CN101612146B - Oxaliplatin medicament composition, preparation method thereof - Google Patents
Oxaliplatin medicament composition, preparation method thereof Download PDFInfo
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Abstract
The invention relates to an oxaliplatin medicament composition as an anticancer medicament, a preparation method thereof and a method for synthesizing oxaliplatin as raw medicinal material. The composition comprises oxaliplatin and lactose, wherein the mass ratio of the oxaliplatin to the lactose is 1:12-1:20. The composition can be added with injection water and pH regulator and made into freeze-dried powder injection through freeze drying. The freeze-dried powder injection not only has the advantages of good formability, plump shape and the like, but also overcomes the prejudice that oxaliplatin freeze-dried powder injection taking the lactose as a freeze-drying carrier is not good in formability and the like. The synthesis method comprises: 1) taking osho trans-diaminocyclohexane as raw materials to prepare an intermediate (I); 2) forming an intermediate (II) through intermediate reaction; and 3) forming the oxaliplatin through the reaction of the intermediate (II) and potassium oxalate solution, wherein the step 2) also comprises a process of adding KI for reaction. The method has the advantages of simple reaction, mild conditions, short time and no silver ions in products.
Description
Technical field
The present invention relates to cancer therapy drug oxaliplatin medicament composition and preparation method thereof, and the synthetic method of crude drug oxaliplatin.
Background technology
It is in 1978 that oxaliplatin (Oxaliplatin) discloses first, requires among the U.S. Pat 4169846A to have protected this chemical compound, has provided the method for preparing of this chemical compound.The basic step of this method is: the solution of (1) dichloro hexamethylene two ammino platinum and silver nitrate reacts; (2) remove silver nitride precipitation; (3) adding binary acid such as oxalic acid reacts.
Though said synthesis route is fairly simple, requirement condition is harsh, and each step all need keep in Dark Place, and increased equipment undoubtedly, and the final step reaction yield is very low, and therefore the proportioning raw materials that needs has increased production cost also than higher, is unfavorable for suitability for industrialized production.
European patent EP 0625523 discloses with cis-dichloro cyclohexanediamine and has closed the method that platinum (II) is raw material and silver oxalate prepared in reaction oxaliplatin, as follows:
Though the said synthesis route operation is shorter; But because silver oxalate sees the photolysis blackening, oven dry and bump might be explosion caused, are a kind of hazardous and unsettled chemical raw material; And can easily not obtain supply from market; So must when producing, self-control use, this has just increased the step of last production. art flow process, has brought the potential safety hazard of producing simultaneously.
" JM-216 synthetic and structural characterization " [general continue flat, Yang Yi Kun, Gao Wengui etc. the synthetic and structural characterization of JM-216. noble metal, 2000,21 (1): 26～27] method that is prepared as follows oxaliplatin disclosed:
The said synthesis route needed raw material is easy to get and purchases, no dangerous materials and explosive material, and also reactions step is simple; Had only for second step needed the lucifuge reaction; Reaction condition is gentle, and the time is short, has therefore shortened the production cycle; Per step can be controlled the quality of intermediate, thereby disposablely obtains purer oxaliplatin finished product.But the existing problem of this method is: silver ion is present in the product.
U.S. Pat 5290961A has discussed the existing problem of synthesis technique that comprises silver nitrate, oxalic acid in the prior art in background technology: silver ion is present in the product.In order to overcome the problems referred to above, the patentee of this patent proposes a solution, and removes excessive silver ion through adding sodium iodide or potassium iodide.The emphasis of this technical scheme is: " the dichloro cyclohexanediamine closes platinum (II) " reacts with silver ion earlier, and the silver ion solution that closes platinum (II) reaction with the dichloro cyclohexanediamine is doubling dose at least, and purpose is to make the dichloro cyclohexanediamine close platinum (II) to react completely as far as possible; Add sodium iodide or potassium iodide again to remove unreacted silver ion, add oxalic acid at last with the preparation oxaliplatin.The inventive point that can find out US5290961A mainly is to use potassium iodide or sodium iodide to remove and participates in the silver ion of reaction and improve degree of purity of production.But, though this method has been removed the silver ion that exists in the product, to carry out owing to be reflected under room temperature and the lucifuge condition, the response time reaches 3 days, and the visible response time is oversize, so the production cycle is longer, is unfavorable for suitability for industrialized production.
In sum, the synthetic method of oxaliplatin all exists some defectives in the prior art, awaits further to improve.
In addition, oxaliplatin (Oxaliplatin) belongs to platinum metal complex, is the platinum series antineoplastic medicament of new generation after cisplatin, carboplatin.By Switzerland Debiopharm company exploitation, the Toxicity of Kidney of cisplatin do not occur the earliest, also do not have the bone marrow depression of carboplatin, it acts on DNA through producing the alkane conjugate, forms in the chain and interchain linkage, thereby suppresses the synthetic of DNA and duplicate.Combine rapidly with DNA, need 15 minutes at most, administration through measuring leukocytic conjugate, can show its existence after one hour in human body.DNA in the reproduction process is synthetic, and the synthetic of the separation of DNA, RNA and cell protein all is suppressed thereafter, and some is to the cell line of cisplatin resistance, and treatment effectively.Be used to treat the patient that the colon cancer after the fluorouracil in treatment failure shifts, can use with the associating fluorouracil separately.
The oxaliplatin principal agent is a parenteral administration, but the less stable of oxaliplatin in water, the passing in time of its aqueous solution can be degraded and produced not commensurability two water DACH platinum, two water DACH platinum dimers and platinum class impurity, obviously influences the toxicology characteristic of medicine.
CN00812119, CN99803276, CN95194443 etc. attempt the allotment through preparation prescription, improving the stability of oxaliplatin injection, but the oxaliplatin Study on Stability are shown: the stationary mode of oxaliplatin formulations is a lyophilized injectable powder.
At present, use a large amount of lactose as the lyophilization carrier in the oxaliplatin freeze-dried powder.But, think at present to be that the aseptic freeze-dried article of oxaliplatin that excipient makes exist defectives such as " molding is bad, and are frangible and be not easy to storage, transportation, and is prone to moisture absorption after the atrophy and causes content to reduce, thereby influences the shelf-life " mostly with the lactose.
Therefore, usually with mannitol as first-selected skeleton agent.Disclose a kind of oxaliplatin freeze-dried powder like WO2005020876, used mannitol as the lyophilization carrier." preparation of injection oxaliplatin and quality investigation thereof " (referring to " preparation technique ", 2006 the 15th volume the 14th phase) discloses a kind ofly makes excipient with mannitol, the lyophilized injectable powder that sodium acetate forms through lyophilization as the pH regulator agent.
But, have some shortcomings too as the mannitol of carrier: cost an arm and a leg as the lyophilizing carrier like other mannitol of injection stage, and oxaliplatin is because dissolubility is relatively poor; Fill volume is big and be prone to separate out, and adding mannitol can play Stabilization to solution to a certain extent, but has also brought problem simultaneously; Because higher solid content and bigger fill volume; In the oxaliplatin freeze-dried powder production process, there is higher fried bottle ratio, greatly reduces the product yield, production capacity, supplementary material and inner packaging material have been caused very big waste; Because oxaliplatin toxicity is bigger; The medicine of revealing with fried bottle damages the operator probably, also clears out a gathering place to production and has brought difficulty, has increased the risk of cross-contamination.
Based on above-mentioned shortcoming, some producer improves the prescription of oxaliplatin freeze-dried powder.Disclose a kind of by containing the lyophilized injectable powder that oxaliplatin, mannitol and the lyophilizing of citron aqueous acid make as 200710191484.2.200610165396.0 disclose lyophilized formulations of a kind of oxaliplatin and preparation method thereof, adopted glucose as carrier.
It is thus clear that, it has been generally acknowledged that in the prior art with lactose to exist molding bad as the oxaliplatin freeze-dried powder of lyophilization carrier, frangible and be not easy to storage, transportation, and be prone to moisture absorption after the atrophy and cause defectives such as content reduction.
Research worker of the present invention is through after the lot of test, starts with from the synthetic route of oxaliplatin and process conditions etc. on the one hand, found a kind of method that solves the ideal synthetic oxaliplatin of above-mentioned composition problem; Consumption through the control lactose and limit preparation process condition etc. and prepared on the other hand with the oxaliplatin medicament composition lyophilized injectable powder with advantages such as forming, profile are full of lactose as the lyophilization carrier; Overcome the prejudice of prior art, thereby accomplished the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of oxaliplatin medicament composition; This pharmaceutical composition with lactose as the lyophilizing carrier; Not only have advantages such as good moldability, profile be full, but also overcome in the prior art with the prejudice of lactose as the bad grade of oxaliplatin medicament composition mouldability of lyophilizing carrier.
Second purpose of the present invention is to provide the method for preparing of oxaliplatin medicament composition of the present invention; This method adopts lactose as the lyophilizing carrier; Simple; Adopt the lyophilized injectable powder of this method preparation not only to have advantages such as good moldability, profile be full, but also overcome in the prior art oxaliplatin freeze-dried powder with the prejudice of lactose as the bad grade of its mouldability of lyophilizing carrier.
The 3rd purpose of the present invention is to provide a kind of synthetic method of crude drug oxaliplatin, and this method needed raw material is easy to get and purchases, no dangerous materials and explosive material; Not only reactions step is simple; Have only a step to need the lucifuge reaction, reaction condition is gentle, and the time is short; Production cycle shortens, and has solved silver ion and be present in the problem in the product.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
A kind of oxaliplatin medicament composition, wherein, described oxaliplatin medicament composition comprises oxaliplatin and lactose, wherein the mass ratio of oxaliplatin and lactose is 1: 12～1: 20, preferred 1: 14～1: 18, more preferably 1: 16.
According to aforesaid oxaliplatin medicament composition, wherein, described oxaliplatin medicament composition adds water for injection and the pH regulator agent is processed lyophilized injectable powder through lyophilization.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of method for preparing of oxaliplatin medicament composition of the present invention, wherein, this method is that the oxaliplatin of said ratio and lactose mixing are promptly got.
Further, the method for preparing of oxaliplatin medicament composition of the present invention also comprises the oxaliplatin medicament composition that obtains after the above-mentioned mixing is added water for injection and the pH regulator agent is processed lyophilized injectable powder through lyophilization.
Among the present invention, the method for described oxaliplatin medicament composition being processed lyophilized injectable powder comprises the steps:
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) use the pH regulator agent to regulate pH value and be 5.5-6.5, benefit adds to the full amount of water for injection;
3) add active carbon then, stir, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization.
According to aforesaid method, wherein, described lyophilization is divided into following three phases:
1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump;
2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off;
3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
For realizing the 3rd purpose of the present invention, the present invention adopts following technical scheme:
A kind of synthetic method of crude drug oxaliplatin, this method comprises:
1) with K
2PtCl
4With trans cyclohexanediamine be feedstock production intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes platinum, and reaction equation is:
2) intermediate (I) and AgNO that step 1) is prepared
3Intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes platinum, and reaction equation is in the reaction generation:
3) with step 2) prepared intermediate (II) and Potassium Oxalate Solution reaction generation oxaliplatin, reaction equation is:
Wherein:
Step 2) at described intermediate (I) and AgNO
3Also comprise the process that adds the KI solution reaction after the reaction.
According to above-mentioned synthetic method, wherein said step 2) be specially: under the room temperature, intermediate that step 1) is prepared (I) and AgNO
3Soluble in water, again under inflated with nitrogen and lucifuge condition in 45 ℃～55 ℃ of reaction temperatures stirring reaction 10-14 hour, and then add liquor kalii iodide, continue reaction 0.5～1.5 hour, filter, washing obtains the solution of intermediate (II).
According to above-mentioned synthetic method, the K described in the step 1) wherein
2PtCl
4With the mol ratio of trans cyclohexanediamine be 1: 1.02～1: 1.08, preferred 1: 1.05;
According to above-mentioned synthetic method, wherein the intermediate described in the step 3) (I) is 1: 1.8～1: 2.2 with the mol ratio of potassium oxalate.
According to above-mentioned synthetic method, wherein said step 1) is specially: under the room temperature, with K
2PtCl
4Soluble in water, feed nitrogen again, under agitation drip trans cyclohexanediamine solution, at ambient temperature stirring reaction 6-12 hour then, filter, water, ethanol and ether washing respectively, drying obtains intermediate (I).
According to above-mentioned synthetic method, wherein said step 3) is specially: under the nitrogen protection condition, in the solution of intermediate (II), drip Potassium Oxalate Solution; Stirring reaction 1-3 hour, filter concentrating under reduced pressure; Cooled and filtered; Water, ethanol and ether washing respectively, drying obtains oxaliplatin.
According to above-mentioned synthetic method, the method for preparing of wherein said oxaliplatin also comprises carries out purified process to the prepared oxaliplatin of step 3).
According to above-mentioned synthetic method, wherein said making with extra care is: the oxaliplatin that step 3) is prepared is soluble in water, stirs, and is warming up to 45 ℃～55 ℃; Concentrating under reduced pressure is filtered in dissolving; Filter, water, ethanol and ether washing respectively, drying obtains the pure article of oxaliplatin.
Below be detailed description of the present invention:
On the one hand, the present invention provides a kind of oxaliplatin medicament composition, and wherein, described oxaliplatin medicament composition comprises oxaliplatin and lactose, and wherein the mass ratio of oxaliplatin and lactose is 1: 12～1: 20, and preferred 1: 14～1: 18, more preferably 1: 16.
At present, though the pharmaceutical composition that exists oxaliplatin and lactose to form, because the oxaliplatin Study on Stability is shown: the stationary mode of oxaliplatin formulations is a lyophilized injectable powder.But; At present think with the lactose to be that the aseptic freeze-dried article of oxaliplatin that excipient makes exist following defective mostly: molding is bad; Frangible and be not easy to storage, transportation, and be prone to moisture absorption after the atrophy and cause content to reduce, thereby the shelf-life influenced; Thereby the pharmaceutical composition that makes oxaliplatin and lactose form does not have actual using value, is being eliminated gradually yet.Among the present invention, the inventor is through regulating and control the mass ratio of oxaliplatin and lactose, thereby a kind of oxaliplatin medicament composition with actual application value is provided.
According to aforesaid oxaliplatin medicament composition, wherein, described oxaliplatin medicament composition adds water for injection and the pH regulator agent is processed lyophilized injectable powder through lyophilization.
Prior art shows that be that the aseptic freeze-dried article of oxaliplatin that excipient makes exist following defective with the lactose: molding is bad, and is frangible and be not easy to storage, transportation, and is prone to moisture absorption after the atrophy and causes content to reduce, thereby influences the shelf-life.The inventor is through regulating and control the mass ratio of oxaliplatin and lactose; Further described oxaliplatin medicament composition adding water for injection and pH regulator agent are processed lyophilized injectable powder through lyophilization; Prepared lyophilized injectable powder has advantages such as good moldability, profile be full, thereby has overcome the prejudice of prior art.
On the other hand, the present invention provides a kind of method for preparing of oxaliplatin medicament composition of the present invention, and this method is that the oxaliplatin of said ratio and lactose mixing are promptly got.
Further, the method for preparing of oxaliplatin medicament composition of the present invention also comprises the oxaliplatin medicament composition that obtains after the above-mentioned mixing is added water for injection and the pH regulator agent is processed lyophilized injectable powder through lyophilization.
Among the present invention, the method for described oxaliplatin medicament composition being processed lyophilized injectable powder comprises the steps:
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) use the pH regulator agent to regulate pH value and be 5.5-6.5, benefit adds to the full amount of water for injection;
3) add active carbon then, stir, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization.
Wherein, the pH regulator agent step 2) is a sodium acetate.
The consumption of the active carbon described in the step 3) (w/v) is 0.05%-0.15%, preferred 0.05%-0.10%, more preferably 0.05%.
For effectively removing bacterial endotoxin, the present invention selects for use active carbon to remove bacterial endotoxin.For guaranteeing the yield of product; The present invention investigates the consumption of active carbon; Select for use the active carbon of variable concentrations to make an experiment respectively; Select the active carbon of four kinds of concentration of 0.00%, 0.05%, 0.1%, 0.15% (w/v) for use, insulated and stirred absorption is 10 minutes under 50 ℃～60 ℃ conditions, check each item important indicator.See Test Example 2.The result shows, add activated carbon adsorption after, visible foreign matters and bacterial endotoxin are all qualified; But the concentration of activated carbon of 0.1% and 0.15% (w/v) is bigger to principal agent absorption; Effectively eliminating under the bacterial endotoxin prerequisite, and adapting to working condition, confirming that amount of activated is that 0.05% (w/v) is for best.
Stirring described in the step 3) is under 50 ℃～60 ℃ conditions insulated and stirred 5-15 minute, preferred 10 minutes.
The adding proper amount of active carbon can improve the clarity of injection, can adsorb thermal source, color level again, but active carbon also has adsorption to oxaliplatin simultaneously.The present invention has investigated the influence to oxaliplatin content in the injection of temperature, adsorption time.The result shows, when 50～60 ℃ of adsorption times 5～15 minutes, adsorption temp, and best results.
Lyophilization described in the step 4) is divided into following three phases:
1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump;
2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off;
3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
Among the present invention, serve as to investigate index, confirmed best freeze-dry process with the character in the freeze-dried products, moisture, content and related substance.
Among the present invention, described crude drug oxaliplatin is to adopt following method preparation:
1) with K
2PtCl
4With trans cyclohexanediamine be feedstock production intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes platinum, and reaction equation is:
2) intermediate (I) and AgNO that step 1) is prepared
3Intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes platinum, and reaction equation is in the reaction generation:
3) with step 2) prepared intermediate (II) and Potassium Oxalate Solution reaction generation oxaliplatin, reaction equation is:
Wherein:
Step 2) at described intermediate (I) and AgNO
3Also comprise the process that adds the KI solution reaction after the reaction.
In the synthetic method of oxaliplatin of the present invention, step 2 wherein) be specially: under the room temperature, intermediate that step 1) is prepared (I) and AgNO
3Soluble in water, again under inflated with nitrogen and lucifuge condition in 45 ℃～55 ℃ of reaction temperatures stirring reaction 10-14 hour, and then add liquor kalii iodide, continue reaction 0.5～1.5 hour, filter, washing obtains the solution of intermediate (II).
In the synthetic method of oxaliplatin of the present invention, the K described in the step 1) wherein
2PtCl
4With the mol ratio of trans cyclohexanediamine be 1: 1.02～1: 1.08, preferred 1: 1.05.
In the synthetic method of oxaliplatin of the present invention, wherein the intermediate described in the step 3) (I) is 1: 1.8～1: 2.2 with the mol ratio of potassium oxalate.
In the synthetic method of oxaliplatin of the present invention, wherein said step 1) is specially: under the room temperature, with K
2PtCl
4Soluble in water, feed nitrogen again, under agitation drip trans cyclohexanediamine solution, at ambient temperature stirring reaction 6-12 hour then, filter, water, ethanol and ether washing respectively, drying obtains intermediate (I).
The rate of addition of wherein trans cyclohexanediamine solution is 1.0-2.0ml/min, preferred 1.5ml/min.
In the synthetic method of oxaliplatin of the present invention, wherein said step 3) is specially: under the nitrogen protection condition, in the solution of intermediate (II), drip Potassium Oxalate Solution; Stirring reaction 1-3 hour, filter concentrating under reduced pressure; Cooled and filtered; Water, ethanol and ether washing respectively, drying obtains oxaliplatin.
Wherein the rate of addition of Potassium Oxalate Solution is 10-14ml/min, preferred 12ml/min.
In the synthetic method of oxaliplatin of the present invention, the method for preparing of wherein said oxaliplatin also comprises carries out purified process to the prepared oxaliplatin of step 3).
Adopt the prepared oxaliplatin of method of the present invention to make with extra care it as the case may be, also can not make with extra care.Described making with extra care can adopt method well known in the art to carry out, but preferably adopts method of the present invention: the oxaliplatin that step 3) is prepared is soluble in water, stirs; Be warming up to 45 ℃～55 ℃, dissolving is filtered; Concentrating under reduced pressure; Filter, water, ethanol and ether washing respectively, drying obtains the pure article of oxaliplatin.
Further, the present invention also provides a kind of synthetic method of crude drug oxaliplatin, and this method comprises:
1) with K
2PtCl
4With trans cyclohexanediamine be feedstock production intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes platinum, and reaction equation is:
2) intermediate (I) and AgNO that step 1) is prepared
3Intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes platinum, and reaction equation is in the reaction generation:
3) with step 2) prepared intermediate (II) and Potassium Oxalate Solution reaction generation oxaliplatin, reaction equation is:
Wherein:
Step 2) at described intermediate (I) and AgNO
3Also comprise the process that adds the KI solution reaction after the reaction.
" JM-216 synthetic and structural characterization " [general continue flat; the Yang Yi Kun; Gao Wengui etc. the synthetic and structural characterization of JM-216. noble metal, 2000,21 (1): 26～27] method that as above prepares oxaliplatin disclosed; But in order to make intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes platinum and AgNO
3React completely, to avoid unnecessary waste, the AgNO that adds usually as far as possible
3At least be doubling dose, this has produced new problem undoubtedly: silver ion will be present in the product.The inventor is through the research to synthetic route, in step 2) be synthetic intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes in the process of platinum, at intermediate (I) and AgNO
3Further add an amount of KI solution after the reaction again, removed excessive silver ion, thereby made high-quality oxaliplatin finished product.
In the synthetic method of oxaliplatin of the present invention, step 2 wherein) be specially: under the room temperature, intermediate that step 1) is prepared (I) and AgNO
3Soluble in water, again under inflated with nitrogen and lucifuge condition in 45 ℃～55 ℃ of reaction temperatures stirring reaction 10-14 hour, and then add liquor kalii iodide, continue reaction 0.5～1.5 hour, filter, washing obtains the solution of intermediate (II).
U.S. Pat 5290961A has also discussed the existing problem of synthesis technique that comprises silver nitrate, oxalic acid in the prior art in background technology: silver ion is present in the product.In order to overcome the problems referred to above, the patentee of this patent proposes a solution, and removes excessive silver ion through adding sodium iodide or potassium iodide.Though but this method has been removed the silver ion that exists in the product, to carry out owing to be reflected under room temperature and the lucifuge condition, the response time reaches 3 days, and the visible response time is oversize, so the production cycle is longer, is unfavorable for suitability for industrialized production.Among the present invention, through the inventor's big quantity research, strict control reaction condition and response time, under inflated with nitrogen and lucifuge condition,, only needed reaction 10-14 hour in 45 ℃～55 ℃ stirring reactions of reaction temperature, shortened reaction time greatly.
In the synthetic method of oxaliplatin of the present invention, the K described in the step 1) wherein
2PtCl
4With the mol ratio of trans cyclohexanediamine be 1: 1.02～1: 1.08, preferred 1: 1.05.
Because trans cyclohexanediamine volatilizees K easily
2PtCl
4With the ingredient proportion of trans cyclohexanediamine be influential to the yield of intermediate (I)." JM-216 synthetic and structural characterization " [general continue flat, Yang Yi Kun, Gao Wengui etc. the synthetic and structural characterization of JM-216. noble metal, 2000,21 (1): 26～27] in the synthetic method of disclosed oxaliplatin, K
2PtCl
4With the ingredient proportion (being mol ratio) of trans cyclohexanediamine be 1: 1.The yield of intermediate (I) was not high when the inventor found this rate of charge through test, to this, had investigated K among the present invention
2PtCl
4With the influence to yield of the ingredient proportion of trans cyclohexanediamine, the result sees table 1:
Table 1, potassium chloroplatinite and trans cyclohexanediamine ingredient proportion are to the influence of intermediate (I)
| Lot number | Molar ratio * | Yield (%) | The product character | Product purity (%) |
| ?ASI060801 | 1∶1.00 | 85.7 | The buff powder | 83.79 |
| ?ASI060802 | 1∶1.02 | 90.1 | Buff powder | 95.68 |
| ?ASI060903 | 1∶1.05 | 92.3 | Buff powder | 98.82 |
| ?ASI060804 | 1∶1.08 | 91.6 | Buff powder | 97.58 |
| ?ASI060905 | 1∶1.10 | 91.2 | Buff powder | 67.23 |
Annotate: rate of charge is a potassium chloroplatinite: trans cyclohexanediamine
Can find out from table 1, work as K
2PtCl
4With the molar ratio of trans cyclohexanediamine be 1: 1.02～1: 1.10 o'clock, the yield of intermediate (I) can reach more than 90%, but when molar ratio was 1: 1.10, product gas purity was too low, took all factors into consideration, among the present invention with K
2PtCl
4Confirm as 1: 1.02 with the molar ratio of trans cyclohexanediamine～1: 1.08, preferred 1: 1.05.
In the synthetic method of oxaliplatin of the present invention, wherein the intermediate described in the step 3) (I) is 1: 1.8～1: 2.2 with the mol ratio of potassium oxalate.
In the prior art; For intermediate (I) is reacted completely as far as possible, the potassium oxalate that is added is usually excessive, as " JM-216 synthetic and structural characterization " [general continue flat; the Yang Yi Kun; Gao Wengui etc. the synthetic and structural characterization of JM-216. noble metal, 2000,21 (1): 26～27] in the synthetic method of disclosed oxaliplatin.The inventor finds that through test the consumption of potassium oxalate is not only to need excessive getting final product, and excessive amount difference all is influential to yield, character and the purity of product oxaliplatin.Investigated the influence of the ingredient proportion of intermediate (I) and potassium oxalate to yield among the present invention, the result sees table 2:
Table 2, intermediate compound I and potassium oxalate ingredient proportion are to the influence of finished product
| Lot number | Molar ratio * | Yield (%) | The product character | Product purity (%) |
| AS060901 | 1∶1.8 | 78.3 | The off-white color crystalline powder | 98.34 |
| AS061001 | 1∶2.0 | 80.1 | White crystalline powder | 99.47 |
| AS061002 | 1∶2.2 | 77.4 | White crystalline powder | 99.54 |
Annotate: rate of charge is an intermediate compound I: potassium oxalate
Can find out that from table 2 when the molar ratio of intermediate (I) and potassium oxalate was 1: 1.8～1: 2.2, the yield of product oxaliplatin can reach more than 77%; When the molar ratio of intermediate (I) and potassium oxalate was 1: 1.8～1: 2.2, the yield of product oxaliplatin can reach more than 80%.
In the synthetic method of oxaliplatin of the present invention, wherein said step 1) is specially: under the room temperature, with K
2PtCl
4Soluble in water, feed nitrogen again, under agitation drip trans cyclohexanediamine solution, at ambient temperature stirring reaction 6-12 hour then, filter, water, ethanol and ether washing respectively, drying obtains intermediate (I).
The rate of addition of wherein trans cyclohexanediamine solution is 1.0-2.0ml/min, preferred 1.5ml/min.
The rate of addition of trans cyclohexanediamine solution is to the raw material direct influence that whether reacted completely.Show through research among the present invention, when the rate of addition of trans cyclohexanediamine solution is 1.0-2.0ml/min, preferred 1.5ml/min, can make trans cyclohexanediamine better with K
2PtCl
4Contact makes to react completely as far as possible, thereby avoids unnecessary waste.
In the synthetic method of oxaliplatin of the present invention, wherein said step 3) is specially: under the nitrogen protection condition, in the solution of intermediate (II), drip Potassium Oxalate Solution; Stirring reaction 1-3 hour, filter concentrating under reduced pressure; Cooled and filtered; Water, ethanol and ether washing respectively, drying obtains oxaliplatin.
Wherein the rate of addition of Potassium Oxalate Solution is 10-14ml/min, preferred 12ml/min.
The rate of addition of Potassium Oxalate Solution has direct influence to the yield of product.Show through research among the present invention that when the rate of addition of Potassium Oxalate Solution is 10-14ml/min, preferred 12ml/min can make intermediate (II) react completely as best one can, thereby improves the yield of product.
In the synthetic method of oxaliplatin of the present invention, the method for preparing of wherein said oxaliplatin also comprises carries out purified process to the prepared oxaliplatin of step 3).
Adopt the prepared oxaliplatin of method of the present invention to make with extra care it as the case may be, also can not make with extra care.Described making with extra care can adopt method well known in the art to carry out, but preferably adopts method of the present invention: the oxaliplatin that step 3) is prepared is soluble in water, stirs; Be warming up to 45 ℃～55 ℃, dissolving is filtered; Concentrating under reduced pressure; Filter, water, ethanol and ether washing respectively, drying obtains the pure article of oxaliplatin.
Among the present invention, the step that relates to washing adopts water, ethanol and ether to wash respectively.Be to adopt water and washing with alcohol mostly in oxaliplatin synthetic in the prior art.And among the present invention after adopting water and washing with alcohol, continue again to wash, because oxaliplatin is insoluble in ether with ether; Ether has the good compatibility to glassware for drinking water simultaneously, can rapidly remove moisture wherein, reduces the oxaliplatin loss; Crystal after the oven dry does not lump as smart as a new pin simultaneously.
In the synthetic method of oxaliplatin of the present invention, the described employing water film filtering that is filtered into.
The present invention relates to filtering step and all can adopt this area filter method commonly used to filter, but preferably adopts water film filtering method provided by the present invention.Use activated carbon filtration in the prior art, but active carbon can produce certain adsorption to product, adopts water film filtering among the present invention, overcomes this defective.
Compared with prior art, the present invention has following advantage:
(1) oxaliplatin freeze-dried powder provided by the present invention; This lyophilized injectable powder with lactose as the lyophilizing carrier; Not only have advantages such as good moldability, profile be full, but also overcome in the prior art with the prejudice of lactose as the bad grade of oxaliplatin freeze-dried powder mouldability of lyophilizing carrier;
(2) method for preparing of oxaliplatin freeze-dried powder provided by the present invention; This method adopts lactose as the lyophilizing carrier; Simple; Adopt the lyophilized injectable powder of this method preparation not only to have advantages such as good moldability, profile be full, but also overcome in the prior art oxaliplatin freeze-dried powder with the prejudice of lactose as the bad grade of its mouldability of lyophilizing carrier;
(3) synthetic method of a kind of crude drug oxaliplatin provided by the present invention, this method needed raw material is easy to get and purchases, no dangerous materials and explosive material; Not only reactions step is simple; Have only a step to need the lucifuge reaction, reaction condition is gentle, and the time is short; Production cycle shortens, and has solved silver ion and be present in the problem in the product.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1-7 relates to the synthetic of crude drug oxaliplatin.
[embodiment 1] intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
Under the room temperature 10g (4.07mmol) potassium chloroplatinite is put in the there-necked flask of 150ml, added the distilled water of 100ml, feeding nitrogen under agitation adds 2.887g (25.28mmol) and is dissolved in the trans cyclohexanediamine in the 15ml distilled water; Approximately 10min dropwises, stirring reaction 8h at ambient temperature then, and thin layer chromatography detects to reaction end; Filtering reacting liquid washs three times with the purified water of 30ml respectively, with the 20ml washing with alcohol once; The washing of 20ml ether once; 65 ℃ of dry 4h obtain yellow solid product 8.42g, yield 91.9%.
[embodiment 2] intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
With 8g (21.16mmol) intermediate compound I, 6.828g (40.19mmol) silver nitrate is put in the 2000ml there-necked flask under the room temperature, adds 1200ml water, logical nitrogen; Stirring reaction under the lucifuge condition is warming up to 50 ℃, under this temperature, reacts 12h, the some board monitoring; In there-necked flask, add the potassium iodide (being dissolved in the 8ml distilled water) of 304mg (1.83mmol) then, add nitrogen, continue to stir 1 hour; Use water film filtering, use a little purified water washing leaching cake then, obtain the intermediate II colourless transparent solution.
Synthesizing of [embodiment 3] oxaliplatin
In the 2000ml there-necked flask, add intermediate II solution, nitrogen protection is stirred under the lucifuge condition, warming-in-water to 50 ℃, and 7.80g (42.31mmol) potassium oxalate (being dissolved in the 60ml distilled water) then slowly progressively increases; About 5min dropwises, and adds nitrogen, continues reaction 3-4h; The point board monitoring, reaction finishes the reactant liquor water is cooled to room temperature, and water film filtering obtains the reactant liquor of oxaliplatin; Under 65 ℃, be evaporated to a large amount of solids and separate out, stop to concentrate, use water for cooling, filter; Filter cake is used 40ml * 3 purified water washing three times respectively, with the absolute ethanol washing of 30ml * 3 three times, washs with the 20ml ether at last, 55 ℃ of dryings 4 hours.Get white oxaliplatin crystal 6 .4g.
Making with extra care of [embodiment 4] oxaliplatin
Oxaliplatin is soluble in water, stir, be warming up to 50 ℃, dissolving.Through the water film filtering reactant liquor, the concentrating under reduced pressure reactant liquor filters to a large amount of solids occurring then, difference water, dehydrated alcohol, ether washing leaching cake, and vacuum drying gets the oxaliplatin finished product.
The preparation of [embodiment 5] oxaliplatin
(1) intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
Under the room temperature 10g (4.07mmol) potassium chloroplatinite is put in the there-necked flask of 150ml, added the distilled water of 100ml, feeding nitrogen under agitation adds 0.474g (4.15mmol) and is dissolved in the trans cyclohexanediamine in the 12ml distilled water; Approximately 12min dropwises, stirring reaction 8h at ambient temperature then, and thin layer chromatography detects to reaction end; Filtering reacting liquid washs three times with the purified water of 30ml respectively, with the 20ml washing with alcohol once; The washing of 20ml ether once; 65 ℃ of dry 4h obtain yellow solid product 10.29g, yield 90.1%.
(2) intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
With 8g (21.16mmol) intermediate compound I, 6.828g (40.19mmol) silver nitrate is put in the 2000ml there-necked flask under the room temperature, adds 1200ml water, logical nitrogen; Stirring reaction under the lucifuge condition is warming up to 50 ℃, under this temperature, reacts 12h, the some board monitoring; In there-necked flask, add the potassium iodide (being dissolved in the 8ml distilled water) of 304mg (1.83mmol) then, add nitrogen, continue to stir 1 hour; Use water film filtering, use a little purified water washing leaching cake then, obtain the intermediate II colourless transparent solution.
(3) oxaliplatin is synthetic
In the 2000ml there-necked flask, add intermediate II solution, nitrogen protection is stirred under the lucifuge condition, warming-in-water to 50 ℃, and 7.02g (38.088mmol) potassium oxalate (being dissolved in the 60ml distilled water) then slowly progressively increases; About 5min dropwises, and adds nitrogen, continues reaction 3-4h; The point board monitoring, reaction finishes the reactant liquor water is cooled to room temperature, and water film filtering obtains the reactant liquor of oxaliplatin; Under 65 ℃, be evaporated to a large amount of solids and separate out, stop to concentrate, use water for cooling, filter; Filter cake is used 40ml * 3 purified water washing three times respectively, with the absolute ethanol washing of 30ml * 3 three times, washs with the 20ml ether at last, 55 ℃ of dryings 4 hours.Get white oxaliplatin crystal 5 .76g.
(4) oxaliplatin is refining
Oxaliplatin is soluble in water, stir, be warming up to 50 ℃, dissolving.Through the water film filtering reactant liquor, the concentrating under reduced pressure reactant liquor filters to a large amount of solids occurring then, difference water, dehydrated alcohol, ether washing leaching cake, and vacuum drying gets the oxaliplatin finished product.
The preparation of [embodiment 6] oxaliplatin
(1) intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
Under the room temperature 10g (4.07mmol) potassium chloroplatinite is put in the there-necked flask of 150ml, added the distilled water of 100ml, feeding nitrogen under agitation adds 0.511g (4.477mmol) and is dissolved in the trans cyclohexanediamine in the 15ml distilled water; Approximately 7.5min dropwises, stirring reaction 8h at ambient temperature then, and thin layer chromatography detects to reaction end; Filtering reacting liquid washs three times with the purified water of 30ml respectively, with the 20ml washing with alcohol once; The washing of 20ml ether once; 65 ℃ of dry 4h obtain yellow solid product 10.42g, yield 91.2%.
(2) intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
With 8g (21.16mmol) intermediate compound I, 6.828g (40.19mmol) silver nitrate is put in the 2000ml there-necked flask under the room temperature, adds 1200ml water, logical nitrogen; Stirring reaction under the lucifuge condition is warming up to 50 ℃, under this temperature, reacts 12h, the some board monitoring; In there-necked flask, add the potassium iodide (being dissolved in the 8ml distilled water) of 304mg (1.83mmol) then, add nitrogen, continue to stir 1 hour; Use water film filtering, use a little purified water washing leaching cake then, obtain the intermediate II colourless transparent solution.
(3) oxaliplatin is synthetic
In the 2000ml there-necked flask, add intermediate II solution, nitrogen protection is stirred under the lucifuge condition, warming-in-water to 50 ℃, and 8.58g (56.552mmol) potassium oxalate (being dissolved in the 60ml distilled water) then slowly progressively increases; About 5min dropwises, and adds nitrogen, continues reaction 3-4h; The point board monitoring, reaction finishes the reactant liquor water is cooled to room temperature, and water film filtering obtains the reactant liquor of oxaliplatin; Under 65 ℃, be evaporated to a large amount of solids and separate out, stop to concentrate, use water for cooling, filter; Filter cake is used 40ml * 3 purified water washing three times respectively, with the absolute ethanol washing of 30ml * 3 three times, washs with the 20ml ether at last, 55 ℃ of dryings 4 hours.Get white oxaliplatin crystal 7.04g.
(4) oxaliplatin is refining
Oxaliplatin is soluble in water, stir, be warming up to 50 ℃, dissolving.Through the water film filtering reactant liquor, the concentrating under reduced pressure reactant liquor filters to a large amount of solids occurring then, difference water, dehydrated alcohol, ether washing leaching cake, and vacuum drying gets the oxaliplatin finished product.
The preparation of [embodiment 7] oxaliplatin
(1) intermediate (I)---cis-dichloro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
Under the room temperature 10g (4.07mmol) potassium chloroplatinite is put in the there-necked flask of 150ml, added the distilled water of 100ml, feeding nitrogen under agitation adds 0.488g (4.274mmol) and is dissolved in the trans cyclohexanediamine in the 15ml distilled water; Approximately 7.5min dropwises, stirring reaction 8h at ambient temperature then, and thin layer chromatography detects to reaction end; Filtering reacting liquid washs three times with the purified water of 30ml respectively, with the 20ml washing with alcohol once; The washing of 20ml ether once; 65 ℃ of dry 4h obtain yellow solid product 8.46g, yield 92.3%.
(2) intermediate (II)---cis-dinitro (trans-(-)-1,2-cyclohexanediamine) closes the synthetic of platinum
With 8g (21.16mmol) intermediate compound I, 6.828g (40.19mmol) silver nitrate is put in the 2000ml there-necked flask under the room temperature, adds 1200ml water, logical nitrogen; Stirring reaction under the lucifuge condition is warming up to 50 ℃, under this temperature, reacts 12h, the some board monitoring; In there-necked flask, add the potassium iodide (being dissolved in the 8ml distilled water) of 304mg (1.83mmol) then, add nitrogen, continue to stir 1 hour; Use water film filtering, use a little purified water washing leaching cake then, obtain the intermediate II colourless transparent solution.
(3) oxaliplatin is synthetic
In the 2000ml there-necked flask, add intermediate II solution, nitrogen protection is stirred under the lucifuge condition, warming-in-water to 50 ℃, and 8.58g (56.552mmol) potassium oxalate (being dissolved in the 60ml distilled water) then slowly progressively increases; About 5min dropwises, and adds nitrogen, continues reaction 3-4h; The point board monitoring, reaction finishes the reactant liquor water is cooled to room temperature, and water film filtering obtains the reactant liquor of oxaliplatin; Under 65 ℃, be evaporated to a large amount of solids and separate out, stop to concentrate, use water for cooling, filter; Filter cake is used 40ml * 3 purified water washing three times respectively, with the absolute ethanol washing of 30ml * 3 three times, washs with the 20ml ether at last, 55 ℃ of dryings 4 hours.Get white oxaliplatin crystal 7.04g.
(4) oxaliplatin is refining
Oxaliplatin is soluble in water, stir, be warming up to 50 ℃, dissolving.Through the water film filtering reactant liquor, the concentrating under reduced pressure reactant liquor filters to a large amount of solids occurring then, difference water, dehydrated alcohol, ether washing leaching cake, and vacuum drying gets the oxaliplatin finished product.
Embodiment 8-16 relates to oxaliplatin medicament composition.
[embodiment 8]
1, prescription
Specification 1:50mg is (with C
8H
14N
2O
4The Pt meter)
Oxaliplatin 50g
Lactose 800g
Water for injection adds to 10000ml
Process 1000 altogether
2. preparation technology
2.1 prepare
(1) process water preparation: with the water for injection of fresh sterile as these article dosing water.
(2) vial, plug, aluminium lid are all made conventional treatment.
2.2 dosing
Take by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving.Using the sodium acetate solution of 1mol/L to regulate pH value is about 6.0, and benefit adds to the full amount of water for injection, and adds the active carbon of 0.05% (W/V) then, and insulated and stirred 10 minutes is taken off charcoal with the filtering with microporous membrane of 0.45 μ m.
2.3 middle article detect
Detect the content of pH value of filtrate and oxaliplatin.
2.4 fill
After middle article detection was qualified, the degerming fine straining was to sterilizing room.Confirm every fill amount according to content, medicinal liquid is sub-packed in the vial, press half plug, go into freeze drying box.
2.5 lyophilization
(1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump.
(2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off.
(3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
2.6 tamponade, outlet rolls aluminium lid.
2.7 full inspection, packing, warehouse-in.
[embodiment 9]
1, prescription
Specification 2:100mg is (with C
8H
14N
2O
4The Pt meter)
Oxaliplatin 100g
Lactose 1600g
Water for injection adds to 20000ml
Process 1000 altogether
2. preparation technology
2.1 prepare
(1) process water preparation: with the water for injection of fresh sterile as these article dosing water.
(2) vial, plug, aluminium lid are all made conventional treatment.
2.2 dosing
Take by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving.Using the sodium acetate solution of 1mol/L to regulate pH value is about 6.0, and benefit adds to the full amount of water for injection, and adds the active carbon of 0.05% (W/V) then, and insulated and stirred 10 minutes is taken off charcoal with the filtering with microporous membrane of 0.45 μ m.
2.3 middle article detect
Detect the content of pH value of filtrate and oxaliplatin.
2.4 fill
After middle article detection was qualified, the degerming fine straining was to sterilizing room.Confirm every fill amount according to content, medicinal liquid is sub-packed in the vial, press half plug, go into freeze drying box.
2.5 lyophilization
(1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump.
(2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off.
(3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 6 hours; Temperature rises to 25 ℃, is incubated 15 hours.
2.6 tamponade, outlet rolls aluminium lid.
2.7 full inspection, packing, warehouse-in.
[embodiment 10]
Oxaliplatin 100g and lactose 1400g mix homogeneously are promptly got oxaliplatin medicament composition.
[embodiment 11]
Oxaliplatin 50g and lactose 600g mix homogeneously are promptly got oxaliplatin medicament composition.
[embodiment 12]
Oxaliplatin 50g and lactose 1000g mix homogeneously are promptly got oxaliplatin medicament composition.
[embodiment 13]
Oxaliplatin 100g and lactose 1800g mix homogeneously are promptly got oxaliplatin medicament composition.
[embodiment 14]
1, prescription
Specification: 100mg is (with C
8H
14N
2O
4The Pt meter)
Oxaliplatin 100g
Lactose 1500g
Water for injection adds to 20000ml
Process 1000 altogether
2, preparation technology
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) using the sodium acetate solution adjusting pH value of 1mol/L is 5.5, and benefit adds to the full amount of water for injection;
3) add 0.15% (W/V) active carbon then, 50? Stirred 10 minutes under the condition, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization; Described lyophilization is divided into following three phases:
A) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump;
B) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off;
C) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
[embodiment 15]
1, prescription
Specification: 100mg is (with C
8H
14N
2O
4The Pt meter)
Oxaliplatin 100g
Lactose 1300g
Water for injection adds to 20000ml
Process 1000 altogether
2, preparation technology
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) using the sodium acetate solution adjusting pH value of 1mol/L is 6.5, and benefit adds to the full amount of water for injection;
3) add 0.10% (W/V) active carbon then, 60? Stirred 5 minutes under the condition, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization; Described lyophilization is divided into following three phases:
A) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump;
B) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off;
C) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
[embodiment 16]
1, prescription
Specification: 100mg is (with C
8H
14N
2O
4The Pt meter)
Oxaliplatin 100g
Lactose 1700g
Water for injection adds to 20000ml
Process 1000 altogether
2, preparation technology
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) using the sodium acetate solution adjusting pH value of 1mol/L is 5.8, and benefit adds to the full amount of water for injection;
3) add 0.10% (W/V) active carbon then, 55? Stirred 15 minutes under the condition, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization; Described lyophilization is divided into following three phases:
A) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump;
B) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off;
C) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
Test Example 1
This Test Example is screened the consumption of excipient lactose, to confirm the consumption of lactose.
For guaranteeing the quality and the outward appearance of freeze-drying prods, the inventor selects for use lactose to experimentize as the excipient of these article, selects to add the lactose of three kinds of concentration of 6%, 8%, 10% (w/v), serves as to investigate index with the product appearance after the lyophilizing.The result is following:
Definite (specification 1) of table 3. excipient
| Lactose consumption (w/v) | 6％ | 8％ | 10％ |
| Product appearance | There is slight crack on the surface | Loose, full | Loose, full |
Definite (specification 2) of table 4. excipient
Therefore the lactose consumption is 8% and 10% o'clock, and sample appearance meets the requirements, according to actual production, so confirm the excipient of the lactose of 8% (w/v) as these article.
Test Example 2
This Test Example is investigated for the consumption of active carbon.
For effectively removing bacterial endotoxin, select for use active carbon to remove bacterial endotoxin.For guaranteeing the yield of product; These article amount of activated is investigated; Select for use the active carbon of variable concentrations to make an experiment respectively; Select the active carbon of four kinds of concentration of 0.00%, 0.05%, 0.1%, 0.15% (w/v) for use, insulated and stirred absorption is 10 minutes under 50 ℃～60 ℃ conditions, check each item important indicator.The result is following:
The selection of table 5. amount of activated
| Concentration of activated carbon (w/v) | Character | Visible foreign matters | Bacterial endotoxin | Content (%) |
| 0.00％ | Colourless clear liquid | Against regulation | Against regulation | 101.8 |
| 0.05％ | Colourless clear liquid | Up to specification | Up to specification | 100.7 |
| 0.1％ | Colourless clear liquid | Up to specification | Up to specification | 91.5 |
| 0.15％ | Colourless clear liquid | Up to specification | Up to specification | 83.7 |
By drawing in the table; After these article add activated carbon adsorption; Visible foreign matters and bacterial endotoxin are all qualified, but the concentration of activated carbon of 0.1% and 0.15% (w/v) is bigger to principal agent absorption, is effectively eliminating under the bacterial endotoxin prerequisite; And the adaptation working condition, the amount of activated of confirming these article is 0.05% (w/v).
Test Example 3
This Test Example is the investigation to lyophilisation condition.
1, the mensuration of low eutectic point
Measure through electric-resistivity method, the low eutectic point of these article is-14.3 ℃.
2, confirming of lyophilisation condition:
2.1 specification 1:50mg
Sample being divided into three batches making an experiment, serves as to investigate index with the character in the freeze-dried products, moisture, content and related substance, confirms best freeze-dry process.
(1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump.
(2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off.
(3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; First temperature rises to 15 ℃, is incubated 10 hours; Second batch of temperature rises to 25 ℃, is incubated 10 hours; The 3rd batch of temperature rises to 35 ℃, is incubated 10 hours.The result is following:
The selection result of the test of table 6. lyophilisation condition (specification 1)
| Batch | First | Second batch | The 3rd batch |
| Character | The white loose block | The white loose block | The white loose block |
| Moisture (%) | 4.25 | 0.86 | 0.67 |
| Content (%) | 100.3 | 100.4 | 100.2 |
| Related substance (%) | 0.70 | 0.67 | 0.69 |
Can be known that by The above results first residual moisture is bigger, the 3rd batch of related substance slightly raises, and second batch of each item index is all up to specification, so confirm that second batch freeze-dry process is best freeze-dry process.
2.2 specification 2:100mg
Sample is divided into three batches makes an experiment, investigate index, confirm best freeze-dry process with the character in the freeze-dried products, moisture, content and related substance.
(1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours.
(2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off.
(3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 6 hours; Temperature rises to 25 ℃, first insulation 10 hours; Second batch is incubated 15 hours; The 3rd batch is incubated 20 hours.The result is following:
The selection result of the test of table 7. lyophilisation condition (specification 2)
| Batch | First | Second batch | The 3rd batch |
| Character | The white loose block | The white loose block | The white loose block |
| Moisture (%) | 4.15 | 0.91 | 0.79 |
| Content (%) | 100.1 | 100.5 | 100.2 |
| Related substance (%) | 0.67 | 0.73 | 0.70 |
Can be known that by The above results first residual moisture is bigger, second batch lower with the 3rd batch of moisture, and second batch of required freeze-drying time is shorter, so confirm that second batch freeze-dry process is best freeze-dry process.
Test Example 4
This Test Example is to confirm the scope of PH.
For investigating the suitable PH scope of these article (the pH value scope of the injection oxaliplatin of listing is 5.0～7.0), secure ph is packing behind 5.0,5.5,6.0,6.5,7.0 the sample solution respectively, after lyophilization, investigates an item index, and the result is following:
Confirming of table 8. PH scope
Therefore these article are between pH value 5.0～7.0, and each item high spot reviews index does not all have obvious variation, so confirm that the pH value scope of these article is 5.0～7.0.
Test Example 5
This Test Example is product oxaliplatin freeze-dried powder influence factor's of the present invention investigation.
1, sample preparation: prepare sample according to FORMULATION EXAMPLE 8 and FORMULATION EXAMPLE 9 described prescriptions and freeze-dry process
2, setting-out: sample is placed room temperature (25 ℃) respectively, under high temperature (60 ℃), high temperature (40 ℃), relative humidity 75%, relative humidity 92.5% and six kinds of conditions of illumination 4500Lx.
3, investigate the result: investigate each item index in sampling in the 5th day, 10 days, and be contrast with 0 day result, the result sees the following form:
Table 9. factors influencing (specification 1)
Table 10. factors influencing (specification 2)
Therefore these article each item index under 25 ℃ of conditions of room temperature does not have significant change; The condition held of relative humidity 75%, relative humidity 92.5% and illumination 4500Lx 5 days, 10 days, except that related substance slightly raise, all the other each item indexs did not have significant change; Under 40 ℃ of high temperature, 60 ℃ of conditions, related substance raises very fast, so confirm the holding conditions of these article is: airtight, and in preservation below 25 ℃.
The product of other embodiment of the present invention has also carried out identical test, and its result is similar.
Claims (9)
1. oxaliplatin medicament composition, it is characterized in that: described oxaliplatin medicament composition comprises oxaliplatin and lactose, wherein the mass ratio of oxaliplatin and lactose is 1: 12～1: 20; Described oxaliplatin medicament composition adds water for injection and the pH regulator agent is processed lyophilized injectable powder through lyophilization; The method for preparing of said lyophilized injectable powder comprises the steps:
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) use the pH regulator agent to regulate pH value and be 5.5-6.5, benefit adds to the full amount of water for injection;
3) add active carbon then, stir, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization.
2. oxaliplatin medicament composition according to claim 1 is characterized in that, the mass ratio of oxaliplatin and lactose is 1: 14～1: 18.
3. oxaliplatin medicament composition according to claim 2 is characterized in that, the mass ratio of oxaliplatin and lactose is 1: 16.
4. the method for preparing of any described oxaliplatin medicament composition of claim 1-3, it is characterized in that: described method for preparing comprises the steps:
1) takes by weighing the oxaliplatin and the lactose of recipe quantity, add the water for injection that accounts for recipe quantity 80%, after 50～60 ℃ of stirring and dissolving;
2) use the pH regulator agent to regulate pH value and be 5.5-6.5, benefit adds to the full amount of water for injection;
3) add active carbon then, stir, filter carbon removal;
4) detect the content of pH value of filtrate and oxaliplatin, detects qualified after, sterile filling is pressed partly and is filled in, and goes into freeze drying box, promptly gets after the lyophilization.
5. the method for preparing of oxaliplatin medicament composition according to claim 4, it is characterized in that: described lyophilization is divided into following three phases:
1) the pre-freeze phase: sample is put into freeze drying box, and temperature drops to-40 ℃, is incubated 3 hours, the open vacuum pump;
2) the distillation phase: the heat conductive oil inlet temperature rises to-15 ℃, is incubated 3 hours; Temperature rises to 0 ℃, is incubated 20 hours, to icing heading line off;
3) dry period: the heat conductive oil inlet temperature rises to 5 ℃, is incubated 4 hours; Temperature rises to 25 ℃, is incubated 10 hours.
6. the method for preparing of oxaliplatin medicament composition according to claim 4, it is characterized in that: described pH regulator agent is a sodium acetate.
7. the method for preparing of oxaliplatin medicament composition according to claim 4, it is characterized in that: the consumption of described active carbon is 0.05-0.15%w/v.
8. the method for preparing of oxaliplatin medicament composition according to claim 7, it is characterized in that: the consumption of described active carbon is 0.05-0.10%w/v.
9. the method for preparing of oxaliplatin medicament composition according to claim 8, it is characterized in that: the consumption of described active carbon is 0.05%w/v.
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| CN102274171A (en) * | 2011-08-04 | 2011-12-14 | 上海希迪制药有限公司 | Oxaliplatin injection |
| CN102670526B (en) * | 2012-05-10 | 2013-12-04 | 南京臣功制药股份有限公司 | Oxaliplatin freeze-dried powder injection and preparation method thereof |
| CN103230371B (en) * | 2012-05-18 | 2014-07-23 | 湖北一半天制药有限公司 | Preparation method of injection-use oxaliplatin freeze-dried preparation |
| CN103232494A (en) * | 2012-05-22 | 2013-08-07 | 湖北一半天制药有限公司 | Oxaliplatin preparation method |
| CN103599079B (en) * | 2013-11-25 | 2016-06-08 | 江苏奥赛康药业股份有限公司 | Injection lobaplatin pharmaceutical composition and its preparation method |
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| Title |
|---|
| 余邦良等.注射用奥沙利铂的制备及其质量考察.《中国药业》.2006,p.28左栏第3、4行，右栏第4-7行，表1. * |
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