle composition of claim 1 or 2, wherein the nanoparticle for rapid suspension in the composition has an average particle size of 30-200 nm, for example selected from the group consisting of 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 165, 170, 175, 180, 185, 190, 195, 200 nm or a range between any two of the above values.
  17. 11. A nanoparticle composition according to claim 1 or 2, wherein the composition does not contain any surfactant.
  18. 12. A pharmaceutical composition for treating cancer, comprising a nanoparticle composition according to claim 1 or 2, wherein the pharmaceutical composition is in solid or liquid form.
  19. 13. The pharmaceutical composition according to claim 12, wherein the composition is an injection solution, a dry powder or a lyophilized powder.
  20. 14. The pharmaceutical composition of claim 13, wherein when the pharmaceutical composition is in liquid form, the nanoparticles for rapid suspension are suspended in a pharmaceutically acceptable carrier, including but not limited to a buffer, a preservative, water for injection, a saline solution and an isotonic solution, and the pharmaceutical composition in liquid form contains the active ingredient in an amount of 0.1-100 mg/ml, preferably 0.5-50 mg/ml, more preferably 1-20 mg/ml, such as 5 mg/ml.

Description

Field of technology of the present invention The present invention relates to the field of pharmaceuticals, and more particularly to a nanoparticle composition for rapid suspending containing human serum albumin and a hydrophobic drug, as well as to a method for producing the same. Prior art of the present invention Paclitaxel, an anticancer drug extracted from the stem and bark of plants of the genus Taxus, is a mitotic microtubule inhibitor that polymerizes and stabilizes intracellular microtubules. During mitosis, paclitaxel prevents microtubule separation, thereby arresting cells in the G2 and M phases of the cell cycle. Thus, paclitaxel causes the fixation of rapidly dividing tumor cells in the mitotic phase, blocking cell replication and leading to cell death. Paclitaxel has significant clinical activity against various types of cancer (such as breast, ovarian, lung, and bladder cancer). However, paclitaxel poses challenges in human administration due to its poor aqueous solubility. To make paclitaxel suitable for intravenous injection, Bristol-Myers Squibb (BMS) developed Taxol®, which combines the surfactant polyoxyethylene castor oil (Cremophor® EL) and absolute ethanol as a solvent to enhance paclitaxel solubility. Taxol exhibits significant activity against ovarian cancer, breast cancer, lung cancer, esophageal cancer, and head and neck cancer. However, Taxol has been shown to cause administration-related toxicity, as well as significant acute and cumulative toxicities, such as myelosuppression, neutropenic fever, anaphylaxis, and others. These side effects are associated with the surfactant used, polyoxyethylene castor oil (Anantbhushan et al., Asia Race J Clin Oncol. 2013, 9:176-181). According to clinical trial reports and safety data after the introduction of Taxol, the overall incidence of allergic reactions to Taxol is approximately 39%. Currently, patients should be prescribed antihistamines and steroids in advance to mitigate surfactant-induced side effects when using Taxol. US 5,439,686, US 6,537,579, US 6,749,868, US 2006121119, CN 97199720.9, CN 03108361.7 and CN 200610077006.4 disclose a method for producing albumin-based paclitaxel nanoparticles, obtaining a formulation with significant advantages and developing a marketed product, Abraxane®, the advantages including: 1) no pre-treatment with antihistamines before administration, a significant reduction in the incidence of allergic reactions compared to Taxol® and no effect on PD-1/PDL1 activity when used in combination with PD-1/PDL1, 2) reducing infusion time from 3 hours for conventional drugs to 30 minutes, 3) improving safety and efficacy because it rapidly disintegrates and disperses after administration into the blood and is carried in tumor tissues through a special transport mechanism. However, this system still has many disadvantages, for example, the preparation of albumin-bound paclitaxel lyophilized powder for injection, Abraxane®, before use is complex and involves six steps: 1) aseptically apply 20 ml of 0.9% sodium chloride injection per vial for dispersion and dissolution, 2) slowly inject 20 ml of 0.9% sodium chloride injection along the inner wall of the vial with a sterile syringe, and the injection time should be at least 1 minute, 3) do not inject 0.9% sodium chloride injection directly onto the lyophilized cake/powder to avoid foaming, 4) after injection, allow the vial to stand for at least 5 minutes to allow the lyophilized cake/powder to be completely soaked, 5) gently shake the vial or slowly turn the vial upside down for at least 2 minutes to ensure that all The lyophilized tablet/powder in the vial is completely dispersed and dissolved to avoid foam formation. 6) If foam forms, leave it for 15 minutes until the foam subsides. According to this standard preparation operation, it takes at least 8 minutes, and if foam is formed accidentally, it takes more than 23 minutes. This preparation operation before clinical use is extremely complex, and the personnel performing the preparation can easily work irregularly. The product dispersion time is long, and the risk of contamination increases during preparation. The preparation operation takes a lot of space and time, which affects the work efficiency of the preparation personnel. When the preparation operation is irregular, excessive foam can easily form and incomplete dissolution occur, which can lead to problems such as inaccurate liquid dosing and clogged infusion lines, and may affect the safety of the drug or lead to medical disputes. Furthermore, this system contains high levels of human serum albumin (HSA), which can cause allergies. The source of HSA remains human blood. The safety of blood products is compromised by potential contamination during blood collection and storage. Furthermore, HSA is expensive and remains in short supply in some regions. CN 201580045838.5, filed by the present applicant in 2015, discloses purified therapeutic nanoparticles c