CN102697710B - Clofarabine injection and preparation method thereof - Google Patents

Abstract

The invention relates to a clofarabine injection which comprises 0.005-0.025 g/mL of clofarabine, 0.045-0.12 g/mL of sodium chloride, and the balance of pH regulator and injection water. The pH regulator regulates pH of the liquid injection to be 6.0-6.5. The invention also relates to a preparation method of the clofarabine injection. Compared with the existing clofarabine injection, the inventive clofarabine injection improves clofarabine concentration by above 5 times, greatly reduces infusion amount in clinical application, reduces administration cost, and increases patient compliance; is stable in quality and has no particle precipitation after long-term storage; can be conveniently matched with multiple drugs in clinical application, and can also be added into sodium chloride or glucose infusion solution for intravenous infusion, thereby broadening applicable scope of patients.

Description

Clofarabine injection and preparation method thereof

Technical field

The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of clofarabine injection and preparation method thereof.

Background technology

Clofarabine (Clofarabine) has another name called Clofarabine, clofarabine, by U.S. Bioenvision company, developed, a kind of nucleoside purines antimetabolite that Genzyme company produces, is used for the treatment of 1～21 years old intractable or recurrent Patients With Acute Lymphoblastic Leukemia.Clofarabine is changed into 5 '-monophosphate metabolite by deoxycytidine kinase in cell, then by monophosphate and diphosphate kinase, changed into the form of activated 5 '-triphosphate, triphosphoric acid clofarabine suppresses the synthetic of DNA by suppressing ribonucleotide reductase and DNA polymerase, and external Fast Growth and static cancerous cell are all had to cytotoxicity.

Clofarabine is white crystalline powder, chemistry is by name: the chloro-9-of 2-(the Arabic furan of 2-deoxidation-2-fluoro-beta-D-)-9H-purine-6-amine, be slightly soluble in water, the dissolubility in water is only 0.02%(w/v), and have microgranule to separate out in aqueous solution put procedure.Therefore, how to strengthen the water solublity of clofarabine and solve the problem that in aqueous solution, microgranule is separated out, becoming one of difficult problem of the high concentration clofarabine injection of preparing at present good stability.

Chinese patent CN1887291A discloses a kind of pharmaceutical composition that contains clofarabine, and it adopts a certain proportion of nicotiamide or meglumine as cosolvent, to improve dissolubility and the stability of clofarabine.Yet nicotiamide is vitamin medicaments, meglumine is diagnostic agent, and both all have the pharmacologically active of self, adds insecurity and complexity that these two kinds of active component have increased injection medication.This patent is also by being used mannitol to prepare the lyophilized injectable powder of clofarabine as excipient.Although injectable powder has avoided separating out in aqueous solution the appearance of the problems such as microgranule, but lyophilized formulations complex process, cost is higher, and in process control procedure, aseptic requirement is far above injection, and need with sodium chloride or glucose dissolved dilution, increase the complexity of medication during clinical use.Equally, also there is such problem in the disclosed clofarabine pharmaceutical composition freeze-dried powder injection of Chinese patent CN101584672A.

In sum, prior art adopts the dissolubility that adds heavy dose of solubilizing agent to improve clofarabine in prescription conventionally, yet, the solubilizing agents such as tween, Polyethylene Glycol, poloxamer, propylene glycol or polyoxyethylene castor oil have certain hemolytic, some bulking agents also can cause serious anaphylaxis as polyoxyethylene castor oil, and the pain of initiation often needs to add extraly benzyl alcohol.Meanwhile, the freezing-dried clofarabine powder injection that prior art provides, because its dissolubility in water is low, causes the stability of freeze-drying prods of gained not high, is not suitable for storing.

As can be seen here, existing clofarabine injection is strengthening the water solublity of clofarabine, and solves the problem aspect that in aqueous solution, microgranule is separated out, and all has some limitations.

Summary of the invention

The object of the present invention is to provide that a kind of concentration is higher, good stability, the long-term clofarabine injection producing without particulate matter of placing.

Concrete technical scheme of the present invention is as follows:

A clofarabine injection, it consists of: clofarabine 0.005～0.025g/mL, sodium chloride 0.045～0.12g/mL, all the other are pH adjusting agent and water for injection; Described pH adjusting agent regulates injection pH to 6.0～6.5.

Described pH adjusting agent is the citrate buffer of pH=6.2.

Described citrate buffer is mixed by the citric acid soln of 0.021g/mL and the sodium hydroxide solution of 0.5g/mL.

The preparation method of above-mentioned clofarabine injection, comprises the steps:

(1) take sodium chloride, add the water for injection of recipe quantity cumulative volume 90～95%, add needle-use activated carbon, after stirring, de-charcoal, obtains medicinal liquid;

(2) get aqueous solution of citric acid, add sodium hydroxide solution to regulate pH value to 6.2, obtain citrate buffer;

(3) in the medicinal liquid obtaining to step (1), add clofarabine, be heated to 80 ℃, stir, add the citrate buffer preparing in step (2), regulate pH to 6.0～6.5 of medicinal liquid, add surplus water for injection standardize solution;

(4) by the solution obtaining in step (3) through 0.22um filtering with microporous membrane, fill, tamponade, Zha Gai, moist heat sterilization, gets product.

The addition of needle-use activated carbon is 0.1% of the water for injection gross weight that adds in step (1).

Moist heat sterilization in step (4) is sterilizing 15min under the condition of 121 ℃.

Compared with prior art, the clofarabine injection tool the present invention relates to has the following advantages:

(1) clofarabine concentration is higher.Compare with existing clofarabine injection, the present invention has improved the concentration of clofarabine more than 5 times, has significantly reduced the amount of infusion in clinical practice, has reduced drug cost, has increased the compliance of patient's medication.

(2) good stability.Clofarabine injection steady quality of the present invention, long-term placement separated out without microgranule.

(3) be applicable to more eurypalynous patient colony.Can be conveniently when clinical use and multi-medicament compatibility, also can join in sodium chloride or glucose infusion liquid to patient's intravenous drip, increased the patient group of applicable use.

The specific embodiment

Be below specific embodiments of the invention, technical scheme of the present invention is further described, but protection scope of the present invention be not limited to following examples.Not every not deviating within design of the present invention or being equal to that it is done substitute and to be all included in protection scope of the present invention.

Table 1 is the recipe quantity of clofarabine injection in each embodiment.

Table 1

The preparation technology of above-described embodiment is as follows:

(1) take sodium chloride, add the water for injection of recipe quantity cumulative volume 90%, add the needle-use activated carbon of water for injection gross weight 0.1%, after stirring, de-charcoal, obtains medicinal liquid;

(2) get aqueous solution of citric acid, add sodium hydroxide solution to regulate pH value to 6.2, obtain citrate buffer;

(3) in the medicinal liquid obtaining to step (1), add clofarabine, be heated to 80 ℃, stir, add the citrate buffer preparing in step (2), regulate pH to 6.0～6.5 of medicinal liquid, add surplus water for injection standardize solution;

(4) by the solution obtaining in step (3) through 0.22um filtering with microporous membrane, fill, tamponade, Zha Gai, moist heat sterilization, gets product, the sterilising conditions of moist heat sterilization: 121 ℃, 15min.

the preparation of comparative example 1 clofarabine injection

The preparation technology of comparative example 1: add citric acid in water for injection 950ml, be uniformly mixed, add clofarabine, be heated to 40 ℃, stir, add surplus water for injection standardize solution (now the pH value of solution is 4.0 left and right), filter, fill is in 2ml ampulla.Melt envelope, sterilizing.

the study on the stability of clofarabine injection of the present invention

Get the clofarabine injection of the embodiment of the present invention 1,3,5 preparations and the clofarabine injection of comparative example 1 preparation, be placed in respectively under 40 ℃ ± 2 ℃, the condition of RH75% and carry out accelerated test, respectively at sampling in the 1st, 2,3,6 months, investigate respectively the variation of its appearance character, pH value and visible foreign matters, related substance, content aspect, test testing result is in Table 2.

Table 2 clofarabine injection accelerated test data

Accelerated test result from table 2, clofarabine injection prepared by the present invention is under acceleration environment, its appearance character, pH value and visible foreign matters, related substance, content are all up to specification, its related substances is low and its variation of growth is in time not obvious, this stability that shows injection of the present invention is higher, is better than the stability of existing clofarabine injection.

Claims (3)

1. a clofarabine injection, is characterized in that it consists of: clofarabine 0.005～0.025g/mL, and sodium chloride 0.045～0.12g/mL, all the other are pH adjusting agent and water for injection; Described pH adjusting agent regulates injection pH to 6.0～6.5; Described pH adjusting agent is the citrate buffer of pH=6.2;

Described citrate buffer is mixed by the citric acid soln of 0.021g/mL and the sodium hydroxide solution of 0.5g/mL;

The preparation method of described clofarabine injection comprises the steps:

(1) take sodium chloride, add the water for injection of recipe quantity cumulative volume 90～95%, add needle-use activated carbon, after stirring, de-charcoal, obtains medicinal liquid, and the addition of needle-use activated carbon is 0.1% of the water for injection gross weight that adds;

(2) get aqueous solution of citric acid, add sodium hydroxide solution to regulate pH value to 6.2, obtain citrate buffer;

(3) in the medicinal liquid obtaining to step (1), add clofarabine, be heated to 80 ℃, stir, add the citrate buffer preparing in step (2), regulate pH to 6.0～6.5 of medicinal liquid, add surplus water for injection standardize solution;

(4) by the solution obtaining in step (3) through 0.22 μm filtering with microporous membrane, fill, tamponade, Zha Gai, moist heat sterilization, gets product.

2. the preparation method of clofarabine injection claimed in claim 1, is characterized in that comprising the steps:

(1) take sodium chloride, add the water for injection of recipe quantity cumulative volume 90～95%, add needle-use activated carbon, after stirring, de-charcoal, obtains medicinal liquid, and the addition of needle-use activated carbon is 0.1% of the water for injection gross weight that adds;

(2) get aqueous solution of citric acid, add sodium hydroxide solution to regulate pH value to 6.2, obtain citrate buffer;

(3) in the medicinal liquid obtaining to step (1), add clofarabine, be heated to 80 ℃, stir, add the citrate buffer preparing in step (2), regulate pH to 6.0～6.5 of medicinal liquid, add surplus water for injection standardize solution;

(4) by the solution obtaining in step (3) through 0.22 μm filtering with microporous membrane, fill, tamponade, Zha Gai, moist heat sterilization, gets product.

3. the preparation method of clofarabine injection according to claim 2, is characterized in that the moist heat sterilization in step (4) is sterilizing 15min under the condition of 121 ℃.