CN108186562A - A kind of production technology of busulfan parenteral solution - Google Patents
A kind of production technology of busulfan parenteral solution Download PDFInfo
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- CN108186562A CN108186562A CN201810271704.0A CN201810271704A CN108186562A CN 108186562 A CN108186562 A CN 108186562A CN 201810271704 A CN201810271704 A CN 201810271704A CN 108186562 A CN108186562 A CN 108186562A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
The invention discloses a kind of production technologies of busulfan parenteral solution, include the following steps：1) by dried and clean air, N2It is passed through with one or more in Ar with liquid isolator and isolated production line；2) by mass, 67 parts of PEG400 are added in Agitation Tank, are passed through dried and clean air, N2In one or more to PEG400 in Ar；1 20 parts of N are added in into PEG400, N dimethylacetylamides obtain mixed solvent；By 1 10 parts of N, N dimethylacetylamides are added in 0.6 part of busulfan bulk pharmaceutical chemicals, obtain busulfan concentrated solution；3) busulfan concentrated solution is added in toward in the mixed solvent, using the N of remaining recipe quantity, N dimethylacetylamides rinse the container of dress bulk pharmaceutical chemicals, stir, and filtering obtains finished product.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of production technology of busulfan parenteral solution.
Background technology
At present, busulfan listing preparation has Busulfex and busulfan parenteral solution, and active constituent is busulfan, is a kind of knot
Crystalline substance powder, chemical constitution are as follows：
Water-soluble very poor (being slightly soluble in water) of busulfan is met water and is easily decomposed so that and the oral absorption of Busulfex is poor,
Dosage is larger, and active material (carbonium ion) serious stimulating intestine and stomach after degrading in enteron aisle.Therefore, existing market
On preparation based on parenteral solution.
According to FDA orange papers (version of in August, 2017), busulfan parenteral solution manufacturer only has 4, and original is ground as Otsuka,
Trade name BUSULFEX (Bai Shufei).The prescription that original is ground is described as：60 milligrams of busulfans are dissolved in 3.3mL N, N- dimethyl second
Amide (DMAC) and 6.7mL polyethylene glycol 400s, in NF.Auxiliary material DMAC and polyethylene glycol 400 (PEG400) are extremely easy in prescription
Water suction so that Environmental Water is extremely easily brought into final products in technical process, and active constituent busulfan is caused to drop
Solution；Meanwhile auxiliary material n,N-dimethylacetamide (DMAC) is a kind of extremely strong solvent of corrosivity, and the production in technical process is set
Standby requirement is high.
For how to control moisture problem in product, have some patent reports.
Patent CN105726467A is refined in process using the method for distillation, 4A molecular sieves or cellulose membrane infiltration evaporation
Auxiliary material PEG 400, and add in activated carbon adsorption.However refining the method for distillation and cellulose membrane infiltration evaporation during PEG400 increases
Technical process, it is difficult to realize big production；4A molecular sieves have the risk for introducing inorganic impurity, are unfavorable for drug safety；Meanwhile
PEG400 viscosity is very big, and filtration resistance is big, and activated carbon is added in technique and further increases technology difficulty.
Patent CN104546698A with other components using being mixed to get preparation again after inert gas saturation PEG400.So
And the moisture of inert gas in itself will be far below the moistures of PEG400 in itself, be possible to obtain water content lower
PEG400, the water removal effect being amplified in big production need further to be evaluated；Still further aspect, PEG400 water imbibitions itself compared with
By force, if do not controlled in process with pendular ring border, the risk that moisture is introduced in product is still very high.Therefore this method does not solve such as
The problem of moisture introduces risk in what control technical process.
Patent CN103446045B uses nitrogen saturation auxiliary material DMA, PEG400 in process.However the volatility of auxiliary material DMAC
It is extremely strong, it volatilizees faster after being passed through nitrogen, causes the risk for feeding intake inaccurate height in production；Meanwhile the auxiliary material of saturation nitrogen is still
Environmental Water is so very likely adsorbed, this method does not address how that moisture introducing risk is asked in control technical process still
Topic.
More than patent do not propose it is a kind of it is simple and feasible, be easy in the solution technical process produced greatly and product moisture and introduce
The solution of risk does not also propose effective measures to the corrosion problems of auxiliary material DMAC.
For the stability problem of product, there are also patent reports.
Patent CN102151257B adds in the stabilizer of 0.01%-5%w/v on the basis of original grinds prescription.However, prescription
It is more complicated to mean that drug safety risk increases, more data is needed to prove the superiority compared with original grinds prescription, it is short-term on
The difficulty in city is big.
Temperature when patent CN103446045B controls are with liquid is at 9 DEG C -11 DEG C.However, the solidification point of auxiliary material PEG400 exists
Between 2-8 DEG C, technology difficulty is larger, and too low temperature is easy to cause moisture condensation in environment, is finally brought into product.
Invention content
To solve problems of the prior art, the present invention provides a kind of production technologies of busulfan parenteral solution.It should
Method controllability is strong, easy to operate, is easy to industrialized production.
In order to achieve the object of the present invention, the technical solution adopted by the present invention is：
A kind of production technology of busulfan parenteral solution, includes the following steps：
1) by dried and clean air, N2It is passed through with one or more in Ar with liquid isolator and isolated production line；
2) 67 parts of PEG400 are added in Agitation Tank, are passed through dried and clean air, N2It is arrived with one or more in Ar
In PEG400；10-20 parts of n,N-dimethylacetamide are added in into PEG400, obtain mixed solvent；
1-10 parts of n,N-dimethylacetamide are added in 0.6 part of busulfan bulk pharmaceutical chemicals, obtain busulfan concentrated solution；
3) busulfan concentrated solution is added in toward in the mixed solvent, dress is rinsed using the n,N-dimethylacetamide of remaining recipe quantity
The container of bulk pharmaceutical chemicals stirs, and filtering obtains finished product.
Preferably, moisture≤0.1% of control material；From source control material moisture, the work of auxiliary material water removal is reduced
Skill step reduces technical process.
Preferably, the pH=4.5-6.5 of PEG400 is conducive to the stability of product.
Optimize feed way, first recipe quantity busulfan is dissolved using 33 parts of DMAC, then with 100-400 revs/min of speed
Degree is mixed with 67 parts of DMAC-PEG400, it is ensured that solution is uniformly mixed.
Preferably, control production line environment temperature is 20 DEG C -25 DEG C, humidity 20RH%-50RH%.It is produced in totally enclosed type
On line, pass through dried and clean air, N2Or remaining dry gas, ambient humidity is maintained, auxiliary material water suction risk substantially reduces, and can
Control property is strong, easy to operate.
Preferably, the described the 2) step, control is with liquid isolator humidity and isolated production line humidity：<30RH%；
Filter method of the present invention is as follows：
A) inceptive filtering：Liquid is filtered from Agitation Tank to surge tank, filter pressure is not more than 0.2Mpa；
B) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, by 1-4 tandem
Filter, filter pressure are not more than 0.2Mpa；
C it is) that liquid after secondary filter is filling, fill N2, jump a queue, roll lid, obtain finished product.
The filter type can ensure that microbial stability of the liquid in filling period.
Preferably, filter membrane material is applied in combination for one kind in PVDF, PES, TFE or two kinds of filter membranes in secondary filter；
The filter of use more than unlike material, carries out appropriate process combination, can solve auxiliary material n,N-dimethylacetamide in prescription
Corrosion problems.
The beneficial effects of the present invention are：
1st, prior art refines auxiliary material PEG 400 using the method for distillation, 4A molecular sieves or cellulose membrane infiltration evaporation；Or
Nitrogen saturation auxiliary material DMA, PEG400；Or it is protected with nitrogen in liquid.But since auxiliary material water imbibition is extremely strong, if in technique not
Ambient humidity is controlled, the unqualified risk of moisture is larger in product, and the requirement of technique time limit is very short, is unfavorable for commercialization amplification production.
This technique controls DMA, PEG400 moisture from source, it is possible to reduce the processing step of auxiliary material water removal reduces technical process；It is sealing entirely
On enclosed production line, pass through dried and clean air, N2Or remaining dry gas maintains ambient humidity 20RH%-50RH%, auxiliary material
Water suction risk substantially reduces, and controllability is strong, easy to operate.
2nd, the pH=4.5-6.5 of control auxiliary material PEG400；20-25 DEG C of room temperature matches liquid；Optimize feed way, first using part
The DMAC dissolving busulfans of recipe quantity, are then mixed with 100-400 revs/min with DMAC-PEG400 solvents, are ground prescription with original and are protected
It holds consistent.
3rd, filter membrane material is applied in combination for one kind in PVDF, PES, TFE or two kinds of filter membranes in secondary filter；Use with
The filter of upper unlike material carries out appropriate process combination, can solve the corrosivity of auxiliary material n,N-dimethylacetamide in prescription
Problem.
Specific embodiment
In order to it is clearer, explain purpose of the present invention technical solution in detail, below by related embodiment to this hair
It is bright to be described further.Following embodiment is only to illustrate the implementation of the present invention, does not limit the protection of the present invention
Range.
Embodiment 1
A kind of production technology of busulfan parenteral solution, includes the following steps：
1) by dried and clean air, N2It is passed through with one or more in Ar with liquid isolator and isolated production line；
2) by mass, 67 parts of PEG400 are added in Agitation Tank, are passed through dried and clean air, N2With it is a kind of in Ar or
Person is a variety of in PEG400；1 part of n,N-dimethylacetamide is added in into PEG400, obtains mixed solvent；
10 parts of n,N-dimethylacetamide are added in 0.6 part of busulfan bulk pharmaceutical chemicals, obtain busulfan concentrated solution；
3) busulfan concentrated solution is added in toward in the mixed solvent, dress bulk pharmaceutical chemicals is rinsed using 12 parts of n,N-dimethylacetamide
Container, stir, filtering, obtain finished product.
Embodiment 2
A kind of production technology of busulfan parenteral solution, includes the following steps：
1) by dried and clean air, N2It is passed through with one or more in Ar with liquid isolator and isolated production line；
2) by mass, 67 parts of PEG400 are added in Agitation Tank, are passed through dried and clean air, N2With it is a kind of in Ar or
Person is a variety of in PEG400；20 parts of n,N-dimethylacetamide are added in into PEG400, obtain mixed solvent；
1 part of n,N-dimethylacetamide is added in 0.6 part of busulfan bulk pharmaceutical chemicals, obtains busulfan concentrated solution；
3) busulfan concentrated solution is added in toward in the mixed solvent, dress bulk pharmaceutical chemicals is rinsed using 12 parts of n,N-dimethylacetamide
Container, stir, filtering, obtain finished product.
Embodiment 3
A kind of production technology of busulfan parenteral solution, includes the following steps：
1) by dried and clean air, N2It is passed through with one or more in Ar with liquid isolator and isolated production line；
2) by mass, 67 parts of PEG400 are added in Agitation Tank, are passed through dried and clean air, N2With it is a kind of in Ar or
Person is a variety of in PEG400；10 parts of n,N-dimethylacetamide are added in into PEG400, obtain mixed solvent；
5 parts of n,N-dimethylacetamide are added in 0.6 part of busulfan bulk pharmaceutical chemicals, obtain busulfan concentrated solution；
3) busulfan concentrated solution is added in toward in the mixed solvent, dress bulk pharmaceutical chemicals is rinsed using 16 parts of n,N-dimethylacetamide
Container, stir, filtering, obtain finished product.
Embodiment 4
The present embodiment is on the basis of embodiment 1：
Moisture≤0.1% of control material.
The pH=4.5 of PEG400.
Embodiment 5
The present embodiment is on the basis of embodiment 2：
Moisture≤0.1% of control material；
The pH=6.5 of PEG400.
It is 20 DEG C -25 DEG C to control production line environment temperature, humidity 20RH%-50RH%.
Described the 2) step, control is with liquid isolator humidity and isolated production line humidity<30RH%.
Embodiment 6
The present embodiment is on the basis of embodiment 3：
The filter method is as follows：
A) inceptive filtering：Liquid is filtered from Agitation Tank to surge tank, filter pressure is not more than 0.2Mpa；
B) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, by 1-4 tandem
Filter, filter pressure are not more than 0.2Mpa；
C it is) that liquid after secondary filter is filling, fill N2, jump a queue, roll lid, obtain finished product.
Embodiment 7
The present embodiment is on the basis of embodiment 1：
The filter method is as follows：
A) inceptive filtering：Liquid is filtered from Agitation Tank to surge tank, filter pressure is not more than 0.2Mpa；
B) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, by 1-4 tandem
Filter, filter pressure are not more than 0.2Mpa；
C it is) that liquid after secondary filter is filling, fill N2, jump a queue, roll lid, obtain finished product.
Filter membrane material is a kind of or two kinds of filter membranes combination in PVDF, PES and TFE in secondary filter.
Embodiment 8
The present embodiment is on the basis of embodiment 1：
The filter method is as follows：
A) inceptive filtering：Liquid is filtered from Agitation Tank to surge tank, filter pressure is not more than 0.2Mpa；
B) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, by 1-4 tandem
Filter, filter pressure are not more than 0.2Mpa；
C it is) that liquid after secondary filter is filling, fill N2, jump a queue, roll lid, obtain finished product.
Filter membrane material is a kind of or two kinds of filter membranes combination in PVDF, PES and TFE in secondary filter.
Described the 3) step, is stirred with 100-400 revs/min of speed.
Embodiment 9
A kind of production technology of busulfan parenteral solution for being easy to produce greatly, the technique are as follows：
1) control ambient temperature and humidity, 20 DEG C -25 DEG C, 20RH%-50RH%；
2) by dried and clean air, N2, one or more are passed through with liquid isolator and isolated production line 10- in Ar
100min, control is with liquid isolator humidity and isolated production line humidity：<30RH%；
3) 67 parts of PEG400 are added to Agitation Tank, are passed through one or more in dried and clean air, N2 or Ar and arrive
In PEG400,30-60min is purged；
4) 1-20 parts of DMAC are added in the API of recipe quantity, stir 20min API concentrated solutions derived above；
5) 1-10 parts of DMAC are added in into PEG400, more than 10min is stirred, obtains mixed solvent；
6) API concentrated solutions are added in toward in the mixed solvent, uses n,N-dimethylacetamide (N, the N- diformazan of remaining recipe quantity
Yl acetamide dosage amounts to 33 parts) dress API concentrated solution containers are rinsed, it stirs 10 minutes or more, obtains busulfan parenteral solution liquid；
7) inceptive filtering：It is connected using filter 1-3 that material is PVDF, PES or TFE, by liquid from Agitation Tank mistake
Filter to surge tank, filter pressure is not more than 0.01-0.2Mpa；
8) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, by 1-4 tandem
Filter, filter pressure are not more than 0.01-0.2Mpa；
9) filter membrane material is applied in combination for one kind in PVDF, PES, TFE or two kinds of filter membranes in secondary filter；
10) liquid after secondary filter is filling to 13mm bore cillin bottles, head space fills N2, jump a queue, roll lid, obtain finished product.
Embodiment 10
A kind of production technology of busulfan parenteral solution for being easy to produce greatly, the technique are as follows：
1) control ambient temperature and humidity, 20 DEG C -25 DEG C,<45RH%；
2) dried and clean air is passed through with liquid isolator and isolated production line 30min, control is with liquid isolator humidity
With isolated production line humidity：<30RH%；
3) 67 parts of PEG400 are added to Agitation Tank, be passed through in dried and clean N2 to PEG400, purge 45min；
4) 12 parts of DMAC are added in the API of recipe quantity, stir 20min API concentrated solutions derived above；
5) 18 parts of DMAC are added in into PEG400, more than 10min is stirred, obtains mixed solvent；
6) API concentrated solutions are added in toward in the mixed solvent, rinses dress API concentrated solution containers using 3 parts of DMAC, stir 10 minutes
More than, obtain busulfan parenteral solution liquid；
7) inceptive filtering：Liquid is filtered from Agitation Tank to surge tank, filtration pressure using 1 filter that material is PTFE
Power is not more than 0.2Mpa；
8) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, by 2 tandem mistakes
Filter, filter pressure are not more than 0.2Mpa；
9) filter membrane material is TFE in secondary filter.
One of PEG400 described in prescription, producer Croda, DOW, Applichem, it is stringent to screen auxiliary material producer,
DMA, PEG400 moisture are controlled from source.
Table 1, present invention self-control sample and the former stability contrast for grinding product.
Embodiment described above only expresses the specific embodiment of the present invention, and description is more specific and detailed, but simultaneously
Cannot the limitation to the scope of the claims of the present invention therefore be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect range.
Claims (8)
1. a kind of production technology of busulfan parenteral solution, which is characterized in that include the following steps：
1) by dried and clean air, N2It is passed through with one or more in Ar with liquid isolator and isolated production line；
2) by mass, 67 parts of PEG400 are added in Agitation Tank, are passed through dried and clean air, N2With it is a kind of in Ar or more
In kind to PEG400；1-20 parts of n,N-dimethylacetamide are added in into PEG400, obtain mixed solvent；
1-10 parts of n,N-dimethylacetamide are added in 0.6 part of busulfan bulk pharmaceutical chemicals, obtain busulfan concentrated solution；
3) busulfan concentrated solution is added in toward in the mixed solvent, dress raw material is rinsed using the n,N-dimethylacetamide of remaining recipe quantity
The container of medicine stirs, and filtering obtains finished product.
2. the production technology of busulfan parenteral solution according to claim 1, which is characterized in that the moisture of control material≤
0.1%.
3. the production technology of busulfan parenteral solution according to claim 1, which is characterized in that the pH=4.5-6.5 of PEG400.
4. the production technology of busulfan parenteral solution according to claim 1, which is characterized in that control production line environment temperature be
20 DEG C -25 DEG C, humidity 20RH%-50RH%.
5. the production technology of busulfan parenteral solution according to claim 1, which is characterized in that the described the 2) step, control is with liquid
Isolator humidity and isolated production line humidity<30RH%.
6. the production technology of busulfan parenteral solution according to claim 1, which is characterized in that the filter method is as follows：
A) inceptive filtering：Liquid is filtered from Agitation Tank to surge tank, filter pressure is not more than 0.2Mpa；
B) secondary filter：By surge tank inner liquid medicine, wear long wall system, in isolated production line, is filtered by 1-4 tandem
Device, filter pressure are not more than 0.2Mpa；
C it is) that liquid after secondary filter is filling, fill N2, jump a queue, roll lid, obtain finished product.
7. the production technology of busulfan parenteral solution according to claim 6, which is characterized in that filter membrane material is in secondary filter
A kind of or two kinds of filter membranes combination in PVDF, PES and TFE.
8. the production technology of busulfan parenteral solution according to claim 1, which is characterized in that the described 3) step, with 100-400
Rev/min speed stirring.
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| CN201810271704.0A CN108186562B (en) | 2018-03-29 | 2018-03-29 | A kind of production technology of busulfan injection |
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| CN201810271704.0A CN108186562B (en) | 2018-03-29 | 2018-03-29 | A kind of production technology of busulfan injection |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446045A (en) * | 2012-06-01 | 2013-12-18 | 四川科瑞德凯华制药有限公司 | Stable busulfan injection |
| CN104546698A (en) * | 2014-12-17 | 2015-04-29 | 华润双鹤药业股份有限公司 | Busulfan injection and preparation method thereof |
-
2018
- 2018-03-29 CN CN201810271704.0A patent/CN108186562B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446045A (en) * | 2012-06-01 | 2013-12-18 | 四川科瑞德凯华制药有限公司 | Stable busulfan injection |
| CN104546698A (en) * | 2014-12-17 | 2015-04-29 | 华润双鹤药业股份有限公司 | Busulfan injection and preparation method thereof |
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