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Pharmaceutical composition containing carfilzomib and preparation method thereof

A carfilzomib and composition technology are applied to pharmaceutical compositions containing carfilzomib, the preparation of sterile freeze-dried preparations, and the fields of sterile freeze-dried preparations, which can solve the problems of aggravating kidney burden, poor stability, Cell damage and other problems, achieve good chemical stability and physical stability, improve compliance and safety, and avoid allergic reactions.

Active Publication Date: 2017-01-11
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although carfilzomib has a good anti-tumor effect, its water solubility is poor and its stability is not good. Freeze-dried preparations are an ideal dosage form. The currently marketed Kyprolis prescription contains 60mg carfilzomib and 3000mg sulfonbutane Cybeta cyclodextrin sodium, 57.7mg citric acid and appropriate amount of sodium hydroxide, although the cyclodextrin inclusion complex improves the solubility of the drug to a certain extent, but its drug loading is still less than 2%, and the use of A relatively large amount of cyclodextrin will increase the burden on the kidneys after entering the human blood circulation system. At the same time, cyclodextrin can interact with the cell membrane on the inner wall of the blood vessel, causing cell damage. Long-term use may cause venous spasm and phlebitis, which poses a safety hazard. Dexamethasone should be given before each dose to prevent infusion reactions
In addition, the drug is very unstable in an aqueous medium solution, and is stable for up to 4 hours at room temperature, which is also a challenge to the safety of the drug in actual clinical applications
[0008] In summary, the currently marketed carfilzomib injection has a good effect in the treatment of multiple myeloma, but it also brings a lot of inconvenience and safety problems to clinical application

Method used

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  • Pharmaceutical composition containing carfilzomib and preparation method thereof
  • Pharmaceutical composition containing carfilzomib and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1 uses water miscible solvent as organic phase solvent——control group

[0050] Dissolve 600 mg of carfilzomib in 2 ml of absolute ethanol as the organic phase. 50ml of human serum albumin (10%, w / v) aqueous solution is the aqueous phase. The aqueous phase and the organic phase were homogenized in a high-pressure microjet (Microfulidics) for 5 cycles under 15,000 psi pressure, and the obtained liquid was transferred to a rotary evaporator, and evaporated under reduced pressure (10-15KPa) at 40°C for 30 minutes Remove absolute ethanol. The average diameter of carfilzomib particles in the resulting dispersion suspension was greater than 300 nm (Malvern Zetasizer).

Embodiment 2

[0051] Example 2 Preparation process of carfilzomib granules that can be aseptically filtered

[0052] Dissolve 1000 mg of carfilzomib in a mixed solution of 3.3 ml of chloroform and 0.58 ml of absolute ethanol as the organic phase. 600ml (20%, w / v) of human serum albumin aqueous solution, as the aqueous phase. The weight ratio of carfilzomib to protein is 1:12. The oil-water phase was transferred to a high-pressure homogenizer (Microfulidics), homogenized for 3 cycles under 25,000 psi pressure, and the obtained liquid was transferred to a rotary evaporator, and evaporated under reduced pressure (10-15KPa) for 30 minutes at 40°C to remove Organic solvents. The obtained dispersion suspension is translucent, the pH is adjusted to 2.0 with citric acid and sodium hydroxide, the Zeta potential is -30mv, and the average diameter of carfilzomib particles is generally 110-130nm (Malvern Zetasizer). Pass the dispersed suspension through a 0.22 μm microporous membrane filter, and the...

Embodiment 3

[0054] Example 3 Preparation process of aseptically filterable carfilzomib granules

[0055] Dissolve 1000 mg of carfilzomib in 3.3 ml of chloroform as the organic phase. 600ml (10%, w / v) of human serum albumin aqueous solution, as the aqueous phase. The weight ratio of carfilzomib to protein is 1:6. The oil-water phase is transferred to a high-pressure homogenizer (Microfulidics), and homogenized for 3 cycles under 25,000 psi pressure. The obtained liquid medicine was transferred to a rotary evaporator, and evaporated under reduced pressure (10-15KPa) at 40°C for 30 minutes to remove chloroform. The obtained dispersion suspension is translucent, the pH is adjusted to 5.0 with hydrochloric acid and sodium bicarbonate, the Zeta potential is -20mv, and the average diameter of carfilzomib particles is generally 120-160nm (Malvern Zetasizer). Pass the dispersed suspension through a 0.22 μm microporous membrane filter, and the turbidity and particle size do not change significan...

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Abstract

The present invention provides a pharmaceutical composition containing carfilzomib and a preparation method thereof. The pharmaceutical composition comprises carfilzomib as an active ingredient, protein and pH regulator. The pH value ranges from 2 to 5, the average particle size is less than 200nm, the Zeta potential is -20 to -30mV, and the mass ratio of carfilzomib to protein is 1:6-12. The invention aims to provide the pharmaceutical composition containing carfilzomib which is better used for the in-vivo delivery of carfilzomib, the pharmaceutical composition does not contain the sulfobutylether-beta-cyclodextrin in currently listed carfilzomib injection, so as to avoid the occurrence of allergic reactions and prevent vasospasm and phlebitis caused by the clinical use of the pharmaceutical composition. The freeze-dried preparation of pharmaceutical composition can be prepared by high-pressure homogenization, and can be transformed into blocks or powder which can re-disperse. After re-dispersing in an aqueous medium, compared with the products in current market, the stability of the pharmaceutical composition is increased significantly, and the safety of medication in clinical application is enhanced.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations. Specifically relates to a pharmaceutical composition containing carfilzomib, a sterile freeze-dried preparation of the pharmaceutical composition, and a preparation method of the sterile freeze-dried preparation. Background technique [0002] Multiple myeloma (MM) is a malignant plasma cell disease that occurs in B lymphocytes, characterized by the clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal proteins in blood or urine and related organ dysfunction; it is the second largest in the world It is the most common hematological malignancy, accounting for about 1% of neoplastic diseases and 13% of hematological malignancies. In Western countries, the annual incidence rate is 5.6 cases / 100,000 people. [0003] Carfilzomib, English name Carfilzomib, its chemical name is (S)-2-((S)-2-(2-(2H-1,4-oxazin-4(3H)-yl)acetamido)- 4-phenyl...

Claims

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Application Information

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IPC IPC(8): A61K38/08A61K9/19A61K47/42A61P35/00
CPCA61K9/0019A61K9/19A61K38/08A61K47/42
Inventor 李霞周志超杨清敏王栋海张明会
Owner QILU PHARMA HAINAN
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