CN104473871B - A kind of posaconazole fat emulsion injection and preparation method thereof - Google Patents
A kind of posaconazole fat emulsion injection and preparation method thereof Download PDFInfo
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- CN104473871B CN104473871B CN201410700574.XA CN201410700574A CN104473871B CN 104473871 B CN104473871 B CN 104473871B CN 201410700574 A CN201410700574 A CN 201410700574A CN 104473871 B CN104473871 B CN 104473871B
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- posaconazole
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Abstract
The invention provides a kind of posaconazole fat emulsion injection and preparation method thereof, it is with posaconazole as medicinal active ingredient, lipomul is made with oil-based solvent, water, osmotic pressure regulator and pH adjusting agent etc., solve the problems, such as that posaconazole dissolubility in water is low, drug loading is high, no medicine is revealed, and improves the stability of posaconazole in preparation.Present invention also offers the preparation technology of said preparation, its process is simple, repeatability is good, it is possible to achieve industrialized production.It is developed into the preparation of injection for intravenous, to for preventing aggressive aspergillus fungi to infect the patient it is adaptable to be badly damaged because of immune system.
Description
Technical field
The present invention relates to field of pharmaceutical preparations is and in particular to a kind of posaconazole fat emulsion injection and preparation method thereof.
Background technology
Posaconazole is the derivant of Itraconazole, posaconazole (posaconazole, trade name Noxafil, CAS
Registration number 171228-49-2, chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- tri-
Azoles -1- ylmethyl) oxa- penta ring -3- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -2- [the amyl- 3- of (2S, 3S) -2- hydroxyl
Base] -1,2,4- triazole -3- ketone) it is the third generation antifungal agent that Schering-Plough pharmaceutical Co. Ltd researches and develops, 2005 years
December listed in Britain in German Initial Public Offering, in March, 2006, on September 18th, 2006, obtains FDA and has been approved by.2014
FDA approved posaconazole injection (18mg/mL), this is a kind of novel form of intravenous injection (IV) of posaconazole, is suitable for
In 18 years old and above patient.This antifungal drug of Mo Shadong is also with posaconazole (100mg) slow releasing tablet and posaconazole
(40mg/mL) oral administration mixed suspension list marketing is it is adaptable to 13 years old and above patient.It is mainly used in preventing aggressive aspergillus fungi
Infect the patient it is adaptable to be badly damaged because of immune system, immune system is badly damaged including hematopoietic stem cell transplantation (HSCT)
The graft versus host disease (GVHD) that receiver suffers from or patients with malignant hematological diseases lead to long-term neutrophilic granulocyte because of chemotherapy
Reduce.
Posaconazole is the medicine of a kind of alkalescence, poorly water-soluble, has with posaconazole in alkaline aqueous solution neutral
Less than the dissolubility of 1 μ g/ml, list preparation posaconazole injection using modified beta-schardinger dextrin-as solubilizing agent, edetic acid two
Sodium is prepared into venoclysises liquor for chelating agen it is achieved that to the patient that can not give peroral dosage form（As dysphagia or stupor
Patient）Administration.Posaconazole injection medication is：It is 300mg (300mg/ in the treatment loading dose of first day
Bottle), two times a day；From the beginning of second day for the treatment of, maintenance dose is 300mg (300mg/ bottle), once a day.Will after preparation mixing
Use at once, instil 90 minutes about by central vein is slow, otherwise should be placed at 2 DEG C ~ 8 DEG C stored refrigerated.Posaconazole
The each bottle of injection（16.7ml）Posaconazole containing 300mg and sulfobutyl ether-beta-cyclodextrin 6.68g, disodium edetate
0.003 g, hydrochloric acid and sodium hydroxide adjust pH to 2.6, and water for injection.
Because injection direct injection enters blood circulation, adjuvant selection is improper may to produce safety risks,
Thus the adjuvant that inert, safety is preferable, it is medicinal to meet or injection requires should be selected.But listing preparation posaconazole note
Penetrate liquid and adopt substantial amounts of modification beta-schardinger dextrin-（Sulfobutyl ether-beta-cyclodextrin）Posaconazole is carried out with inclusion solubilising, substantially solves
Determine the water solubility problems of posaconazole, but result of study has shown, beta-schardinger dextrin-series derivates are in terms of pharmacological toxicology research
Display has greater risk to human body, and beta-schardinger dextrin-class adjuvant has nephrotoxicity and haemolysiss；Such adjuvant is above-mentioned due to existing
Shortcoming, European medicine thing meeting, U.S. FDA and Chinese SFDA also require that the safety of the adjuvant to the type is reappraised, serious shadow
Ring the clinical safety application of posaconazole injection.
Content of the invention
For prior art, the invention provides a kind of posaconazole fat milk note without beta-schardinger dextrin-series derivates
Penetrate liquid, posaconazole contained among fat milk milk particle, solve the problems, such as that its dissolubility in water is low, improve its to
Dissolubility in medicine body system, solves serious adverse reaction that in clinical practice, beta-schardinger dextrin-series derivates bring etc. a series of
Application limits, and enhances the compliance of patient.Present invention also offers the preparation method of said preparation, its process is simple, repeatability
Well, it is possible to achieve industrialized production.
The present invention employs the following technical solutions realization：
A kind of posaconazole fat emulsion injection is it is characterised in that each component presses following percentage by weight composition：
Posaconazole 1.6-2.0%
Oil-based solvent 5-15%
Emulsifying agent 1-2%
Osmotic pressure regulator 4.5-5.5%
PH adjusting agent adjusts pH to 2～3
Remaining is water for injection.
Preferably, described oil-based solvent include one of soybean oil, Semen Maydis oil, Oleum sesami, Medium chain Triglyceride or
Several.
Preferably, described emulsifying agent include one of lecithin, poloxamer, soybean lecithin, Egg Yolk Lecithin (PC-98T) or
Several.
Preferably, described osmotic pressure regulator is Mannitol or glucose, more preferably Mannitol.
Preferably, described pH adjusting agent is one or more of hydrochloric acid, sodium hydroxide, citric acid or acetic acid.
It is further preferred that the preparation method of posaconazole fat emulsion injection is it is characterised in that comprise the following steps：
（1）Under nitrogen protection oil-based solvent is mixed homogeneously with emulsifying agent, be heated to 70-80 DEG C, add while stirring
Principal agent posaconazole, mixes, obtains oil phase；
（2）Add osmotic pressure regulator in 65-75% water for injection, be uniformly dissolved, while heated to 70-80 DEG C, obtain
Aqueous phase；
（3）Under nitrogen protection, gained oil phase is added dropwise in aqueous phase under high-speed stirred 1800-2500rpm, dimension
Hold stirring 5-15min, pH to 2～3 is adjusted with pH adjusting agent, benefit adds to the full amount of water for injection, mix, obtain just emulsion；
（4）Under nitrogen protection, under room temperature condition, by gained just emulsion in high pressure homogenizer with 350-1000bar
Pressure under mesohigh circulate 4 times, obtain Emulsion；
（5）By gained Emulsion, cross 5 μm for microporous filter membrane after, inflated with nitrogen, embedding, 121 DEG C of sterilizing 15min, obtain final product.
With respect to prior art, the present invention has advantages below：
1）The fat milk of the present invention is O/W type Emulsion, with phospholipid or poloxamer as emulsifying agent, soybean oil etc. molten for oiliness
Agent, is scattered in aqueous phase, and posaconazole is fat-soluble medicine, therefore can be dispersed in oil phase with molecular forms dissolving, is wrapped in emulsion droplet
Among.Therefore, the present invention contains posaconazole among milk particle, solves the problems, such as that posaconazole dissolubility in water is low；
Simultaneously as the oral administration biaavailability of posaconazole is relatively low（8-47%）, solve pool after being therefore prepared into injection husky
The low problem of health azoles oral formulations bioavailability；
2）The preparation process is simple of invention formulation, repeatability is good, and in preparation process, the loss of medicine is less, and
Improve the stability of posaconazole in preparation, it is possible to achieve industrialized production.Through inspection, the envelop rate of said preparation is up to 97%
More than, drug loading is high, and quality appearance is homogeneous, and stability is high；Accelerated 6 months of the made sample of the present invention and long-term December are stable
Property investigate every quality index there is not significant change, all meet quality criteria requirements, illustrate the present invention prepare sample have
There is good quality stability.
3）This invention also solves listing what beta-schardinger dextrin-series derivates in posaconazole injection clinical practice brought
A series of application such as serious adverse reaction limits, and reduces medicine irritation and toxicity, enhances the compliance of patient and faces
The safety of bed medication.It is developed into the preparation of injection for intravenous, to for preventing aggressive aspergillus fungi to infect, fitting
For the patient being badly damaged because of immune system.
Brief description
The present invention is further illustrated below in conjunction with the accompanying drawings.
Accompanying drawing 1 is the granularity data figure that fat milk prepared by embodiment 1 detects under particle size analyzer.
Specific embodiment
With reference to the accompanying drawings and examples the present invention is described in detail.Following embodiment is all to the present invention
One kind describes in detail rather than is limitation of the present invention.
Embodiment 1：1000ml posaconazole fat emulsion injection preparation method
Under nitrogen protection soybean oil 100g is mixed homogeneously with soybean lecithin 10g, be heated to 80 DEG C, while stirring
Add principal agent posaconazole 18g, mix, obtain oil phase；
Add Mannitol 50g in 750ml water for injection, be uniformly dissolved, while heated to 80 DEG C, obtain aqueous phase；
Under nitrogen protection, by gained oil phase under high velocity agitation（2500rpm）It is added dropwise among aqueous phase, maintain
Stirring 5min, adjusts pH to 2.0 with pH adjusting agent, benefit adds to the full amount of water for injection, and mixes, and obtains just emulsion；
Under nitrogen protection, under room temperature condition, by gained, just emulsion circulates 4 times in high pressure homogenizer mesohigh（If
Fixed homogenization pressure is 600bar）, obtain Emulsion；
By gained Emulsion, cross 5 μm for microporous filter membrane after, inflated with nitrogen, embedding, sterilizing（121℃、15min）Obtain final product.
Embodiment 2：1000ml posaconazole fat emulsion injection preparation method
Under nitrogen protection soybean oil 100g is mixed homogeneously with soybean lecithin 20g, be heated to 75 DEG C, while stirring
Add principal agent posaconazole 20g, mix, obtain oil phase；
Add Mannitol 50g in 700ml water for injection, be uniformly dissolved, while heated to 75 DEG C, obtain aqueous phase；
Under nitrogen protection, by gained oil phase under high velocity agitation（1800rpm）It is added dropwise among aqueous phase, maintain
Stirring 5min, adjusts pH to 2.6 with pH adjusting agent, benefit adds to the full amount of water for injection, and mixes, and obtains just emulsion；
Under nitrogen protection, under room temperature condition, by gained, just emulsion circulates 4 times in high pressure homogenizer mesohigh（If
Fixed homogenization pressure is 400bar）, obtain Emulsion；
By gained Emulsion, cross 5 μm for microporous filter membrane after, inflated with nitrogen, embedding, sterilizing（121℃、15min）Obtain final product.
Embodiment 3：1000ml posaconazole fat emulsion injection preparation method
Under nitrogen protection soybean oil 75g, soybean lecithin 5g are mixed homogeneously with poloxamer 5g, be heated to 75
DEG C, add principal agent posaconazole 18g while stirring, mix, obtain oil phase；
Add glucose 55g in 650ml water for injection, be uniformly dissolved, while heated to 75 DEG C, obtain aqueous phase；
Under nitrogen protection, by gained oil phase under high velocity agitation（2500rpm）It is added dropwise among aqueous phase, maintain
Stirring 5min, adjusts pH to 3.0 with pH adjusting agent, benefit adds to the full amount of water for injection, and mixes, and obtains just emulsion；
Under nitrogen protection, under room temperature condition, by gained, just emulsion circulates 4 times in high pressure homogenizer mesohigh（If
Fixed homogenization pressure is 500bar）, obtain Emulsion；
By gained Emulsion, cross 5 μm for microporous filter membrane after, inflated with nitrogen, embedding, sterilizing（121℃、15min）Obtain final product.
Embodiment 4：
In order to investigate some basic physicochemical properties of this preparation, the present invention has carried out following experiment：
1）Fat milk particle size determination
By the lipomul of embodiment 1 gained, add a certain amount of normal saline dilution suitable multiple, be placed under particle size analyzer
Detection granularity, result is as shown in Figure 1.As can be seen from Figure, the mean diameter of said preparation is in 220-300nm.
）Envelop rate is measured with drug loading
By the fat emulsion formulation of embodiment 1-3 gained, with the content of high phase liquid chromatography for measuring posaconazole, calculate bag
Envelope rate（EE）With drug loading（DL）, specific formula for calculation is as follows, and experimental result see table：
The envelop rate of medicine be can be seen that all more than 97% by result in table, in formulation process the loss of medicine is relatively
Few.
Embodiment 5：Posaconazole fat emulsion injection stability test is investigated
Posaconazole fat emulsion injection prepared by embodiment 2 is carried out accelerate June（25℃）And it is long-term 36 months（2-8
℃）Stability test is investigated, to evaluate the quality of the made sample of the present invention.Obtain data result as follows：
Result of the test shows that the made sample of the present invention accelerates 6 months and every quality of long-term December study on the stability refers to
There is not significant change in mark, all meet quality criteria requirements, illustrates that the sample of present invention preparation has good quality stability.
Claims (6)
1. a kind of posaconazole fat emulsion injection is it is characterised in that each component presses following percentage by weight composition：
Posaconazole 1.6-2.0%
Oil-based solvent 5-15%
Emulsifying agent 1-2%
Osmotic pressure regulator 4.5-5.5%
PH adjusting agent adjusts pH to 2～3
Remaining is water for injection.
2. a kind of posaconazole fat emulsion injection according to claim 1 it is characterised in that：Described oil-based solvent includes
One or more of soybean oil, Semen Maydis oil, Oleum sesami, Medium chain Triglyceride.
3. a kind of posaconazole fat emulsion injection according to claim 1 it is characterised in that：Described emulsifying agent includes ovum
One or more of phospholipid, poloxamer, soybean lecithin, Egg Yolk Lecithin (PC-98T).
4. a kind of posaconazole fat emulsion injection according to claim 1 it is characterised in that：Described osmotic pressure regulator
For Mannitol or glucose.
5. a kind of posaconazole fat emulsion injection according to claim 1 it is characterised in that：Described pH adjusting agent is salt
Acid, sodium hydroxide, citric acid or acetic acid one or more.
6. the preparation method of the arbitrary described posaconazole fat emulsion injection of claim 1-5 is it is characterised in that include following
Step：
（1）Under nitrogen protection oil-based solvent is mixed homogeneously with emulsifying agent, be heated to 70-80 DEG C, add principal agent while stirring
Posaconazole, mixes, obtains oil phase；
（2）Add osmotic pressure regulator in 65-75% water for injection, be uniformly dissolved, while heated to 70-80 DEG C, obtain water
Phase；
（3）Under nitrogen protection, gained oil phase is added dropwise in aqueous phase under high-speed stirred 1800-2500rpm, maintenance is stirred
Mix 5-15min, pH to 2～3 is adjusted with pH adjusting agent, benefit adds to the full amount of water for injection, mix, obtain just emulsion；
（4）Under nitrogen protection, under room temperature condition, by gained just emulsion in high pressure homogenizer with the pressure of 350-1000bar
Under power, mesohigh circulates 4 times, obtains Emulsion；
（5）By gained Emulsion, after crossing 5 μm of microporous filter membrane, inflated with nitrogen, embedding, 121 DEG C of sterilizing 15min, obtain final product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410700574.XA CN104473871B (en) | 2014-11-28 | 2014-11-28 | A kind of posaconazole fat emulsion injection and preparation method thereof |
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| CN106913520A (en) * | 2015-12-25 | 2017-07-04 | 上海医药集团股份有限公司 | The particulate administration composition of Chinese mugwort Saperconazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739519A (en) * | 2005-09-12 | 2006-03-01 | 沈阳药科大学 | Itraconazole emulsion for injection and its prepn |
| CN101129376A (en) * | 2006-08-09 | 2008-02-27 | 上海医药工业研究院 | Hydrochloric acid Itraconazole emulsion and method of producing the same |
| CN102485210A (en) * | 2010-12-03 | 2012-06-06 | 齐鲁制药有限公司 | Voriconazole intravenous injection submicron emulsion and its preparation method |
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| CN1682741A (en) * | 2005-03-11 | 2005-10-19 | 中国药科大学 | Anti-cancer medicine 23-hydroxy betulic acid fat emulsion and its preparing method |
| CA2802929C (en) * | 2010-06-29 | 2019-01-08 | David Monteith | Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin |
| US8883177B2 (en) * | 2011-06-28 | 2014-11-11 | Nian Wu | Pharmaceutical compositions for parenteral administration |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739519A (en) * | 2005-09-12 | 2006-03-01 | 沈阳药科大学 | Itraconazole emulsion for injection and its prepn |
| CN101129376A (en) * | 2006-08-09 | 2008-02-27 | 上海医药工业研究院 | Hydrochloric acid Itraconazole emulsion and method of producing the same |
| CN102485210A (en) * | 2010-12-03 | 2012-06-06 | 齐鲁制药有限公司 | Voriconazole intravenous injection submicron emulsion and its preparation method |
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| CB03 | Change of inventor or designer information |
Inventor after: Zhang Ying Inventor after: Liu Yuanxin Inventor after: Yang Chunfen Inventor after: He Hong Inventor after: Qu Yanwei Inventor after: Yang Jiangyong Inventor after: He Hua Inventor before: Zhang Ying Inventor before: Liu Peng Inventor before: Yang Chunfen Inventor before: He Hong Inventor before: Qu Yanwei Inventor before: Yang Jiangyong Inventor before: Wang Xuebin Inventor before: He Hua |
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Free format text: CORRECT: INVENTOR; FROM: ZHANG YING LIU PENG YANG CHUNFEN HE HONG QU YANWEI YANG JIANGYONG WANG XUEBIN HE HUA TO: ZHANG YING LIU YUANXIN YANG CHUNFEN HE HONG QU YANWEI YANG JIANGYONG HE HUA |
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