Stable tirofiban hydrochloride liquid composition and preparation method thereof

Abstract

The invention discloses a stable tirofiban hydrochloride liquid composition and a preparation method thereof. The liquid composition comprises a pharmaceutically acceptable amount of tirofiban hydrochloride, a pharmaceutically acceptable amount of an osmotic pressure regulator, a pharmaceutically acceptable amount of a stabilizing agent, a pharmaceutically acceptable amount of a pH buffer and water for injection, and is characterized in that , the stabilizer is a chemically modified derivative of cyclodextrin or a salt thereof. The present invention can solve the problem of tirofiban hydrochloride injection well by selecting the chemically modified derivative of cyclodextrin or its salt as a stabilizer and utilizing the properties of the chemically modified derivative of cyclodextrin or its salt. The problem of stability, so the tirofiban hydrochloride injection prepared by the present invention has better stability, mainly reflected in the quality index that visible foreign matters and insoluble particles of the injection affect clinical safe drug use, completely solved the problem of this product Product quality and safety issues that cannot be solved under huge and repeated changes in temperature.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a parenteral administration liquid preparation tirofiban hydrochloride liquid composition and a preparation method thereof. Platelet cross-linking and platelet aggregation. Background technique [0002] Platelet activation, adhesion and aggregation are the key initial steps in the formation of arterial thrombosis on the ruptured surface of atherosclerotic plaque. Key pathophysiological questions in ischemic complications. Tirofiban hydrochloride is a non-peptide antagonist of platelet glycoprotein IIb / IIIa receptor, which is the main platelet surface receptor involved in platelet aggregation process. Tirofiban hydrochloride prevents fibrinogen from binding to glycoprotein IIb / IIIa, thereby blocking platelet cross-linking and platelet aggregation. In vitro tests have shown that tirofiban hydrochloride can inhibit adenosine diphosphate (ADP)-induced platelet aggregat...

AI Technical Summary

Problems solved by technology

Products currently on the market It is clearly stipulated in the instructions that no freezing is allowed, and the storage temperature needs to be controlled at 25°C. The reason is that the solubility of tirofiban hydrochloride is greatly affected by temperature. Huge temperature difference), and if the pH value of the liquid medicine shifts, tirofiban hydrochloride in the product is easy to precipitate, and at the same time, the insoluble particles increase sharply, which affects the clinical safety of drug use

[0016] Patent CN96197877.5 discloses a tirofiban injection using citric acid (also known as: citrate) salt as a buffer, and its stability reaches more than 18 months, while the phosphate preparation of the same active ingredient is not stable enough , the hazard is that the preparation contains visible particles with a particle size greater than 50 μm, which seriously leads to clinical safety hazards

[0017] Patent CN200410061014.0 discloses tirofiban hydrochloride injection without using citrate buffer, only using hydrochloric acid or sodium hydroxide to adjust the pH range of 5.5-6.5, the test shows that the pH value can be maintained without using buffer Under normal circumstances, after the liquid medicine is sterilized at 121°C for 15 minutes, the pH value changes by about 0.5 units, which is very easy to exceed the upper limit of pH 6.5, resulting in unqualified products, and the insoluble particles have not been effectively improved

[0018] Patent CN200910231232.7 discloses the use of ethanol and 1,2-propanediol to prepare high-concentration tirofiban hydrochloride injection, and its total organic solvent ratio is as high as 10%-20% (W / V), especially with specific For patients with sexual constitution allergic to alcohol, unexpected side effects can be foreseen, and there are great hidden dangers in clinical safety

[0019] Patent CN201210421359.7 discloses the use of glycerol as a solubilizer to ensure the stability of high-concentration tirofiban hydrochloride injection, and its organic solvent consumption reaches 20% (W / V). However, large doses of glycerin-containing preparations are prone to known side effects such as hemolysis, and the dehydration side effect of glycerol-containing intravenous preparations is the highest clinical adverse reaction

[0020] Patent CN201110046858.8 discloses the use of acetate buffer to replace citrate buffer. It has been proved by experiments that changing the type of buffer cannot solve the problem of the rapid change of insoluble particles caused by the huge change in temperature (three cycles of freezing cycle and low temperature cycle inspection). Increased and Tirofiban Precipitation Problems

[0021] Patent CN201210089970.4 discloses the use of L-arginine to maintain the stability of tirofiban hydrochloride in the water base, and the three-cycle freezing cycle and low temperature cycle investigation cannot solve the problem of the increase of insoluble particles during storage

[0022] Patents CN201010134013.X, CN200510015295.0, CN200910231233.1, and CN201110371552.X are all patent applications for freeze-dried products formed by freeze-dried proppants and various buffers, but none of them can solve the problem of external The problem of insoluble particles and pollution, and the product can be used for terminal sterilization to ensure aseptic preparations. It is unreasonable to modify the invention into a freeze-dried dosage form

[0023] From the analysis of the above patents, it can be seen that the biggest pharmaceutical safety hazard of tirofiban hydrochloride injection is that its inherent water solubility is very low, and it cannot withstand huge changes in temperature (3-cycle freezing cycle and low-temperature cycle inspection), resulting in the quality index "insoluble". Particles "exceeding the standard affect the safety of clinical medication

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