CN110339341A - A kind of composition of Daptomycin or its salt - Google Patents
A kind of composition of Daptomycin or its salt Download PDFInfo
- Publication number
- CN110339341A CN110339341A CN201910260008.4A CN201910260008A CN110339341A CN 110339341 A CN110339341 A CN 110339341A CN 201910260008 A CN201910260008 A CN 201910260008A CN 110339341 A CN110339341 A CN 110339341A
- Authority
- CN
- China
- Prior art keywords
- daptomycin
- salt
- inositol
- composition
- content
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
-
- 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
- A61K38/10—Peptides having 12 to 20 amino acids
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The present invention provides a kind of Daptomycin or the compositions of its salt.Specifically, providing a kind of daptomycin preparation comprising inositol as excipient the present invention relates to field of medicaments, with better stability and rate is rebuild, and then can be improved its antibacterial curative effect.
Description
Technical field
The present invention relates to field of medicaments, provide a kind of Daptomycin or the composition of its salt and preparation method thereof.
Background technique
Daptomycin is for treating complexity skin and skin structure infection and bacteremic cyclic annular lipopeptide antibiotics.Note
Penetrate with Daptomycin can intravenous administration, before the liquid form for being prepared into injectable mainly in the form of freeze-dried powder
It saves, redissolves its dissolved for reconstitution using preceding.
In order to improve freeze-dried powder form Daptomycin storage stability, need that jelly is added in freeze-dried powder preparation process
Dry protective agent has substance in many to can be used as freeze drying protectant use, and common freeze drying protectant includes lactose, sucrose, cotton
It is sub- sugar, glucan, mannitol, inositol, galactolipin, ribose, xylose, mannose, cellobiose, maltose, trehalose, sweet
Propylhomoserin etc., but be different the protective effect that freeze drying protectant plays in different drugs there are biggish differences, therefore, seek
Looking for the suitable protective agent for improving medicine stability is the problem of researcher pays close attention to always.
Patent WO2011063419 is disclosed using glycine, sucrose, trehalose or mannitol as freeze drying protectant, can
It improves the stability of Daptomycin solid pharmaceutical preparation and rebuilds rate.Patent CN1616083A is disclosed comprising mannitol and dextrose
The daptomycin freeze-dried preparation of acid anhydride also discloses lactinated daptomycin freeze-dried preparation.WO2013103801 discloses spraying
Drying means prepares the lyophilized preparation containing Daptomycin and polyethylene glycol.
Summary of the invention
Present invention finds it is a kind of better than it is existing using sucrose be as excipient Daptomycin new composition, with
Inositol is greatly improved Daptomycin powder and reconstruction as the excipient of Daptomycin or redissolves the stability of solution, while energy
Enough improve the reconstruction rate of lyophilized preparation.
The present invention provides a kind of composition comprising Daptomycin or its salt and inositol, can be liquid form, can also
To be powder type.
In some embodiments of the invention, Daptomycin or its salt and inositol are included in composition.
In other embodiments of the invention, the mass ratio of Daptomycin or its salt and inositol is 1:5 to 10:1 range
Interior arbitrary value.
In other embodiment of the invention, the mass ratio of Daptomycin or its salt and inositol is 1:2 to 5:1 range
Interior arbitrary value.
In some other embodiments of the invention, the mass ratio of Daptomycin or its salt and inositol is 1:1 to 5:2 range
Interior arbitrary value.
In some embodiments of the invention, the mass ratio of Daptomycin or its salt and inositol is 5:4.
In some embodiments of the invention, the composition also includes buffer.
In other embodiments of the invention, the buffer is selected from phosphate, citrate, maleate, boron
At least one of hydrochlorate and carbonate.
In some embodiments of the invention, Daptomycin or its salt content are the arbitrary value within the scope of 5%-15%, flesh
Alcohol content is the arbitrary value within the scope of 2%-30%.Wherein illustrative 5% indicate mould up to holding in the palm comprising 5g in every 100ml solution
Element or its salt, the content of inositol are explained similar with its.
In other embodiments of the invention, the composition includes Daptomycin or its salt, inositol and buffer,
Wherein Daptomycin or its salt content are the arbitrary value within the scope of 8%-12%, and inositol content is any within the scope of 2%-15%
Value.The explanation of content is same as above.
In other embodiment of the invention, the composition includes Daptomycin or its salt, inositol and buffer,
Wherein Daptomycin or its salt content are the arbitrary value in 10% range, and inositol content is the arbitrary value in 8% range.Content
Explanation is same as above.
In some embodiments of the invention, the pH of the composition is the arbitrary value within the scope of 4.0-8.0.
In other embodiments of the invention, the pH of the composition is the arbitrary value within the scope of 4.7-7.4.
In other embodiment of the invention, the pH of the composition is the arbitrary value within the scope of 5.5-7.4.
In some other embodiments of the invention, the pH of the composition is selected from 5.5,6.0,6.5,7.0 or 7.4.
In one embodiment of the invention, the composition includes Daptomycin or its salt, inositol and phosphate-buffered
Liquid, wherein the mass ratio of Daptomycin or its salt and inositol is 5:4, and pH is selected from 5.5,6.0,6.5,7.0 or 7.4.
In yet another embodiment of the present invention, the composition includes that Daptomycin or its salt, inositol and phosphate are slow
The content of fliud flushing, the Daptomycin or its salt is 10%, the content of the inositol be 8%, pH be selected from 5.5,6.0,6.5,
7.0 or 7.4.
The present invention also provides a kind of aseptic powderies, by the way that the composition of liquid form in the embodiment above to be converted to
Powder is prepared.
In some embodiments of the invention, by the method that is freeze-dried or is spray-dried by liquid in the embodiment above
The composition of body form is prepared into Daptomycin or its salt aseptic powdery preparation.
The present invention also provides a kind of compositions, by rebuilding or redissolving Daptomycin or its salt aseptic powder in the present invention
End obtains.
The present invention also provides a kind of method for preparing Daptomycin or its salt aseptic powdery composition, the method includes
The composition of liquid form in foregoing embodiments is freeze-dried or is spray-dried and is prepared into powder formulation.
Term
" composition " indicates the mixing containing one or more Daptomycins described herein or its salt and other chemical constituents
Object, the other components such as physiology/pharmaceutical carrier and excipient.The purpose of pharmaceutical composition is promoted to organism
Administration, conducive to active constituent absorption so that play bioactivity.Herein, " composition " and " preparation " is not arranged mutually
Reprimand.
Specific embodiment
By following embodiment and experimental example, present invention be described in more detail.These embodiments and experimental example are only used for
Bright property purpose, and the range being not intended to restrict the invention.Test method without specific conditions in the embodiment of the present invention is led to
Often according to the normal condition for being conducive to production or according to condition proposed by raw material or commodity manufacturer.Specific source is not specified
Reagent, for market purchase conventional reagent.
Embodiment 1: daptomycin freeze-dried dose of preparation
A, the preparation of solution
20% Daptomycin aqueous solution: weighing about 5g Daptomycin into 100mL beaker, and about 15mL purified water, ice is added
Stirring in water bath extremely dissolution (in course of dissolution, magneton is mixed slowly, and is avoided generating too many foam, is unfavorable for later period constant volume).Transfer
To 25mL volumetric flask, purified water constant volume.
4M NaOH solution: weighing about 1.6g sodium hydroxide into 25mL beaker, and about 6mL purified water stirring and dissolving is added, and turns
10mL volumetric flask is moved to, is cooled to room temperature, purified water constant volume.
1M NaOH solution: weighing about 0.8g sodium hydroxide into 50mL beaker, and about 15mL purified water stirring and dissolving is added,
It is transferred to 20mL volumetric flask, is cooled to room temperature, purified water constant volume.
Phosphate buffer: preparing phosphate buffer according to known methods, accordingly adjusts as required different
PH value.
B, the preparation of daptomycin freeze-dried preparation
Prescription information 1:
Prescription information 2:
Prescription information 3:
Prescription 084: 20% Daptomycin aqueous solution of 5mL is pipetted, 0.0358g disodium hydrogen phosphate, ice-water bath are weighed
Stirring and dissolving.PH to 6.0 is adjusted with sodium hydroxide, above-mentioned solution is transferred in 10mL volumetric flask, purified water constant volume.
Prescription 085: 20% Daptomycin aqueous solution of 5mL is pipetted, 0.0358g disodium hydrogen phosphate, ice-water bath are weighed
Stirring and dissolving, weighs the addition of 1.5g sucrose, and ice-water bath stirs dissolution.PH to 6.0 is adjusted with sodium hydroxide, above-mentioned solution is shifted
Into 10mL volumetric flask, purified water constant volume.
Prescription 231: 20% Daptomycin aqueous solution of 5mL is pipetted, 0.0358g disodium hydrogen phosphate, ice-water bath are weighed
Stirring and dissolving, weighs the addition of 0.8g inositol, and ice-water bath stirs dissolution.PH to 6.0 is adjusted with sodium hydroxide, above-mentioned solution is shifted
Into 10mL volumetric flask, purified water constant volume.
According to above-mentioned prescription preparation method, adjusts buffer and pH value prepares other solution in above-mentioned list.Prescription information
4:
265: pipetting 20% Daptomycin aqueous solution of 5mL, weigh the addition of 1.5g sucrose, ice-water bath stirs dissolution.Use hydroxide
Sodium adjusts pH to 4.7, and above-mentioned solution is transferred in 10mL volumetric flask, phosphate buffer constant volume appropriate is added.
266: pipetting 20% Daptomycin aqueous solution of 5mL, adjust pH to 4.7 with sodium hydroxide, above-mentioned solution is transferred to
In 10mL volumetric flask, phosphate buffer (final concentration 10mM) appropriate is added, phosphate buffer constant volume appropriate is added.
267: pipetting 20% Daptomycin aqueous solution of 5mL, weigh the addition of 0.8g inositol, ice-water bath stirs dissolution.Use hydroxide
Sodium adjusts pH to 4.7, and above-mentioned solution is transferred in 10mL volumetric flask, phosphate buffer constant volume appropriate is added.
268-282: according to above three prescription preparation method, corresponding prescription information replacement protective agent is matched with adjustment pH
Solution processed.
By above-mentioned prescription sample freeze-drying process, placement 7 days by it under the conditions of 40 DEG C, detect Daptomycin later
Stability and reconstruction rate.
Interpretation of result:
Influence of the freeze drying protectant different under condition of different pH to Daptomycin stability is screened, from table 1, table 2, table 5
Data it can be found that freeze drying protectant in addition to sucrose no matter the investigation result from stability or in terms of rebuilding rate not
Ideal is not much different with protectant preparation is not added.Freeze drying protectant is further screened, discovery inositol is suitable with sucrose effect,
Even better than sucrose, data are shown in Table 3, table 4, table 6.
Further to investigate under condition of different pH, 7 data of table are shown, unprotected dose of prescription stability is worst, 40 DEG C 7
Purity reduces by 1.5% or more after it；And Daptomycin-sucrose lyophilized preparation and Daptomycin-inositol lyophilized preparation show it is good
Good stability.In addition to 4.7 condition of pH, Daptomycin-inositol lyophilized preparation purity changing value is respectively less than and reaches under the conditions of other pH
Tobramycin-sucrose lyophilized preparation.Wherein Daptomycin-inositol lyophilized preparation (pH=6.0) stability is best, 40 DEG C of -7 days realities
Purity only reduces by 0.17% under the conditions of testing, hence it is evident that it is better than Daptomycin-sucrose lyophilized preparation (pH=6.0), it is slightly mould better than up to holding in the palm
Element-sucrose (pH=4.7), data are shown in Table 7.Reconstructed results are shown, in addition to inositol reconstruction time > 3min under the conditions of pH=4.7,
Other prescription reconstruction times about 1min is rebuild rapidly, and data are shown in Table 8.
The purity variation of Daptomycin under the different freeze drying protectant condition of different pH of table 1
In relation to substance and moisture under the different freeze drying protectant condition of different pH of table 2
The screening (variation of Daptomycin purity) of different freeze drying protectants under the conditions of table 3pH 6
The screening (total impurities variation) of different freeze drying protectants under the conditions of table 4pH 6
Reconstruction time under the different freeze drying protectant condition of different pH of table 5
Different freeze drying protectant reconstruction times under the conditions of table 6pH 6
The purity of lyophilized preparation, which changes, when sucrose and inositol are as protective agent under 7 condition of different pH of table compares
The reconstruction rate comparison of lyophilized preparation when sucrose and inositol are as protective agent under 8 condition of different pH of table
Claims (11)
1. a kind of composition includes Daptomycin or its salt and inositol.
2. the mass ratio of composition described in claim 1, Daptomycin or its salt and inositol is 1:5 to 10:1, preferably 1:2 is extremely
5:1, more preferable 1:1 to 5:2, most preferably 5:4.
3. composition as claimed in claim 2, also includes buffer, preferred buffer is selected from phosphate, citrate, Malaysia
At least one of hydrochlorate, borate and carbonate.
4. composition as claimed in claim 2, wherein Daptomycin or its salt content are 5%-15%, preferably 8%-12%, more
It is preferred that 10%.
5. composition as claimed in claim 4, wherein inositol content is 2%-30%, preferably 2%-15%, more preferable 8%.
6. composition as claimed in claim 4, pH 4.0-8.0, preferably pH are 4.7-7.4, and more excellent pH is 5.5-7.4, most
It is preferred that pH is selected from 5.5,6.0,6.5,7.0 or 7.4.
7. composition described in claim 1, it includes Daptomycin or its salt, inositol, phosphate buffer, the Da Tuo
The mass ratio of mycin or its salt and inositol is 5:4, and pH is selected from 5.5,6.0,6.5,7.0 or 7.4.
8. composition described in claim 1, it includes Daptomycin or its salt, inositol, phosphate buffer, the Da Tuo
The content of mycin or its salt is 10%, and the content of the inositol is that 8%, pH is selected from 5.5,6.0,6.5,7.0 or 7.4.
9. a kind of aseptic powdery is to convert powder type for the described in any item compositions of claim 1-8 to be prepared；
Preferred transform mode is freeze-drying, vacuum drying or spray drying.
10. a kind of composition is by obtaining sterile powder reconstitution as claimed in claim 9 or redissolution.
11. a kind of method for preparing Daptomycin or its salt aseptic powdery includes by the described in any item combinations of claim 1-8
Object is converted to powder type by freeze-drying, vacuum drying or method dry by spraying.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810289239 | 2018-04-03 | ||
| CN2018102892393 | 2018-04-03 |
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| Publication Number | Publication Date |
|---|---|
| CN110339341A true CN110339341A (en) | 2019-10-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910260008.4A Pending CN110339341A (en) | 2018-04-03 | 2019-04-02 | A kind of composition of Daptomycin or its salt |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021131314A1 (en) * | 2019-12-26 | 2021-07-01 | ニプロ株式会社 | Stable freeze-dried formulation containing daptomycin |
| WO2022160531A1 (en) * | 2021-01-26 | 2022-08-04 | 浙江创新生物有限公司 | High-stability daptomycin composition for injection, and preparation method therefor and use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1345333A (en) * | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | Echinocandin/carbohydrate complexes |
| CN1616083A (en) * | 2004-09-01 | 2005-05-18 | 魏雪纹 | Daptomycin freeze-dried preparation for injection and preparing method |
| CN101287446A (en) * | 2005-09-29 | 2008-10-15 | 尼克塔治疗公司 | Antibiotic formulations, unit doses, kits, and methods |
| CN102712677A (en) * | 2009-11-23 | 2012-10-03 | 丘比斯特药物股份有限公司 | Lipopeptide compositions and related methods |
| CN106943587A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | A kind of daptomycin freeze-dried powder pin of injection and its preparation technology |
-
2019
- 2019-04-02 CN CN201910260008.4A patent/CN110339341A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1345333A (en) * | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | Echinocandin/carbohydrate complexes |
| CN1616083A (en) * | 2004-09-01 | 2005-05-18 | 魏雪纹 | Daptomycin freeze-dried preparation for injection and preparing method |
| CN101287446A (en) * | 2005-09-29 | 2008-10-15 | 尼克塔治疗公司 | Antibiotic formulations, unit doses, kits, and methods |
| CN102712677A (en) * | 2009-11-23 | 2012-10-03 | 丘比斯特药物股份有限公司 | Lipopeptide compositions and related methods |
| CN106943587A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | A kind of daptomycin freeze-dried powder pin of injection and its preparation technology |
Non-Patent Citations (1)
| Title |
|---|
| J. SÁNCHEZ-RUBIO FERRÁNDEZ等: "Stability of daptomycin reconstituted vials and infusion solutions", 《EUR J HOSP PHARM》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021131314A1 (en) * | 2019-12-26 | 2021-07-01 | ニプロ株式会社 | Stable freeze-dried formulation containing daptomycin |
| WO2022160531A1 (en) * | 2021-01-26 | 2022-08-04 | 浙江创新生物有限公司 | High-stability daptomycin composition for injection, and preparation method therefor and use thereof |
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