CN107260681A - A kind of preparation method and applications of Tedizolid Phosphate liposome - Google Patents
A kind of preparation method and applications of Tedizolid Phosphate liposome Download PDFInfo
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- CN107260681A CN107260681A CN201710658875.4A CN201710658875A CN107260681A CN 107260681 A CN107260681 A CN 107260681A CN 201710658875 A CN201710658875 A CN 201710658875A CN 107260681 A CN107260681 A CN 107260681A
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- Prior art keywords
- liposome
- tedizolid phosphate
- preparation
- cholesterol
- tedizolid
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Classifications
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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
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
Abstract
The invention provides a kind of preparation method and applications of Tedizolid Phosphate liposome, it is characterized in that being using soybean lecithin, cholesterol as membrane material, using Calcium acetate gradient, Tedizolid Phosphate encapsulating is prepared into Tedizolid Phosphate liposome.Average grain diameter 183.7nm, its envelop rate is up to 70%~75%.The liposome has passive targeting, slow release, cellular affinity and histocompatbility, nontoxic, while improving the stability of medicine.Calcium acetate gradient, which prepares Tedizolid Phosphate liposome, can not only realize continuous production, moreover it is possible to preferably adapt to industrialization demand, therefore the prospect being widely used in field of medicaments.
Description
Technical field
The invention belongs to technical field of medicine, it is related to a kind of preparation method of Tedizolid Phosphate liposome and answers
With.
Background technology
Nowadays, the abuse of antibiotic causes the phenomenon of multidrug resistance to grow in intensity, and continues to dislike to tackle such a phenomenon
Change, the research of antibiotics is very urgent.As new oxazolidinone antibacterial medicine, Tedizolid Phosphate obtained the U.S. in 2013
FDA preferentially evaluates qualification, and ratifies listing on June 20th, 2014, is commonly used for methicillin resistant strains (MRSA) and methoxy
XiLin sensitive strain（MSSA）Acute, bacterial cutaneous and skin structure infection (ABSSSI) Deng caused by.The trade name of listing
For SivextroTM, have two kinds of formulations of freeze drying powder injection used for intravenous injection and tablet, specification is 200mg.Powder ampoule agent for injection exists
1h just can reach peak plasma concentrations after injection, and oral tablet needs 3h, absolute bioavailability about 91%.
Liposome is a kind of micro- shape vesicle formed by lipoids bilayer, also known as lipoid bead or liquid crystal microcapsules,
According to the dissolution characteristics of medicine, oil-soluble medicine is encapsulated in phospholipid bilayer, and water soluble drug is then present in center
Cavity in.Liposome is due to passive targeting, slow release, cellular affinity and histocompatbility, reducing the poison of medicine
Property, the features such as improve the stability of medicine, thus in field of medicaments extensive use.
The method for preparing liposome is varied, is divided into two major classes of active loading method and Passive loading method.Active loading
Method is also known as chemical gradient method, and certain density solion is encapsulated in blank liposome first, and dialysis removes foreign minister's ion,
Chemical gradient is formed, drug solution incubation is added, is delivered drugs into using chemical gradient in liposome.Passive loading method bag
Include：（1）Film dispersion method：Lipid is dissolved in organic solvents such as dichloromethane, chloroform, methanol and ethanol, recycles rotation to steam
Hair instrument makes the solvent in round-bottomed bottle volatilize, and uniform lipid film is formed in bottle wall, under temperature conditionss more than critical-temperature,
The aqueous solution and the lipid film mixing of coating medicine are intended to, by the mechanical force such as hand or ultrasonic, the lipid film in bottle wall is shaken
Get off, multilamellar liposome will be formed in aqueous（MLV）.（2）Multigelation method：Can again voluntarily after being ruptured using liposome
Closely sealed characteristic, in the way of repeatedly freezing, thaw again, causes the rupture and restructuring of liposome closely sealed again, can finally form big
Small more uniform unilamellar liposome.（3）Reverse phase evaporation：It is super with pharmaceutical aqueous solution with the lipid of organic solvent dissolution of high-concentration
Sound cuts into colostrum, then organic solvent is volatilized with Rotary Evaporators, forms the higher liposome of envelop rate.This method pair
It is of a relatively high in the envelop rate of water soluble drug.（4）Proliposome method：The suspension of carrier granular and lipid soln is rotated
Evaporimeter makes organic solvent volatilize, and lipid uniform adsorption forms liposome precursor on carrier granular.Again by drug solution, plus
Enter into liposome precursor, stir, ultrasound forms uniform liposome.
Because Tedizolid Phosphate is unstable at room temperature, facile hydrolysis, therefore storage and transport are extremely inconvenient, also increase
The product cost of storage and cost of transportation.The present invention prepares Tedizolid Phosphate liposome there is provided a kind of Calcium acetate gradient, no
The stability of medicine can be only improved, cellular affinity can also realize continuous production, better adapt to industrialization demand,
Therefore the prospect being widely used in field of medicaments.
The content of the invention
The invention provides a kind of preparation method and applications of Tedizolid Phosphate liposome.Prepare described phosphoric acid special
The method of ground azoles amine liposome, step is as follows：Soybean lecithin, cholesterol are weighed in proportion, add 2mL absolute ethyl alcohols in 50
~60 DEG C of rotary evaporations（0.02~0.07MPa of vacuum）Into dry film, plus the 5mL calcium acetate aqueous solution（120mmol/L）, aquation
3~7min is uniformly dispersed（Ultrasonic disperse if necessary）, blank liposome is made.The blank liposome prepared is placed in bag filter
（8000~14000Da）In, with normal saline dialysis three times, lasting 1h every time.It is special that blank liposome after dialysis adds phosphoric acid
Ground azoles amine aqueous solution（It is water-soluble for increase, react into disodium salt with NaOH）, 45~55 DEG C of water-baths produce after being incubated 10~20min,
Its physicochemical property such as Fig. 1~4.
A kind of advantage of Tedizolid Phosphate liposome of the present invention has：1. the Tedizolid Phosphate liposome has good
Cellular affinity and histocompatbility.Occur without haemolysis, injection safety is high, such as Fig. 5~6.Medicine is improved simultaneously
Stability；2. the Tedizolid Phosphate liposome has slow release effect, such as Fig. 7.It also has certain targeting, drop simultaneously
Its low drug resistance to body.
The Tedizolid Phosphate liposome is to methicillin resistant strains（MRSA）With methicillin sensitive strain (MSSA)
Infection is effective Deng caused by.
Tedizolid Phosphate liposome is prepared using Calcium acetate gradient, envelop rate is high, can not only realize continuous metaplasia
Production, moreover it is possible to preferably adapt to industrialization demand, therefore the prospect being widely used in field of medicaments.
Brief description of the drawings
Fig. 1 Tedizolid Phosphate liposome photos（A is fresh to prepare liposome, B freeze-dried powders, lipid after the lyophilized redissolution of C
Body）；
Fig. 2 Tedizolid Phosphate liposome transmission electron microscope photos；
Fig. 3 Tedizolid Phosphate liposomal particle size distribution maps；
Fig. 4 Tedizolid Phosphate liposome potential images；
Fig. 5 Tedizolid Phosphate liposome hemolytic test results（1. negative control, the TDZA-Lips groups of 2~6. various concentrations,
7. positive control）；
Fig. 6 Tedizolid Phosphate liposome hemolysis rate results；
Fig. 7 Tedizolid Phosphate liposome In-vitro release curves.
Embodiment
Embodiment 1 in mass ratio 6：1 weighs soybean lecithin, cholesterol, adds 2mL absolute ethyl alcohols in 55 DEG C of rotations
Turn evaporation（Vacuum 0.05MPa）Into dry film, plus the 5mL calcium acetate aqueous solution（120mmol/L）, aquation 5min is uniformly dispersed（Must
Ultrasonic disperse when wanting）, blank liposome is made.The blank liposome prepared is placed in bag filter（8000~14000Da）In,
With normal saline dialysis three times, lasting 1h every time.Blank liposome after dialysis adds Tedizolid Phosphate solution（For increase water
Dissolubility, disodium salt is reacted into NaOH）, 50 DEG C of water-baths produce after being incubated 15min.
Embodiment 2 in mass ratio 6：1 weighs egg yolk lecithin, cholesterol, adds 2mL absolute ethyl alcohols in 55 DEG C of rotations
Turn evaporation（Vacuum 0.05MPa）Into dry film, plus the 5mL calcium acetate aqueous solution（120mmol/L）, aquation 5min is uniformly dispersed（Must
Ultrasonic disperse when wanting）, blank liposome is made.The blank liposome prepared is placed in bag filter（8000~14000Da）In,
With normal saline dialysis three times, lasting 1h every time.Blank liposome after dialysis adds Tedizolid Phosphate solution（For increase water
Dissolubility, disodium salt is reacted into NaOH）, 50 DEG C of water-baths produce after being incubated 15min.
Embodiment 3 in mass ratio 6：1 weighs soybean lecithin, cholesterol, adds 2mL dichloromethane in 42 DEG C of rotations
Turn evaporation（Vacuum 0.04MPa）Into dry film, plus the 5mL calcium acetate aqueous solution（120mmol/L）, aquation 5min is uniformly dispersed（Must
Ultrasonic disperse when wanting）, blank liposome is made.The blank liposome prepared is placed in bag filter（8000-14000Da）In,
With normal saline dialysis three times, lasting 1h every time.Blank liposome after dialysis adds Tedizolid Phosphate solution（For increase water
Dissolubility, disodium salt is reacted into NaOH）, 50 DEG C of water-baths produce after being incubated 15min.
It is degerming that liposome turbid liquor containing 3% mannose is crossed 0.22 μm of filter membrane by embodiment 4, be put into ultra low temperature freezer-
Obtained sample, is then transferred in freeze drier and freezes -50 DEG C, freeze drying powder injection is made in 48 h by 80 DEG C of h of pre-freeze 24.
It is degerming that liposome turbid liquor containing 3% sucrose is crossed 0.22 μm of filter membrane by embodiment 5, is put into ultra low temperature freezer -80
Obtained sample, is then transferred in freeze drier and freezes -50 DEG C, freeze drying powder injection is made in 48 h by DEG C h of pre-freeze 24.
Claims (7)
1. a kind of preparation method of Tedizolid Phosphate liposome, it is characterised in that：Tedizolid Phosphate liposome is with soybean ovum
Phosphatide, cholesterol are membrane material, and using Calcium acetate gradient, Tedizolid Phosphate encapsulating is prepared from.
2. the preparation method of Tedizolid Phosphate liposome as claimed in claim 1, its step is as follows：（1）Weigh in proportion
Soybean lecithin, cholesterol, add 2mL absolute ethyl alcohols in 55 DEG C of rotary evaporations（Vacuum 0.05MPa）Into dry film, plus
The 5mL calcium acetate aqueous solution（120mmol/L）, aquation 5min is uniformly dispersed, and blank liposome is made；（2）By the blank prepared
Liposome is placed in bag filter（8000~14000Da）In, with normal saline dialysis three times, persistently 1h, the blank after dialysis every time
Liposome adds Tedizolid Phosphate drug solution, and 50 DEG C of water-baths are produced after being incubated 15min.
3. the preparation method of Tedizolid Phosphate liposome as claimed in claim 2, it is characterised in that in S1, the soybean
Lecithin, the vacuum of cholesterol rotary evaporation film forming are 0.05MPa.
4. the preparation method of Tedizolid Phosphate liposome as claimed in claim 2, it is characterised in that in S1, the acetic acid
The calcium aqueous solution is 120mmol/L.
5. the preparation method of Tedizolid Phosphate liposome as claimed in claim 1, it is characterised in that the cholesterol and institute
It is the basic substance for collectively forming cell membrane and liposome to state soybean lecithin；The cholesterol is used as mobility buffer, tool
Play the role of to adjust membrane fluidity；The mass ratio of the cholesterol and the soybean lecithin is 1:6.
6. the application of the Tedizolid Phosphate liposome as described in claim 1-5 is any, it is characterised in that pass through calcium acetate ladder
The Tedizolid Phosphate liposome that degree method is made, can be applied to the medicine system of the formulations such as powder spray, injection, freeze drying powder injection
Agent.
7. a kind of phosphoric acid according to made from the preparation method of any described Tedizolid Phosphate liposomes of claim 1-5 is specially
Azoles amine liposome, it is characterised in that the Tedizolid Phosphate liposome has targeting, slow release, cellular affinity and group
Compatibility is knitted, while improving the stability of medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710658875.4A CN107260681A (en) | 2017-08-04 | 2017-08-04 | A kind of preparation method and applications of Tedizolid Phosphate liposome |
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| CN201710658875.4A CN107260681A (en) | 2017-08-04 | 2017-08-04 | A kind of preparation method and applications of Tedizolid Phosphate liposome |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070014845A1 (en) * | 2005-07-01 | 2007-01-18 | Yuanpeng Zhang | Liposomal delivery vehicle for hydrophobic drugs |
| CN105164143A (en) * | 2013-03-14 | 2015-12-16 | 杰罗米.J.申塔格 | Cholestosome vesicles for incorporation of molecules into chylomicrons |
-
2017
- 2017-08-04 CN CN201710658875.4A patent/CN107260681A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070014845A1 (en) * | 2005-07-01 | 2007-01-18 | Yuanpeng Zhang | Liposomal delivery vehicle for hydrophobic drugs |
| CN105164143A (en) * | 2013-03-14 | 2015-12-16 | 杰罗米.J.申塔格 | Cholestosome vesicles for incorporation of molecules into chylomicrons |
Non-Patent Citations (3)
| Title |
|---|
| 崔福德，等: "《药剂学 第2版》", 31 January 2011, 中国医药科技出版社 * |
| 段康颖，等: "新型的药物载体-脂质体", 《中国医院药学杂志》 * |
| 潘卫三，等: "《工业药剂学 第2版》", 30 June 2010, 中国医药科技出版社 * |
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