Overview[1]
Fludarabine phosphate, chemical name 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-phosphate, is used to treat chronic lymphocytic leukemia. The synthesis of fludarabine phosphate usually uses guanosine as the starting material, and synthesizes fludarabine through a multi-step reaction, and then performs an esterification reaction with phosphorus oxychloride. Fludarabine phosphate is an antimetabolite fluorinated purine nucleoside analogue that is highly selective for lymphocytes. It can inhibit the repair of DNA in cells in the resting phase and the synthesis of DNA in cells in the dividing phase, and It has the effect of promoting the apoptosis of these cells and has shown good curative effect. It is currently widely used to treat various blood system diseases, especially chronic lymphocytic leukemia. Fludarabine phosphate improves disease remission rate by promoting tumor cell apoptosis. Its pro-apoptotic method is mainly achieved by regulating the following pathways: death receptor pathway, mitochondrial pathway, P53, ceramide, Bcl-2 family and some apoptosis promoters and inhibitors. .
Preparation[1][3]
Freeze-dried powder injection:
Add 1530ml of water for injection into the liquid preparation tank. The temperature of the liquid preparation tank is 10°C. Then add 50g of fludarabine phosphate. After stirring thoroughly, add an appropriate amount of 5mol/L sodium hydroxide solution and stir until the fludarabine phosphate reaches the required temperature. Labine is completely dissolved; then add 40g of mannitol and stir to make the solution become a clear solution; adjust the pH value of the solution to 7.7 with 5mol/L sodium hydroxide solution, add 270ml of water for injection, and mix well.
Add 5.4g of activated carbon to the clear solution, stir and adsorb for 30 minutes, then use a 0.45 μm microporous filter membrane to filter and decarburize while circulating, a 0.2 μm filter membrane for one-time sterilization filtration, and a 0.2 μm filter membrane. Secondary terminal sterilization and filtration, the filtrate obtained is put into the medicinal solution bottle for filling.
The filtrate is divided into bottles, each bottle contains 25 mg of fludarabine phosphate, half-stoppered, and put into a freeze-drying machine for freeze-drying. Freeze-drying is divided into three stages: pre-freezing, primary drying and secondary drying;
Pre-freezing stage: lower the shelf temperature to -3℃ at a rate of 0.5℃/min, keep it warm for 0.5 hours, then drop it to -30℃ at a speed of 0.72℃/min, and stop cooling. Keep it warm for 1 hour, slowly raise the temperature to -5℃, keep it warm for 1 hour, then cool it down to -45℃ at a speed of 0.72℃/min, continue to keep it warm for 4 hours, and evacuate until the vacuum in the box reaches 10pa;
Primary drying stage: The shelf temperature is raised in a stepwise manner. Heating and heat preservation are carried out alternately. Each temperature rise is 10 minutes, followed by 5 minutes of heat preservation. The temperature rise rate is 0.34°C/min. When the temperature rises to -3°C, continue Keep warm for 4 hours;
Secondary drying stage: Raise the shelf temperature to 18°C at a rate of 0.55°C/min and keep it warm for 1 hour. The shelf will continue to rise to 40°C at a rate of 0.2°C/min. The products in the secondary drying process After the temperature reaches 35℃, continue to keep warm for 3 hours.
The entire freeze-drying process is completed, the plug is fully pressed, and it is shipped out of the box after passing the test.
Capsules:
Fludarabine phosphate solution
1. The pharmacodynamic properties are solved in a pH 6.0 aqueous solution, and the solution is coated on the microcrystalline cellulose pellets. Finally, the coated pellets are wrapped with a gastric-soluble moisture-proof film coating, with a weight increase of 0.3%, and put into capsules. Ready in the shell.
Pharmacological effects[2]
This product is a fluorinated nucleotide analogue of the antiviral drug vidarabine, namely 9-β-D-arabinic acid-furyl adenine (ara-A), which is relatively resistant to adenosine deamination. Enzyme deamination.
Fludarabine phosphate is rapidly dephosphorylated into fludarabine (2F-ara-A), which can be taken up by cells and then phosphorylated by intracellular deoxycytidine kinase to become active. Triphosphate 2F-ara-ATP. This metabolite can inhibit DNA synthesis by inhibiting ribonucleotide reductase, DNA polymerase α, δ and Σ, DNA primase and DNA ligase. In addition, it can also partially inhibit RNA polymerase II to reduce protein synthesis.
Although the mechanism of action of 2F-ara-ATP is not very clear in some aspects, it is inferred that it mainly inhibits cell growth by affecting the synthesis of DNA, RNA and protein, among which inhibiting the synthesis of DNA is its main effect. In addition, in vitro studies have shown that after lymphocytes from chronic lymphocytic leukemia (CLL) were treated with 2F-ara-A, extensive DNA fragmentation and cell death characterized by apoptosis occurred.
Safety information
1) Systemic toxicity
In acute toxicity studies, single doses of fludarabine phosphate that were two orders of magnitude higher than the therapeutic dose could cause severe toxic symptoms or death. As predicted with cytotoxic drugs, bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys, and male gonads are affected. Serious adverse reactions, including severe neurotoxicity and some with fatal consequences, have been observed in patients at doses close to recommended therapeutic doses (3 to 4 times) (see Overdose).
Systemic toxicity studies following multiple doses of fludarabine phosphate above critical doses also showed expected effects in rapidly proliferating tissues. Morphological changes worsen with increasing dosage and duration of administration, but the observed changes are generally believed to be reversible. In principle, existing treatment experience with fludarabine phosphate shows that it has similar toxicological characteristics in humans, although��relationship. The median half-life of 2F-ara-ATP clearance from target cells is 15 and 23 hours.
Drug interactions[2]
1. In a clinical study, a high incidence of fatal disease occurred when fludarabine phosphate was combined with pentostatin (deoxycofamycin) in the treatment of refractory chronic lymphocytic leukemia (CLL). Pulmonary toxicity. Therefore, concomitant use of pentostatin is not recommended when using this product.
2. The therapeutic effect of fludarabine phosphate will be weakened by dipyridamole and other adenosine absorption inhibitors.
Main reference materials
[1] [China invention, China invention authorization] CN201110036856.0 A kind of fludarabine phosphate freeze-dried powder injection and its preparation method
[2] Fludarabine Phosphate Injection Instructions
[3] [Invented in China] CN201210069049.3 A capsule containing fludarabine phosphate and its preparation method
