CN106924195A - A kind of lyophilized technique of injection Paclitaxel liposome composition - Google Patents
A kind of lyophilized technique of injection Paclitaxel liposome composition Download PDFInfo
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- CN106924195A CN106924195A CN201511031953.5A CN201511031953A CN106924195A CN 106924195 A CN106924195 A CN 106924195A CN 201511031953 A CN201511031953 A CN 201511031953A CN 106924195 A CN106924195 A CN 106924195A
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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
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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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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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Abstract
The present invention provides injection Paclitaxel liposome composition obtained in a kind of new freeze drying process, specifically related to a kind of lyophilization cycle is short, low cost, steady quality are homogeneous, product appearance is good and the injection Paclitaxel liposome composition of suitable production, said composition process is simple, and lyophilized rear preparation stabilization, be conducive to industrialized production, reduce production cost, it is to avoid the fluctuating change of liposomal particle size, ensure the performance of drug effect, improve the security of clinical application.
Description
Technical field
The present invention relates to a kind of lyophilized technique method for shortening the injection Paclitaxel liposome composition freeze-drying cycle.
Background technology
Paclitaxel injection in 1992 by U.S. FDA approval listing tumour first-line treatment medicine, but taxol be insoluble in water and
Many pharmaceutical medias, therefore, the parenteral solution at home and abroad listing at present be by taxol be dissolved in Cremophor EL with it is anhydrous
The preparation being made in the double solvent of ethanol.Cremophor EL in double solvent in vivo can the release of promotion organization amine,
Make human body produce the incidence of allergic reaction, milder hypersensitivity reaction to be up to 50%, or even threat to life, and Japanese yew can be aggravated
The toxicities such as peripheral nerve toxicity, generation hepatotoxicity, the influence antitumous effect of alcohol, limit traditional paclitaxel injection
Clinical practice.
The targeting of liposome, low toxicity, it is efficient the advantages of, increasingly recognize but because liposome existence and stability is poor by people
Problem, easily there is aggregation, fusion and Medicated Permeation during storage, and main membrane material is easily aoxidized, hydrolyzed.In order to solve
Above-mentioned liposome stability problem not high, presently disclosed lyophilized formulations and preparation method thereof are generally vacuum freeze drying, spraying
Drying, supercritical fluid technique etc..
Wherein, liposome is made by freeze drying powder injection using freeze-drying, its holding time in vitro can not only be greatly prolonged,
Also it is avoided that medicine produces denaturation simultaneously, is protected oxidizable material in medicine, and microorganism cannot almost be carried out, from
And improve the physics and chemical stability of liposome.Such as the patent of invention of Shanghai Ai Lisi Pharmaceutical Technology Co., Ltd
A kind of liposome composition of stabilization is disclosed in CN200610028725.7A, by saturated phospholipid and cholesterol as into membrane lipid,
Add vitamin E as antioxidant, using sucrose as freeze-dried excipient, prepared using the method for thin film evaporation-freeze-drying, this
Planting liposome can be used as the carrier of anti-cancer medicine paclitaxel.The patent of invention of Qingdao Dong Hui medical sci-teches Development Co., Ltd
CN201310376983.4 discloses a kind of Docetaxel for Injection nanoparticle and preparation method thereof, is prepared using freeze-drying.
But, above-mentioned freeze drying process there is problems：
Lyophilization cycle is long, influences production capacity, and required input cost is high, additionally, because mostly with actual system in actual production process
Product temperature degree is major control temperature, there is larger variable and is difficult to accomplish that front and rear batch products are stable and controllable for quality, causes to criticize and criticizes it
Between product quality heterogeneity, and then have an effect on product appearance color and luster, shape and envelop rate etc., percent defective is high in production process.
The present invention is directed to above-mentioned technical problem, there is provided a kind of lyophilization cycle is short, low cost, steady quality are homogeneous, product appearance
It is good, improve yield and be adapted to the injection Paclitaxel liposome composition of production, said composition process is simple, and it is lyophilized after system
Agent stabilization, is conducive to large-scale industrial production, reduces production cost, it is to avoid the fluctuating change of liposomal particle size, it is ensured that
The performance of drug effect, improves the security of clinical application.
The content of the invention
The present invention provides injection Paclitaxel liposome composition obtained in a kind of new pre-freeze method.
The freeze drying process of the preparation injection Paclitaxel liposome that the present invention is provided, comprises the steps of：
During the Japanese yew raw polyol of recipe quantity, lecithin, cholesterol first are dissolved in into isopropanol or alcohol solvent, 50~60 DEG C of constant temperature are removed
Solvent, adds the amino acid and mannitol or the aqueous solution of glucose dissolved with recipe quantity, after dissolving, with ultrasonic wave or high-pressure homogenization
Pump treatment, quantitative separating enters in the bottle container of 30ml XiLin, places in freeze drier, and solution was dropped rapidly in 0.5~2 hour
To -50 DEG C~-80 DEG C, and 4~8 hours are incubated, obtain freezes body, application of vacuum makes vacuum less than 10pa, then by freezes body
- 5 DEG C were warming up in 0.1~2 hour, 1~4 hour is incubated, then freezes body was warming up to 30 DEG C, insulation 3~6 in 1~2 hour
Hour, nitrogen, helium or argon gas are passed through, obtain Paclitaxel liposome preparation.
The freeze drying process that the present invention is provided, preferably comprises the steps of：
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 50~60 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus 1.4g containing lysine
5% glucose solution dissolving film, be homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of filter membrane mistake
Bacterium is filtered, is sub-packed in 30ml cillin bottles, placed in freeze drier, solution was rapidly decreased to -60 DEG C in 0.5~2 hour
~-70 DEG C, and 6~8 hours are incubated, freezes body is obtained, application of vacuum makes vacuum less than 10pa, then by freezes body 0.1~0.5
- 5 DEG C are warming up in hour, 1~4 hour is incubated, then freezes body was warming up to 25~35 DEG C in 1~2 hour, insulation 4~6 is small
When, nitrogen, helium or argon gas are passed through, obtain Paclitaxel liposome preparation.
More preferably：
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 50~60 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus 1.4g containing lysine
5% glucose solution dissolving film, be homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of filter membrane mistake
Bacterium is filtered, is sub-packed in 30ml cillin bottles, placed in freeze drier, solution was rapidly decreased to -65 DEG C in 1 hour, and
Insulation 8 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body was warming up in 0.5 hour
- 5 DEG C, 2 hours are incubated, then freezes body was warming up to 30 DEG C in 1 hour, be incubated 4 hours, be passed through nitrogen, helium or argon
Gas, obtains appearance uniform, off-white color bulk Paclitaxel liposome preparation, content of taxol 100%, envelop rate 99%, volume
Average grain diameter 130nm, peroxidase 12 %, moisture 1%, overall lyophilization cycle 16.5 hours.
The present invention is processed by the cooling to liquid, shortens lyophilization cycle, reduces production cost, is improve product quality and is obtained
Rate, is conducive to industrialized production.
Specific embodiment
Embodiment 1：
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 50 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus containing lysine 1.4g's
5% glucose solution dissolving film, is homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of membrane filtration
It is degerming, it is sub-packed in 30ml cillin bottles, place in freeze drier, solution was rapidly decreased to -65 DEG C in 1 hour, and protect
Temperature 8 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body is warming up into -5 DEG C in 0.3 hour,
Insulation 4 hours, then freezes body was warming up to 30 DEG C in 1 hour, 4 hours are incubated, nitrogen, helium or argon gas are passed through, obtain
Paclitaxel liposome preparation, obtains the off-white color bulk Paclitaxel liposome preparation of appearance uniform, content of taxol 100%, envelop rate
99%, average grain diameter 130nm, peroxidase 12 %, overall lyophilization cycle 18.3 hours.
Embodiment 2：
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 60 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus containing lysine 1.4g's
5% glucose solution dissolving film, is homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of membrane filtration
It is degerming, it is sub-packed in 30ml cillin bottles, place in freeze drier, solution was rapidly decreased to -50 DEG C in 0.5 hour, and protect
Temperature 7 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body is warming up into -5 DEG C in 1.5 hours,
Insulation 3 hours, then freezes body was warming up to 35 DEG C in 1 hour, 4 hours are incubated, nitrogen, helium or argon gas are passed through, obtain
Paclitaxel liposome preparation, obtains the off-white color bulk Paclitaxel liposome preparation of appearance uniform, content of taxol 98%, envelop rate
99%, average grain diameter 119nm, peroxide 1%, overall lyophilization cycle 17 hours.
Embodiment 3：
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 55 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus containing lysine 1.4g's
5% glucose solution dissolving film, is homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of membrane filtration
It is degerming, it is sub-packed in 30ml cillin bottles, place in freeze drier, solution was rapidly decreased to -65 DEG C in 1 hour, and protect
Temperature 8 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body is warming up into -5 DEG C in 1 hour,
Insulation 2 hours, then freezes body was warming up to 30 DEG C in 1 hour, 4 hours are incubated, nitrogen, helium or argon gas are passed through, obtain
Paclitaxel liposome preparation, obtains the off-white color bulk Paclitaxel liposome preparation of appearance uniform, content of taxol 99%, envelop rate
99%, average grain diameter 125nm, peroxidase 12 %, overall lyophilization cycle 17 hours.
Embodiment 4：
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 50~60 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus 1.4g containing lysine
5% glucose solution dissolving film, be homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of filter membrane mistake
Bacterium is filtered, is sub-packed in 30ml cillin bottles, placed in freeze drier, solution was rapidly decreased to -65 DEG C in 2 hours, and
Insulation 8 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body was warming up in 0.1 hour
- 5 DEG C, 3 hours are incubated, then freezes body was warming up to 25 DEG C in 1 hour, be incubated 4 hours, be passed through nitrogen, helium or argon
Gas, obtains Paclitaxel liposome preparation.Content of taxol 100%, envelop rate 100%, average grain diameter 110nm, peroxidase 12 %,
Overall lyophilization cycle 18.1 hours.
Embodiment 5
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 55 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus containing lysine 1.4g's
5% mannitol solution dissolving film, is homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of membrane filtration
It is degerming, it is sub-packed in 30ml cillin bottles, place in freeze drier, solution was rapidly decreased to -65 DEG C in 2 hours, and protect
Temperature 8 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body is warming up into -5 DEG C in 0.3 hour,
Insulation 3 hours, then freezes body was warming up to 25 DEG C in 1 hour, 4 hours are incubated, nitrogen, helium or argon gas are passed through, obtain
Paclitaxel liposome preparation, obtains the off-white color bulk Paclitaxel liposome preparation of appearance uniform, content of taxol 98%, envelop rate
98%, average grain diameter 140nm, peroxide 3%, overall lyophilization cycle 18.3 hours.
Embodiment 6
First the taxol 6.0g of recipe quantity, refined lecithin 72g and cholesterol 10.8g are put in round-bottomed flask, plus ethanol in proper amount
Make to be completely dissolved into clear solution into said mixture, put 55 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus containing lysine 1.4g's
5% mannitol solution dissolving film, is homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then with 0.2 μm of membrane filtration
It is degerming, it is sub-packed in 30ml cillin bottles, place in freeze drier, solution was rapidly decreased to -65 DEG C in 1 hour, and protect
Temperature 8 hours, obtains freezes body, and application of vacuum makes vacuum less than 10pa, then freezes body is warming up into -5 DEG C in 0.5 hour,
Insulation 2 hours, then freezes body was warming up to 30 DEG C in 1 hour, 4 hours are incubated, nitrogen, helium or argon gas are passed through, obtain
Paclitaxel liposome preparation, obtains the off-white color bulk Paclitaxel liposome preparation of appearance uniform, content of taxol 99%, envelop rate
99%, average grain diameter 130nm, peroxidase 12 %, overall lyophilization cycle 16.5 hours.
Comparative example 1：
Note is prepared according to the lyophilized technique method provided in Chinese invention patent CN201310376983 specification specific embodiments
Penetrate and use Paclitaxel liposome：
Injection taxol 6.0g, refined lecithin 72g and cholesterol 10.8g is weighed to put in round-bottomed flask, plus ethanol in proper amount is extremely
Make to be completely dissolved into clear solution in said mixture, put 50 DEG C of drying under reduced pressure film forming of water bath with thermostatic control, plus containing lysine 1.4g's
5% mannitol solution dissolving film, is homogenized with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, then is removed with 0.2 μm of membrane filtration
Bacterium, is sub-packed in 30ml cillin bottles, places in freeze drier, and the temperature of lyophilized separator for container is reduced into less than -40 DEG C, fast
The pallet that speed will be equipped with preparation is put into freeze drying box, is maintained overnight 12 hours, then carries out application of vacuum, makes vacuum in case small
In 10pa, then kept for 48 hours by -40 DEG C, -35 DEG C are kept for 24 hours, and -30 DEG C are kept for 12 hours, and -25 DEG C of holdings 12 are small
When, -20 DEG C are kept for 6 hours, and -10 DEG C are kept for 6 hours, and -5 DEG C are kept for 6 hours, and 0 DEG C is kept for 6 hours, and 4 DEG C of holdings 4 are small
When, nitrogen, helium or argon gas are passed through, obtain off-white color bulk Paclitaxel liposome preparation.Content of taxol 99%, envelop rate 99%,
Average grain diameter 130nm, peroxidase 12 %, overall lyophilization cycle 136 hours.
Compared with comparative example 1 by the embodiment of the present application 1-6 as can be seen that the lyophilized technique that the application patent is provided prepares same matter
The Paclitaxel liposome of amount standard, lyophilization cycle is greatly shortened, and production capacity is greatly improved, and is effectively reduced production cost.
Claims (3)
1. it is a kind of with desivac prepare injection Paclitaxel liposome composition when freeze drying process, it is characterised in that comprise the steps of：
First the Japanese yew raw polyol of recipe quantity, phosphatide, cholesterol are dissolved in ethanol, 50-60 DEG C of constant temperature removes solvent, adds dissolved with prescription
The amino acid and mannitol or the aqueous solution of glucose of amount, after dissolving, quantitative separating enters in container, in placement freeze drier,
Solution was rapidly decreased to -50 DEG C~-80 DEG C in 0.5~2 hour, and is incubated 4~8 hours, obtain freezes body, application of vacuum makes
Vacuum is less than 10pa, then freezes body was warming up into -5 DEG C in 0.1~2 hour, is incubated 1~4 hour, then by freezes body 1~2
30~35 DEG C are warming up in hour, 3~6 hours are incubated, nitrogen, helium or argon gas is passed through, Paclitaxel liposome preparation is obtained.
2. freeze drying process according to claim 1, it is characterized by freeze-drying process is comprised the steps of：By solution in 1~2 hour
- 60 DEG C~-70 DEG C are rapidly decreased to, and are incubated 6~8 hours, obtain freezes body, application of vacuum makes vacuum less than 10pa, then will
Freezes body was warming up to -5 DEG C in 0.1~0.5 hour, was incubated 1~4 hour, then freezes body was warming up in 1~2 hour
30~35 DEG C DEG C, it is incubated 2~4 hours.
3. freeze drying process according to claim 1, it is characterized by freeze-drying process is：Solution was rapidly decreased to -65 DEG C in 1 hour,
And 8 hours are incubated, and freezes body is obtained, application of vacuum makes vacuum less than 10pa, then freezes body was heated up in 0.5 hour
To -5 DEG C, 2 hours are incubated, then freezes body was warming up to 30 DEG C in 1 hour, be incubated 4 hours.
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| CN201511031953.5A CN106924195B (en) | 2015-12-31 | 2015-12-31 | Freeze-drying process of paclitaxel liposome composition for injection |
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| CN201511031953.5A CN106924195B (en) | 2015-12-31 | 2015-12-31 | Freeze-drying process of paclitaxel liposome composition for injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112789472A (en) * | 2018-09-27 | 2021-05-11 | 玛阿特制药公司 | Freeze-drying container |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1291474A (en) * | 2000-10-19 | 2001-04-18 | 南京振中生物工程有限公司 | Taxusol-lipid composition and its preparing process |
| WO2001056548A2 (en) * | 2000-02-04 | 2001-08-09 | Lipoxen Technologies Limited | Liposomes composition produced by a dehydration-rehydration process |
| CN102716095A (en) * | 2012-06-29 | 2012-10-10 | 海南灵康制药有限公司 | Paclitaxel vesicle type phospholipid gel injection |
-
2015
- 2015-12-31 CN CN201511031953.5A patent/CN106924195B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001056548A2 (en) * | 2000-02-04 | 2001-08-09 | Lipoxen Technologies Limited | Liposomes composition produced by a dehydration-rehydration process |
| CN1291474A (en) * | 2000-10-19 | 2001-04-18 | 南京振中生物工程有限公司 | Taxusol-lipid composition and its preparing process |
| CN102716095A (en) * | 2012-06-29 | 2012-10-10 | 海南灵康制药有限公司 | Paclitaxel vesicle type phospholipid gel injection |
Non-Patent Citations (1)
| Title |
|---|
| 张蓓: "紫杉醇脂质体及其冻干制剂的研究", 《中国优秀博硕士学位论文全文数据库（硕士） 医药卫生科技辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112789472A (en) * | 2018-09-27 | 2021-05-11 | 玛阿特制药公司 | Freeze-drying container |
| CN112789472B (en) * | 2018-09-27 | 2023-02-17 | 玛阿特制药公司 | Freeze-drying container |
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