CN107970210A - A kind of non-pre- dissolubility docetaxel injection - Google Patents
A kind of non-pre- dissolubility docetaxel injection Download PDFInfo
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- CN107970210A CN107970210A CN201711271054.1A CN201711271054A CN107970210A CN 107970210 A CN107970210 A CN 107970210A CN 201711271054 A CN201711271054 A CN 201711271054A CN 107970210 A CN107970210 A CN 107970210A
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- injection
- docetaxel
- dissolubility
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- dissolved
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
Abstract
The present invention relates to a kind of non-pre- dissolubility docetaxel injection, it is to be prepared with following methods, citric acid, sodium citrate are dissolved in absolute ethyl alcohol, docetaxel, polysorbate-80 for injection, injection activated carbon are sequentially added while stirring, after charging, it is stirred abundant dissolving, remove carbon with stud filter successively to filter, polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, after common filtering with microporous membrane, filtrate is sub-packed in cillin bottle, tamponade, rolls lid, labelling, packaging, is made non-pre- dissolubility docetaxel injection.The proton supply buffer anhydrous alcohol solution that the present invention is made of by use citric acid and sodium citrate, the pH value for being held essentially constant solution, with the change of temperature and time, the change unobvious in relation to material；Solve the problems, such as that docetaxel injection dissolubility difference and stability are poor, can be with room temperature storage and transport, when use, need not be pre-dissolved, and instant can match somebody with somebody；Process is few, technological process is short.
Description
Technical field
The present invention relates to a kind of non-pre- dissolubility docetaxel injection.
Background technology
After many slightly solubilities, insoluble drugs add solvent for injection, it is impossible to which dissolving is, it is necessary to be previously added specific molten immediately
Matchmaker, or dissolved in advance with the methods of heating, shaking, ultrasound, then supply Clinical practice after diluting.
Existing docetaxel injection, is divided to two bottles of packagings, one bottle is made of docetaxel and polyoxyethylene sorbitan monoleate, another bottle
It is made of 95% ethanol and water for injection.The preparation process of docetaxel injection is that docetaxel is added to polysorbate
In 80, add certain organic solvent and be diluted, filtration sterilization, freezing or decompression method remove organic solvent, filling, and are made
Concentrated solution；It is formulated by 95% injection ethanol and water for injection, it is degerming, it is filling, and dedicated solvent (13% ethanol) is made.
In multiple formulation operations, because of factors such as environment, facilities and equipment, personnel, secondary pollution is easily caused, increases clinical application patient
Risk；Medicine is toxic chemical in itself, easily causes physical impairment to makers-up.
Therefore, by varying pharmaceutical preparation technology, when manufactured Clinical practice, need not be dissolved in advance, can be instant
The non-pre- soluble preparation matched somebody with somebody is necessary.
CN1850056A discloses a kind of Taxotere lyophilized powder and preparation method thereof, there is provided the more convenient clinic of one kind
Using, more stable docetaxel freeze-dried powder-injection, but it is disadvantageous in that and adds substantial amounts of solubilizer and pharmaceutical adjunct,
The lyophilized production energy consumption of industrialization is big, and time length, needs to redissolve before use, then dilutes, and adds the possibility of microbiological contamination.
CN104546694A discloses a kind of docetaxel injection and preparation method thereof, docetaxel that raw material is 1%,
0.4% citric acid, 26% polyoxyethylene sorbitan monoleate, 17.225% absolute ethyl alcohol, 55.35% polyethylene glycol 400,
0.025% medical charcoal.CN101327206B discloses a kind of parenteral solution with injection made of docetaxel bulk pharmaceutical chemicals
And its its preparation process, lewis acid is added in parenteral solution, docetaxel is under acid condition, its chemical molecular structure
In double bond can with lewis acidic hydrogen ion formed hydrogen bond, the stabilization of double bond is added, so as to increase the stabilization of docetaxel
Property.
The content of the invention
The purpose of the present invention is for above-mentioned present situation, it is desirable to provide one kind can be with room temperature storage and transport, and when use is not required to
It is pre-dissolved, instant can matches somebody with somebody；The non-pre- dissolubility docetaxel injection that process is few, technological process is short.
The implementation of the object of the invention is that a kind of non-pre- dissolubility docetaxel injection, is prepared with following methods：
0.4-0.8g citric acids, 0.08-0.16g sodium citrates are dissolved in 30-45g absolute ethyl alcohols, it is more to sequentially add 1-3g while stirring
Xi Tasai, 30-55g polysorbate-80 for injection, 2-5g injection activated carbon, after charging, are stirred 30 minutes, fully
Dissolving, removes carbon classified filtering with stud filter 30um, stud filter 3um successively, then micro- with 1.0 μm of polytetrafluoroethylene (PTFE) successively
Hole membrane filtration, 0.22 μm of polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, finally with after 0.22um filtering with microporous membrane, by filtrate
Cillin bottle is sub-packed in, tamponade, rolls lid, labels, and packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
The invention has the advantages that：
1st, docetaxel is added in the solubilized proton supply liquid prepared, docetaxel is combined from other factors with proton
Interference, adds speed and degree, improves the stability of the non-pre- dissolubility parenteral solution of docetaxel；
2nd, the dosage of ethanol is greatly reduced, reduces the allergic reaction because of caused by amount of alcohol height in injection；
3rd, using non-aqueous technique, the foaming phenomena in transportational process is reduced, is extended the shelf life the time；
4th, a production line and its input are reduced；Process is shortened, technological process, reduces several mistakes of solvent recovery process
Pollution risk in journey；Packaging is packed by the two bottled single bottles that become, and saves packaging material；
5th, degerming using terminal, depyrogenation, adds the security of parenteral solution.
Embodiment
Citric acid, sodium citrate are dissolved in absolute ethyl alcohol by the present invention, sequentially add docetaxel while stirring, injection is gathered
Sorb ester 80, injection activated carbon, after charging, are stirred abundant dissolving, classified filtering is (successively with stud filter
30um, stud filter 3um are filtered except carbon, 1.0 μm of filtering with microporous membrane of teflon membrane filter, teflon membrane filter 0.22
μm miillpore filter aseptic filtration), finally with after filter membrane, filtrate is sub-packed in cillin bottle, tamponade, rolls lid, labels, packaging,
Non- pre- dissolubility docetaxel injection is made.
The mass ratio of citric acid-sodium citrate is 5:1.
It is of the invention to be had the advantage that compared with existing docetaxel injection：
1st, prescription is changed, the proton being made of citric acid-sodium citrate is with the addition of and supplies buffer, solve proton confession
To problem, the pH value fluctuation problem in also solving production and preserving, pH value fluctuating range is reduced to ± 0.5% by ± 40%,
The pH value being held essentially constant；With the change of temperature and time, the change unobvious in relation to material, moreover it is possible to avoid drastic conditions from drawing
The ester linkage breaking of the docetaxel side chain risen, preferably ester bond fragile in protection production and double bond, improve the steady of parenteral solution
It is qualitative；
2nd, preparation process flow is changed, former technique uses and is eventually adding lewis acid, therefore causes pH value in production
Low early and high after, fluctuating range is big, and the surfactant easily first added disturbs, and the present invention first will be more using in stirring
Xi Tasai is added in proton supply buffer solution, after the completion for the treatment of ligand complex reaction, is added other auxiliary materials, is avoided auxiliary material to network
The interference of conjunction；
3rd, the dosage of ethanol is greatly reduced, ethanol usage amount is only 1/10th of the prescription or so, ensures that solution is molten
Xie Xing, while reduce the allergic reaction because of caused by amount of alcohol height in injection；
4th, former method increases filtering times, has elongated technological process using being remixed after dissolving, filtration sterilization respectively, more
Secondary married operation considerably increases the probability polluted again, and company of our company is degerming using terminal, and depyrogenation, adds parenteral solution
Security；
5th, ratio is produced at the same time with former two production lines of concentrated solution and dedicated solvent, the workshop that can reduce by a production line is set
Standby, facility, the input of personnel, reduce middle process of clearing out a gathering place, when time shortening 24-48 is small；
6th, existing parenteral solution needs 2-8 DEG C of low-temperature storage, cold chain transportation, and the term of validity is 24 months；Note prepared by the present invention
2-25 DEG C of normal temperature storage of liquid energy, transport are penetrated, cost of transportation is reduced, adds the clinical application accessibility of remote mountain areas hospital；
7th, existing parenteral solution is placed to room temperature in use, first taking out, then is pasted bottle wall and added dedicated solvent (13% ethanol
Aqueous solution) be first pre-dissolved, then shake be diluted to administration concentration after use, dissolution velocity is slow, foam easy to foaming, it is not easy to mixes, liquid
In oily, viscosity is big, is not easy to exhaust out of medicine bottle, and operating technology requires height, and process is more, cumbersome；And easily because preparing ring
Border and the reason for operating personnel, causes the dose difference of medication, it is often more important that multi-pass operation, it is contaminated general to add liquid
Rate, need not be dissolved in advance when the present invention prepares Clinical practice, instant can be matched somebody with somebody, it is not necessary to dedicated oscillator is used,
Special formulator need not be set, substantially increase clinical position efficiency, reduced because personnel, environment, installations and facilities are brought
Security risk；
8th, by the two bottled packing timbers for becoming non-pre- soluble preparation single bottle packaging, saving half of original ordinary preparation
Material.
Citric acid, sodium citrate are dissolved in absolute ethyl alcohol by the present invention, sequentially add docetaxel while stirring, injection is gathered
Sorb ester 80, injection activated carbon, after charging, are stirred abundant dissolving, classified filtering is (successively with stud filter
30um, stud filter 3um are filtered except carbon, 1.0 μm of filtering with microporous membrane of teflon membrane filter, teflon membrane filter 0.22
μm miillpore filter aseptic filtration), finally with after filter membrane, filtrate is sub-packed in cillin bottle, tamponade, rolls lid, labels, packaging,
Non- pre- dissolubility docetaxel injection is made.
For the applicant by substantial amounts of comparative experimental research, the molar ratio for finding citric acid-sodium citrate is 5:It is right when 1
The extent of the destruction of ester bond is minimum, the optimal stability of parenteral solution, is significantly better than single with or without citric acid, malic acid or tartaric acid
Preparation, in addition, using the buffer condition of this ratio, compared to list with or without citric acid, malic acid or tartaric acid, long-term
The change that related goods and materials rise in stability test and accelerated stability test is equally lower.The result shows that (being shown in Table 1)：Common system
Agent is extremely unstable under the conditions of accelerated test condition and long-term stable experiment, and the more west of the non-pre- dissolubility for preparing of the present invention he
Parenteral solution is matched no matter under the conditions of accelerated test or again under the conditions of long-term stable experiment, total impurities without obvious change,
Have good stability.
Table 1
By table 1 as it can be seen that non-pre- dissolubility docetaxel injection prepared by the present invention can at normal temperatures be stored, transports, made
With；Preserve, transport, is easy to use, increase common cancer patient's accessibility, be one really efficient, safety is economical, conveniently
Parenteral solution.
The present invention is described in detail with specific embodiment below.
Embodiment 1, by 0.8g citric acids, 0.16g sodium citrates be dissolved in 45g absolute ethyl alcohols, sequentially adds 1g while stirring
Docetaxel, 30g polysorbate-80 for injection, 1g injection activated carbon, after charging, are stirred 30 minutes, fully molten
Solution, first uses stud filter 30um, stud filter 3um to be filtered except carbon successively, then is filtered successively with 1.0 μm of polytetrafluoroethylene (PTFE) micropores
Membrane filtration, 0.22 μm of polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, finally with 0.22um often with after filtering with microporous membrane, by filtrate
It is sub-packed in cillin bottle, tamponade, rolls lid, label, packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
Embodiment 2, with by 0.6g citric acids, 0.12g sodium citrates be dissolved in 37.5g absolute ethyl alcohols, while stirring successively plus
Enter 2g docetaxels, 42.5g polysorbate-80 for injection, 2g injection activated carbon, after charging, be stirred 30 minutes,
Fully dissolving, first uses stud filter 30um, stud filter 3um to be filtered except carbon successively, then successively with 1.0 μm of polytetrafluoroethylene (PTFE)
Filtering with microporous membrane, 0.22 μm of polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, finally with 0.22um often with after filtering with microporous membrane,
Filtrate is sub-packed in cillin bottle, tamponade, rolls lid, labelled, packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
Embodiment 3, by 0.4g citric acids, 0.08g sodium citrates be dissolved in 30g absolute ethyl alcohols, sequentially adds 3g while stirring
Docetaxel, 55g polysorbate-80 for injection, 3g injection activated carbon, after charging, are stirred 30 minutes, fully molten
Solution, first uses stud filter 30um, stud filter 3um to be filtered except carbon successively, then is filtered successively with 1.0 μm of polytetrafluoroethylene (PTFE) micropores
Membrane filtration, 0.22 μm of polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, finally with 0.22um often with after filtering with microporous membrane, by filtrate
It is sub-packed in cillin bottle, tamponade, rolls lid, label, packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
Embodiment 4, by 0.5g citric acids, 0.1g sodium citrates be dissolved in 35g absolute ethyl alcohols, sequentially adds 2.5g while stirring
Docetaxel, 50g polysorbate-80 for injection, 1g injection activated carbon, after charging, are stirred 30 minutes, fully molten
Solution, first uses stud filter 30um, stud filter 3um to be filtered except carbon successively, then is filtered successively with 1.0 μm of polytetrafluoroethylene (PTFE) micropores
Membrane filtration, 0.22 μm of polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, finally with 0.22um often with after filtering with microporous membrane, by filtrate
It is sub-packed in cillin bottle, tamponade, rolls lid, label, packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
Embodiment 5, by 0.75g citric acids, 0.15g sodium citrates be dissolved in 40g absolute ethyl alcohols, sequentially adds while stirring
1.5g docetaxels, 40 are penetrated with polyoxyethylene sorbitan monoleate, 0.5g injection activated carbon, after charging, are stirred 30 minutes, fully
Dissolving, first uses stud filter 30um, stud filter 3um to be filtered except carbon successively, then successively with 1.0 μm of polytetrafluoroethylene (PTFE) micropores
Membrane filtration, 0.22 μm of polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, will finally be filtered with 0.22um often with after filtering with microporous membrane
Liquid is sub-packed in cillin bottle, tamponade, rolls lid, is labelled, and packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
Claims (2)
- A kind of 1. non-pre- dissolubility docetaxel injection, it is characterised in that：It is to be prepared with following methods：By 0.4-0.8g lemons Acid, 0.08-0.16g sodium citrates are dissolved in 30-45g absolute ethyl alcohols, sequentially add 1-3g docetaxels, 30-55g notes while stirring Penetrate and use polyoxyethylene sorbitan monoleate, 2-5g injection activated carbon, after charging, be stirred 30 minutes, fully dissolving, use stud successively Filter 30um, stud filter 3um remove carbon classified filtering, then successively with 1.0 μm of polytetrafluoroethylene (PTFE) filtering with microporous membrane, 0.22 μm polytetrafluoroethylene (PTFE) miillpore filter aseptic filtration, finally with after 0.22um filtering with microporous membrane, cillin bottle is sub-packed in by filtrate, is pressed Plug, rolls lid, labels, and packaging, is made the non-pre- dissolubility docetaxel injections of 100ml.
- A kind of 2. preparation method of non-pre- dissolubility docetaxel injection according to claim 1, it is characterised in that：Lemon The mass ratio of acid-sodium citrate is 5:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711271054.1A CN107970210A (en) | 2017-12-05 | 2017-12-05 | A kind of non-pre- dissolubility docetaxel injection |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711271054.1A CN107970210A (en) | 2017-12-05 | 2017-12-05 | A kind of non-pre- dissolubility docetaxel injection |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102451155A (en) * | 2010-10-26 | 2012-05-16 | 海南中化联合制药工业股份有限公司 | Prescription and preparation method of docetaxel injection |
| CN102895183A (en) * | 2012-11-05 | 2013-01-30 | 江苏红豆杉生物科技股份有限公司 | Cabazitaxel for injection and preparation method thereof |
| CN103054798A (en) * | 2005-08-31 | 2013-04-24 | 阿布拉科斯生物科学有限公司 | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
| CN103585142A (en) * | 2013-11-27 | 2014-02-19 | 哈尔滨誉衡药业股份有限公司 | Medicine composition containing docetaxel |
| CN104546694A (en) * | 2013-10-15 | 2015-04-29 | 悦康药业集团有限公司 | Docetaxel injection and preparation method thereof |
| CN105395477A (en) * | 2015-11-26 | 2016-03-16 | 李宏 | Docetaxel injection and preparation method thereof |
-
2017
- 2017-12-05 CN CN201711271054.1A patent/CN107970210A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054798A (en) * | 2005-08-31 | 2013-04-24 | 阿布拉科斯生物科学有限公司 | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
| CN102451155A (en) * | 2010-10-26 | 2012-05-16 | 海南中化联合制药工业股份有限公司 | Prescription and preparation method of docetaxel injection |
| CN102895183A (en) * | 2012-11-05 | 2013-01-30 | 江苏红豆杉生物科技股份有限公司 | Cabazitaxel for injection and preparation method thereof |
| CN104546694A (en) * | 2013-10-15 | 2015-04-29 | 悦康药业集团有限公司 | Docetaxel injection and preparation method thereof |
| CN103585142A (en) * | 2013-11-27 | 2014-02-19 | 哈尔滨誉衡药业股份有限公司 | Medicine composition containing docetaxel |
| CN105395477A (en) * | 2015-11-26 | 2016-03-16 | 李宏 | Docetaxel injection and preparation method thereof |
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