CN105055308A - Platinum-based antitumor drug oxaliplatin composition liquid injection - Google Patents

Abstract

The invention discloses a platinum-based antitumor drug oxaliplatin composition liquid injection, and belongs to the technical field of medicines. The composition is prepared from oxaliplatin and calcium chloride, wherein oxaliplatin is a crystal, and is as shown in a diagram I which is an X-ray powdered diffraction diagram measured by using a Cu-K alpha ray. Different from the crystal form structure in the prior art, tests verify that the new crystal form of oxaliplatin has the advantages of high purity, good fluidity, good stability, low impurity content and hard moisture absorption, is safe and reliable in clinical application. The liquid injection prepared from the new crystal form compound is simple in ingredient and high in stability.

Description

A kind of platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection

Technical field

The invention belongs to medical art, relate to a kind of platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection.

Background technology

Oxaliplatin is the third generation platinum-containing anticancer drug after cisplatin, carboplatin, all has broad-spectrum anti-tumor activity in vivo and in vitro, also has cytotoxicity to the tumor cell of resistance to cisplatin.In vivo with in vitro study, all can be observed the synergistic cytotoxicity of oxaliplatin and 5-fluorouracil use in conjunction.Oxaliplatin untoward reaction is few, there is not the Toxicity of Kidney of cisplatin, the bone marrow depression of carboplatin is not had yet, its Main Function position is DNA, by forming conjugate with DNA, stop it to copy and transcribe, reach the object of killing tumor cell, and anti-tumor activity spectrum, to colorectal cancer, nonsmall-cell lung cancer, gastric cancer, ovarian cancer to various kinds of cell tumor, especially there is significant inhibitory action to the tumor cell of resistance to carboplatin, cisplatin, be used for the treatment of the patient of the transfer of the colon cancer after fluorouracil Endodontic failure, can use by fluorouracil alone or in combination.

At present, oxaliplatin as the first-line treatment medicinal application of metastatic colorectal carcinoma in clinical.When being used as treatment, oxaliplatin is with intravenous form administration.Intravenous injection is that one absorbs without human gastrointestinal tract, directly by the administering mode of infusion of medicine blood of human body, if contain from the impurity produced in raw material or production process in the preparation of injection, these impurity directly will enter blood circulation of human body without gastrointestinal tract barrier, and these impurity, even quantity is extremely small also may cause great infringement to human body.Because compound chemical change can occur in storage process as oxidation, decompose, impurity will be accumulated along with the prolongation of medicine storage time, determines that the principal element of Oxaliplatin for Injection effect duration is also the growth of total impurities in storage process.

The stability of oxaliplatin in water is all more poor, and its aqueous solution can be degraded and be produced oxalic acid, two water DACH platinum, two water DACH platinum dimers and platinum class impurity.Its mesoxalic acid has toxicity because of itself, is one of impurity clearly controlled in European Pharmacopoeia oxaliplatin crude drug standard, within 2010, also has control in the first enlarged edition standard regulation to oxalic acid: must not cross 0.20% of oxaliplatin labelled amount at Chinese Pharmacopoeia.Therefore, in finished product, the minute differences of moisture also can produce significant impact to effect duration of product, the residual moisture in finished product be chemical change provide reaction medium.

In the quality standard of existing product, total impurities is an important index, therefore, strict requirement is had to total impurities in drug quality, the national drug standards (the WS1-(X-090)-2003Z of such as State Food and Drug Administration) in related substance is limited to " summation of each impurity peak area must not be greater than 1.0% of the peak area at reference substance solution main constituent peak ".(standard No.: JX20020117) regulation " total amount of impurity must not cross 1.0% of oxaliplatin labelled amount " in import drugs registered standard.

Meanwhile, oxaliplatin wettability power is comparatively strong, and especially after preparing aqueous injection, wettability power grow, mobility is deteriorated, and the easy moisture absorption goes bad and occurs content uniformity.If the amount of oxaliplatin impurity, moisture therefore can be controlled well, will effectively improve the quality of product, reduce the generation of side effect, make medication safer; Also will improve the stability of medicine simultaneously, extend the effect duration of product, thus reduce selling cost.

The present inventor starts with from the research of oxaliplatin solid chemical material existence, through a large amount of experimental studies, obtain a kind of oxaliplatin crystalline compounds being different from prior art, passed through verification experimental verification, surprisingly find that this crystal compound purity is high, good fluidity, good stability, impurity content is low, not easily moisture absorption, clinical practice is safe and reliable, and the aqueous injection component utilizing this crystal compound obtained is simple, good stability.

In prior art, for the crystal formation of oxaliplatin, had many research, but the hygroscopicity of impurity content, stability and crystal formation is still undesirable, brings difficulty also to while have impact on self stability the preparation of preparation.

The present invention is through a large amount of experimental studies, obtain a kind of oxaliplatin crystalline compounds being different from prior art, by verification experimental verification, surprisingly find that this crystal compound purity is high, good fluidity, good stability, impurity content is low, not easily moisture absorption, and clinical practice is safe and reliable, the aqueous injection component utilizing this crystal compound obtained is simple, good stability.

Summary of the invention

Goal of the invention of the present invention is to provide a kind of platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection.

In order to complete object of the present invention, the technical scheme of employing is:

A kind of platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection, described compositions is made up of oxaliplatin, calcium chloride; Described oxaliplatin is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.

Preferably, in described compositions, the weight ratio of oxaliplatin and calcium chloride is 1:0.3-0.7.

Preferably, in described compositions, the weight ratio of oxaliplatin and calcium chloride is 1:0.4-0.6.

Preferably, in described compositions, the weight ratio of oxaliplatin and calcium chloride is 1:0.5.

The preparation method of described compositions aqueous injection comprises the following steps:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

The preparation method of the oxaliplatin crystal in the present composition comprises the following steps:

(1) by oxaliplatinum in the solvent of N-methylacetamide, the solvent load that needs of every gram of oxaliplatin is 100ml;

(2), after being heated to 40 DEG C of dissolvings, after cool to room temperature, crystal seed is added;

(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains oxaliplatin crystal.

The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.

Accompanying drawing explanation

Fig. 1 is the X-ray powder diffraction that the oxaliplatin crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.

Detailed description of the invention

Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.

embodiment 1:the preparation of oxaliplatin crystal

(1) by oxaliplatinum in the solvent of N-methylacetamide, the solvent load that needs of every g oxaliplatin is 100ml;

(2), after being heated to 40 DEG C of dissolvings, after cool to room temperature, crystal seed is added;

(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains oxaliplatin crystal.

The X-ray powder diffraction pattern that the oxaliplatin crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.

embodiment 2:the preparation of oxaliplatin combination thing aqueous injection

Consist of: oxaliplatin crystal 1 weight portion prepared by the present invention, calcium chloride 0.3 weight portion.

Preparation method is:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

embodiment 3:the preparation of oxaliplatin combination thing aqueous injection

Consist of: oxaliplatin crystal 1 weight portion prepared by the present invention, calcium chloride 0.4 weight portion.

Preparation method is:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

embodiment 4:the preparation of oxaliplatin combination thing aqueous injection

Consist of: oxaliplatin crystal 1 weight portion prepared by the present invention, calcium chloride 0.5 weight portion.

Preparation method is:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

embodiment 5:the preparation of oxaliplatin combination thing aqueous injection

Consist of: oxaliplatin crystal 1 weight portion prepared by the present invention, calcium chloride 0.6 weight portion.

Preparation method is:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

embodiment 6:the preparation of oxaliplatin combination thing aqueous injection

Consist of: oxaliplatin crystal 1 weight portion prepared by the present invention, calcium chloride 0.7 weight portion.

Preparation method is:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

test example 1:draw moist test

It is moist that this test example has investigated drawing of oxaliplatin compound crystal provided by the invention, and this experiment is drawn moist test direction principle according to Chinese Pharmacopoeia 2010 editions second annex XIXJ medicine and carried out, and the results are shown in Table 1.

Table 1 draws moist result of the test

Wherein, sample 1 is embodiment 1 product;

Sample 2 is embodiment 2 products;

Sample 3 is embodiment 3 products;

Sample 4 is the Oxaliplatin crystal compound prepared with reference to patent CN102643308B embodiment 1;

Sample 5 is the Oxaliplatin crystal compound prepared with reference to patent CN100372858C embodiment;

Sample 6 is commercially available oxaliplatin crude drug, originates from Jiangsu Aosaikang Pharmaceutical Co., Ltd..

As seen from Table 1, compared with the Oxaliplatin crystal compound of prior art, oxaliplatin hydrate crystal of the present invention to draw wet percentage weight increase little, hygroscopicity is little.

Also carried out above-mentioned test to the oxaliplatin compound prepared by other embodiment of the present invention, its result obtained is similar.

test example 2:fluidity test

This experimental example has investigated the mobility of oxaliplatin compound crystal provided by the invention.

This experimental example by working sample angle of repose assess sample mobility, concrete grammar is as follows: sample thief granule, flow into from fixing little funnel in circular surface plate, know and obtain the highest cone, measure cone height H and radius R, calculate α angle of repose by tan α=H/R, the results are shown in Table 2, angle of repose is larger, and mobility is poorer.

Table 2 fluidity test result

Wherein, sample 1-3 is 3 batches of products that embodiment 1 obtains;

Sample 4 is the Oxaliplatin crystal compound prepared with reference to patent CN102643308B embodiment 1;

Sample 5 is the Oxaliplatin crystal compound prepared with reference to patent CN100372858C embodiment;

Sample 6 is commercially available oxaliplatin crude drug, originates from Jiangsu Aosaikang Pharmaceutical Co., Ltd..

As seen from Table 2, compared with the Oxaliplatin crystal compound of prior art, oxaliplatin compound crystal of the present invention has excellent mobility, is conducive to the accuracy improving subpackage, and is easy to mix homogeneously when mixing with other compositions.

experimental example 3:long term test

Sample thief, by commercially available back, place after 4 years under long term test (temperature 25 DEG C ± 2 DEG C, relative humidity 65% ± 5%) condition, checked for impurities content, result is as following table 3.

The rear three batch sample assays of table 3:4

As can be seen from Table 3, the embodiment of the present invention 2,3,4 product, after temperature 25 ± 2 DEG C, relative humidity 65 ± 5% place 4 years, impurity index is obviously better than commercially available and prior art products, and stability is better.

Similar test is carried out to other embodiments, has obtained similar result of the test.

Above-mentioned test shows the hygroscopicity that the compound tool of novel crystal forms structure of the present invention has clear improvement and higher stability, the aqueous injection prepared of this oxaliplatin crystal compound comparatively prior art to compare component simple, good stability, impurity content is low.

Claims (6)

1. a platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection, is characterized in that: described compositions is made up of oxaliplatin, calcium chloride; Described oxaliplatin is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.

2. platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection according to claim 1, is characterized in that: the weight ratio of described oxaliplatin and calcium chloride is 1:0.3-0.7.

3. platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection according to claim 2, is characterized in that: the weight ratio of described oxaliplatin and calcium chloride is 1:0.4-0.6.

4. platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection according to claim 3, is characterized in that: the weight ratio of described oxaliplatin and calcium chloride is 1:0.5.

5. the platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection according to any one of claim 1-4, it is characterized in that, the preparation method of described compositions aqueous injection comprises the following steps:

Get the oxaliplatin of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30 minutes of 1% of oxaliplatin weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizings 45 minutes, lamp inspection, obtains oxaliplatin aqueous injection.

6. platinum series antineoplastic medicament oxaliplatin combination thing aqueous injection according to claim 1, it is characterized in that, the crystal preparation method of described oxaliplatin is:

(1) by oxaliplatinum in the solvent of N-methylacetamide, the solvent load that needs of every gram of oxaliplatin is 100ml;

(2), after being heated to 40 DEG C of dissolvings, after cool to room temperature, crystal seed is added;

(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains oxaliplatin crystal.