CN106821983A - A kind of preparation method of new Daptomycin carrier preparation capable of permeating skin - Google Patents
A kind of preparation method of new Daptomycin carrier preparation capable of permeating skin Download PDFInfo
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- CN106821983A CN106821983A CN201710101303.6A CN201710101303A CN106821983A CN 106821983 A CN106821983 A CN 106821983A CN 201710101303 A CN201710101303 A CN 201710101303A CN 106821983 A CN106821983 A CN 106821983A
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- daptomycin
- carrier
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin, including：Lecithin and cholesterol are weighed, and uniform film is made in flask interior；PBS is added, then flask is fixed in 37 DEG C of water bath with thermostatic control shaking table, 1h is shaked with the rotating speed of 130rpm/s, until the film in flask walls is complete by aquation, obtain final product Daptomycin carrier sample solution；The ultrasonication in Ultrasonic Cell Disruptor, opens the liposomal dispersion of aggregation；Make Daptomycin carrier sample solution respectively by the film of 200nm, 100nm, 50nm respectively on homogeneous instrument, make the particle diameter distribution of Daptomycin carrier uniform；Daptomycin carrier is fitted into the bag filter that molecule interception is 3500 8h that dialyses and obtains Daptomycin carrier.Easy to operate, visual result of the invention, it is predictive good, can be widely applied for the preparation technology of Daptomycin preparation capable of permeating skin.
Description
Technical field
The present invention relates to the preparation technology of Daptomycin carrier, particularly a kind of new Daptomycin carrier transdermal system
The preparation method of agent.
Background technology
Daptomycin be the 1980s later stage from the tunning of Streptomyces roseosporus separation and Extraction obtain
Arrive, be a kind of antibiotic of new cyclic lipopeptide, be first antibiotic of the cyclic lipopeptide being found.It belongs to ring ten
The structure group of lipopeptid class.Thus, Daptomycin is first product of cyclic ester peptides antibiotics family.It is from streptomyces parvus
The novel Cyclic lipopeptide antibiotic of the structure of the 13 amino acid composition for obtaining is extracted in the middle of zymotic fluid, wherein ten amino acid
Cyclic structure is constituted, is esterified in the outer capric acid of ring and tryptophan.It not only has novel chemical constitution, and its binding mode
Also from any to be approved antibiotic different.It can destroy bacterial cell membrane function in many aspects, thus rapid to kill the blue sun of leather
Property bacterium.Daptomycin decapacitation is acted on outside most of clinically relevant gram positive bacterias, it is often more important that in vitro to being in methoxy
The drug resistance isolated strains such as XiLin, vancomycin and Linezolid still have strong active.
Penetrating agent refers to the general name for entering blood and subcutaneous each layer tissue by skin outside, and penetrating agent is able to maintain that body
Interior haemoconcentration is maintained at constant active drug concentration level, moreover it is possible to medicine is avoided by intestines and stomach, in intestines and stomach degraded
With the first pass effect of liver；Administering mode is gentle, reliable, simple.
However, the preparation on Daptomycin penetrating agent and imperfection, the application is optimized for the problem.
The content of the invention
It is an object of the invention to overcome the deficiencies in the prior art, there is provided a kind of new Daptomycin carrier preparation capable of permeating skin
Preparation method, this method is easy to operate, visual result, predictive good, can be widely applied for Daptomycin preparation capable of permeating skin
Preparation technology.
The purpose of the present invention is achieved through the following technical solutions：A kind of new Daptomycin carrier preparation capable of permeating skin
Preparation method, comprise the following steps：
S1, lecithin and cholesterol are weighed, and use chloroform：Methyl alcohol=1：After the mixed solution dissolving of 3 (V/V), it is transferred to
In flask, the solvent evaporated on 37 DEG C of Rotary Evaporators so that lecithin and cholesterol are uniformly distributed film forming in flask interior；
S2, after after the solvent volatilization completely in flask, add the PBS of 0.01M, then flask is fixed on 37 DEG C
In water bath with thermostatic control shaking table, 1h is shaked with the rotating speed of 130rpm/s；
Whether film in S3, observation flask walls get off by aquation, if also film is not by aquation, continues to shake until flask
Film on wall completely, obtains final product Daptomycin carrier sample solution by aquation；
In EP pipes, the ultrasonication in Ultrasonic Cell Disruptor makes aggregation for S4, taking-up Daptomycin carrier sample solution
Liposomal dispersion is opened；
S5, make on homogeneous instrument Daptomycin carrier sample solution respectively by 200nm, 100nm, 50nm respectively
Film, makes the particle diameter distribution of Daptomycin carrier uniform；
S6, the 8h that dialysed in the bag filter that molecule interception is 3500 will be fitted into by the Daptomycin carrier of step S5,
A dialyzate is changed per 4h, dialyzate is the PBS of 0.1M, the Daptomycin for making it to be not encapsulated in liposome interior
Remove, obtain final product Daptomycin carrier.
Further, lecithin：Daptomycin=10-2 (m：m)；Lecithin：Cholesterol=10-20 (m：m).
Further, in step s 2, the pH of PBS is 7.4.
Further, in step s 2, dissolved with a small amount of Daptomycin in PBS.
Further, in step s 4, the power of Ultrasonic Cell Disruptor is 800W, and ultrasonic wave occurs 10s gap 10s.
The beneficial effects of the invention are as follows：
(1) preparation technology of traditional Daptomycin is optimized so that the preparation of Daptomycin preparation capable of permeating skin is easy, as a result directly
See, it is predictive good；
(2) envelop rate of Daptomycin carrier preparation capable of permeating skin, drugloading rate, particle diameter, current potential and stability are compared to tradition
Preparation technology improves a lot.
Brief description of the drawings
Fig. 1 is Daptomycin carrier preparation capable of permeating skin grain size distribution of the present invention and transmission electron microscope picture.
Specific embodiment
Technical scheme is described in further detail below in conjunction with the accompanying drawings, but protection scope of the present invention is not limited to
It is as described below.
The present invention includes a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin, specifically includes following steps：
S1, lecithin and cholesterol are weighed, and use chloroform：Methyl alcohol=1：After the mixed solution dissolving of 3 (V/V), it is transferred to
In flask, the solvent evaporated on 37 DEG C of Rotary Evaporators so that lecithin and cholesterol are uniformly distributed film forming in flask interior；
S2, after after the solvent volatilization completely in flask, add the PBS of 0.01M, then flask is fixed on 37 DEG C
In water bath with thermostatic control shaking table, 1h is shaked with the rotating speed of 130rpm/s；
Whether film in S3, observation flask walls get off by aquation, if also film is not by aquation, continues to shake until flask
Film on wall completely, obtains final product Daptomycin carrier sample solution by aquation；
In EP pipes, the ultrasonication in Ultrasonic Cell Disruptor makes aggregation for S4, taking-up Daptomycin carrier sample solution
Liposomal dispersion is opened；
S5, make on homogeneous instrument Daptomycin carrier sample solution respectively by 200nm, 100nm, 50nm respectively
Film, makes the particle diameter distribution of Daptomycin carrier uniform；
S6, the 8h that dialysed in the bag filter that molecule interception is 3500 will be fitted into by the Daptomycin carrier of step S5,
A dialyzate is changed per 4h, dialyzate is the PBS of 0.1M, the Daptomycin for making it to be not encapsulated in liposome interior
Remove, obtain final product Daptomycin carrier.
The present invention is prepared into Daptomycin carrier preparation capable of permeating skin, its envelop rate, drugloading rate, grain using film dispersion method
Footpath, current potential and stability improve a lot compared to conventional preparation techniques.However, learning that influence reaches according to pertinent literature and experiment
The factors such as the envelop rate of Tobramycin carrier, drugloading rate and particle diameter mainly have following 3 aspects：Lecithin and Daptomycin medicine
Ratio, the ratio of lecithin and cholesterol, the ultrasonic time on Ultrasonic Cell Disruptor.
The measure of envelop rate, drugloading rate：
Optimal preparation technology according to Daptomycin carrier preparation capable of permeating skin prepares Daptomycin carrier preparation capable of permeating skin.
After having been processed with homogenizer, sample is divided into two groups：First group, directly with 0.1% (v/v) Triton X-100 treatment, makes
The Daptomycin for being encapsulated in liposome interior is discharged, then is detected on HPLC, and the amount for determining wherein Daptomycin is W., the
Two groups are taken out through dialysis without being demulsified with 10%v/v Triton X-100 after the Daptomycin encapsulated, and HPLC detections wherein reach
The amount of Tobramycin is W.So its envelop rate and drugloading rate are respectively：
Envelop rate=W/W.× 100%；
Drugloading rate=2W/ (2W.The amount of the amount of+added lecithin+added cholesterol) × 100%.
In addition, the measure of the particle diameter of Daptomycin carrier preparation capable of permeating skin and current potential is determined by Malvern particle instrument,
Determine figure as shown in Figure 1.
For being determined as Daptomycin carrier preparation capable of permeating skin stability：The Daptomycin carrier transdermal that will be prepared
Formulation samples are placed in 4 DEG C of refrigerator, and often 7d takes sample segment and out detects its envelop rate, drugloading rate, particle diameter, current potential excessively
Deng compared with 1d, seeing whether to change.
According to the Daptomycin carrier preparation capable of permeating skin that the Daptomycin optimal preparation technology of carrier preparation capable of permeating skin is prepared
Envelop rate be 87.85 ± 2.15%, drugloading rate is 5.61 ± 0.14%, and particle diameter is 55.4nm, and current potential is -15.1mv, at 4 DEG C
Refrigerator in place 2 months, as shown in table 1.
Table 1：The contrast table of Daptomycin Stability Determination
As seen from the above table, the envelop rate of Daptomycin carrier preparation capable of permeating skin, drugloading rate, particle diameter, current potential almost do not become
Change.Illustrate that Daptomycin carrier preparation capable of permeating skin envelop rate, drugloading rate that this preparation technology prepares are high, particle diameter is small, stability
It is good.
Embodiment described above only expresses specific embodiment of the invention, and its description is more specific and detailed, but simultaneously
Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one 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 guarantor of the invention
Shield scope.
Claims (5)
1. a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin, it is characterised in that comprise the following steps：
S1, lecithin and cholesterol are weighed, and use chloroform：Methyl alcohol=1：After the mixed solution dissolving of 3 (V/V), flask is transferred to
It is interior, the solvent evaporated on 37 DEG C of Rotary Evaporators so that lecithin and cholesterol are uniformly distributed film forming in flask interior；
S2, after after the solvent volatilization completely in flask, add the PBS of 0.01M, then the constant temperature that flask is fixed on 37 DEG C
In shaking bath, 1h is shaked with the rotating speed of 130rpm/s；
Whether film in S3, observation flask walls get off by aquation, if also film is not by aquation, continues to shake until in flask walls
Film by aquation completely, obtain final product Daptomycin carrier sample solution；
In EP pipes, the ultrasonication in Ultrasonic Cell Disruptor makes the lipid of aggregation for S4, taking-up Daptomycin carrier sample solution
Body scatter；
S5, make on homogeneous instrument Daptomycin carrier sample solution respectively by the film of 200nm, 100nm, 50nm respectively, allow
The particle diameter distribution of Daptomycin carrier is uniform；
S6, the 8h that dialysed in the bag filter that molecule interception is 3500 will be fitted into by the Daptomycin carrier of step S5, per 4h
A dialyzate is changed, dialyzate is the PBS of 0.1M, it is removed the Daptomycin for not being encapsulated in liposome interior
Fall, obtain final product Daptomycin carrier.
2. a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin according to claim 1, it is characterised in that ovum
Phosphatide：Daptomycin=10-2 (m：m)；Lecithin：Cholesterol=10-20 (m：m).
3. a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin according to claim 1, it is characterised in that
In step S2, the pH of PBS is 7.4.
4. a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin according to claim 1, it is characterised in that
In step S2, dissolved with a small amount of Daptomycin in PBS.
5. a kind of preparation method of new Daptomycin carrier preparation capable of permeating skin according to claim 1, it is characterised in that
In step S4, the power of Ultrasonic Cell Disruptor is 800W, and ultrasonic wave occurs 10s gap 10s.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710101303.6A CN106821983A (en) | 2017-02-24 | 2017-02-24 | A kind of preparation method of new Daptomycin carrier preparation capable of permeating skin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710101303.6A CN106821983A (en) | 2017-02-24 | 2017-02-24 | A kind of preparation method of new Daptomycin carrier preparation capable of permeating skin |
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| CN106821983A true CN106821983A (en) | 2017-06-13 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710101303.6A Pending CN106821983A (en) | 2017-02-24 | 2017-02-24 | A kind of preparation method of new Daptomycin carrier preparation capable of permeating skin |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322690A (en) * | 2007-06-12 | 2008-12-17 | 广州瑞济生物技术有限公司 | Stable medicament lipid complexes |
| CN103006562A (en) * | 2013-01-21 | 2013-04-03 | 西南大学 | Daptomycin ethosome preparation |
-
2017
- 2017-02-24 CN CN201710101303.6A patent/CN106821983A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322690A (en) * | 2007-06-12 | 2008-12-17 | 广州瑞济生物技术有限公司 | Stable medicament lipid complexes |
| CN103006562A (en) * | 2013-01-21 | 2013-04-03 | 西南大学 | Daptomycin ethosome preparation |
Non-Patent Citations (1)
| Title |
|---|
| 张晓林: ""达托霉素透皮制剂的研究"", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
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Application publication date: 20170613 |
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