CN107158359A - A kind of Caspofungin freeze-dried composition of stabilization and preparation method thereof - Google Patents
A kind of Caspofungin freeze-dried composition of stabilization and preparation method thereof Download PDFInfo
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- CN107158359A CN107158359A CN201710383153.2A CN201710383153A CN107158359A CN 107158359 A CN107158359 A CN 107158359A CN 201710383153 A CN201710383153 A CN 201710383153A CN 107158359 A CN107158359 A CN 107158359A
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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
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- 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
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- 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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Abstract
The invention provides Caspofungin freeze-dried composition of a kind of stabilization and preparation method thereof.The freeze-dried composition contains Caspofungin or its officinal salt and buffer salt, and overcoming caspofungin formulations needs the shortcoming of cryopreservation, is shaped while structure is homogeneous, with preferable preparation solubility, stability.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, the Caspofungin freeze-dried composition of specially a kind of stabilization and its preparation side
Method.
Background technology
Caspofungin is a kind of echinocandin class antifungal compound of semi-artificial synthesis, the suppression that can be synthesized as glucan
Preparation, the synthesis of β (1,3)-D- glucans of Noncompetition inhibition fungal cell wall and play bactericidal action.2001, obtain
FDA approval listing, with following structure：
There are multiple peptide bonds in Caspofungin structure, while also containing multiple hydroxyls, amino and phenolic hydroxyl structure, naturally
Ground, its chemical stability extreme difference, it is easy to because of oxidation, hydrolyze and generation impurity of degrading, therefore, during longer-term storage, Ka Bo
Fragrant net needs can maintain stablize relatively or so June under the conditions of being placed in -70 DEG C.
The problem of in order to solve caspofungin formulations shelf-stability, using addition additional stabilization agent or fill out more than prior art
Fill the method for agent.For example, it is more than 90 DEG C containing Caspofungin and glass transition temperature that US2010/0137197, which is disclosed a kind of,
Nonreducing sugar lyophilized dry composition, its stability will be significantly better than Cancidas (Cancidas), can preserve at 5 DEG C
The longer time, even preserved at room temperature.CN1132624C then discloses a kind of Ka Bo containing sucrose, mannitol
Fragrant net injecta composition, CN10216648A discloses the Caspofungin containing Caspofungin, sorbierite and mannitol and freezes group
Compound, CN102614493A discloses a kind of Caspofungin composition containing stabilizer such as trehalose or sucrose, and
Caspofungin freeze-dried composition of being protected containing carbohydrate in CN103386117A and amino acid, etc..
The content of the invention
The invention provides a kind of pharmaceutical composition, the pharmaceutical composition contains Caspofungin or its officinal salt, buffering
Salt and the tert-butyl alcohol/C1-C3Alcoholic solution is constituted, and moisture is not higher than 1% (weight/mass percentage composition, w/ in the pharmaceutical composition
W%), in specific embodiment, water content can be less than or equal to 0.02,0.04,0.06,0.08,0.1,0.2,0.3,0.4,
0.5th, 0.6,0.7,0.8,0.9,1.0% or lower.
In embodiments, in foregoing pharmaceutical composition Caspofungin or its officinal salt concentration for 3mg/ml~
200mg/ml, can for 3mg/ml, 5mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 45mg/ml,
50mg/ml、55mg/ml、60mg/ml、65mg/ml、70mg/ml、75mg/ml、80mg/ml、90mg/ml、100mg/ml、
120mg/ml, 150mg/ml, 200mg/ml, further, in order to avoid Caspofungin in pharmaceutical composition or its officinal salt
The concentration of the natural precipitation phenomenon in placement process, Caspofungin or its officinal salt is 10mg/ml~80mg/ml.
Further, the C1-C3What alcohol was well known to those skilled in the art, selected from methanol, ethanol, normal propyl alcohol, isopropyl
At least one of alcohol or n-butanol, preferably methanol, ethanol or its combination.C of the present invention1-C3Alcohol is anhydrous solvent, its
Water content is not higher than 0.05%.
In some embodiments, the C1-C3The volume ratio (v/v) of alcohol and the tert-butyl alcohol is 95:5~60:40, it is ensured that card
The maxima solubility of fragrant net or its officinal salt of pool, its volume ratio can be 95:5、90:10、85:15、80:20、75:25,70:
30、65:35、60:40, further, the solvent volume ratio is 90:10~80:20.
In some embodiments, described pharmaceutical composition contains 25mg/ml Caspofungin or its officinal salt, 2mg/
Ml buffer salts and the methanol/ethanol/tert-butyl alcohol=70:20:10 solution.
In some embodiments, described pharmaceutical composition contains 40mg/ml Caspofungin or its officinal salt, 2mg/
Ml buffer salts and the methanol/ethanol/tert-butyl alcohol=75:5:20 solution.
In some embodiments, described pharmaceutical composition contains 25mg/ml Caspofungin or its officinal salt, 4mg/
Ml buffer salts and the methanol/ethanol/tert-butyl alcohol=60:20:20 solution.
In some embodiments, described pharmaceutical composition contains 60mg/ml Caspofungin or its officinal salt, 6mg/
Ml buffer salts and the methanol/ethanol/tert-butyl alcohol=80:10:10 solution.
In some embodiments, described pharmaceutical composition contain 100mg/ml Caspofungin or its officinal salt,
10mg/ml buffer salts and the methanol/ethanol/tert-butyl alcohol=85:5:10 solution.
In some embodiments, described pharmaceutical composition contain 150mg/ml Caspofungin or its officinal salt,
10mg/ml buffer salts and the methanol/tert-butyl alcohol=80:20 solution.
In some embodiments, described pharmaceutical composition contains 50mg/ml Caspofungin or its officinal salt, 5mg/
Ml buffer salts and the ethanol/tert-butyl alcohol=80:20 solution.
Further, buffer salt of the present invention is sodium acetate, in pharmaceutical composition the concentration of sodium acetate for 0.5~
20mg/ml, in embodiments the concentration of sodium acetate can for 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,
6.5th, 7,7.5,8,8.5,9,9.5,10mg/ml, is further 1~10mg/ml.
In embodiments, pharmaceutical composition pH=5~7 of the present invention, can for 5.0,5.2,5.4,5.6,5.8,
6.0、6.2、6.4、6.6、6.8、7.0。
In some embodiments, described pharmaceutical composition contains 40mg/ml caspofungin acetate, 2mg/ml sodium acetates
With the methanol/ethanol/tert-butyl alcohol=75:5:20 solution.
In some embodiments, described pharmaceutical composition contains 25mg/ml caspofungin acetate, 4mg/ml sodium acetates
With the methanol/ethanol/tert-butyl alcohol=60:20:20 solution.
In some embodiments, described pharmaceutical composition contains 60mg/ml caspofungin acetate, 6mg/ml sodium acetates
With the methanol/ethanol/tert-butyl alcohol=80:10:10 solution.
In some embodiments, described pharmaceutical composition contains 100mg/ml caspofungin acetate, 10mg/ml acetic acid
Sodium and the methanol/ethanol/tert-butyl alcohol=85:5:10 solution.
In some embodiments, described pharmaceutical composition contains 150mg/ml caspofungin acetate, 10mg/ml acetic acid
Sodium and the methanol/tert-butyl alcohol=80:20 solution.
In some embodiments, described pharmaceutical composition contains 50mg/ml caspofungin acetate, 5mg/ml sodium acetates
With the ethanol/tert-butyl alcohol=80:20 solution.
Further, freeze drying protectant or lyophilized proppant, for example, sugarcane are also contained in pharmaceutical composition of the present invention
Carbohydrate/the polyalcohol such as sugar, trehalose, mannitol, lactose, glucose, maltose；The polymer such as glucan, albumin；Sweet ammonia
The amino acid such as acid, methyl amimoacetic acid, alanine, sodium glutamate, Serine.
There are a variety of hydroxyls, amino and phenolic groups in caspofungin acetate structure, it has height not to heat and humidity
Stability.Tested by shelf-stability, using detection means such as LC-MC, NMR, substantially can confirm that impurity 3-7 is fragrant for card pool
Net catabolite, impurity 5 and 6 under high humidity or hot conditions between two molecule Caspofungins by hydrogen bond it is presumed that to be formed
Dimer compound, impurity 3,4 and 7 chemical constitutions are as follows：
Take foregoing pharmaceutical composition as test sample, place 72 hours (h) in 2~8 DEG C, be measured by sampling.The medicine group
Compound shows excellent stability, is easy to caspofungin acetate in the long term storage of 2~8 DEG C of placements.
In some embodiments, pharmaceutical composition places 72h (relative to 3 days), the wherein content of impurity 3 in 2~8 DEG C
Can be 0.1,0.09,0.08,0.07,0.06,0.05,0.04,0.03,0.02,0.01% or lower less than 0.1%；Impurity
4 content is less than 0.40%, can for 0.40,0.39,0.38,0.37,0.36,0.35,0.34,0.33,0.32,0.31,
0.30th, 0.29,0.25,0.22,0.21,0.18,0.16,0.14,0.12,0.10,0.08,0.06,0.04,0.02 or lower；
The content of impurity 5 is less than 0.2%, can for 0.20,0.19,0.18,0.17,0.16,0.15,0.14,0.13,0.12,0.11,
0.10th, 0.09,0.08,0.07,0.06,0.05,0.04,0.03,0.02 or lower；The content of impurity 6 is less than 0.1%, can be with
For 0.1,0.09,0.08,0.07,0.06,0.05,0.04,0.03,0.02,0.01% or lower；The content of impurity 7 is less than
0.1%, can be 0.1,0.09,0.08,0.07,0.06,0.05,0.04,0.03,0.02,0.01% or lower.
Present invention also offers a kind of freeze-dried composition, the freeze-dried composition is obtained by foregoing pharmaceutical composition is freeze-dried
.
Preparing freeze-dried composition step includes：A) Caspofungin or its officinal salt are dissolved in t-butanol solution, gradually
Buffer salt is added, pH=5~7 are adjusted；B) 0.22um filtering with microporous membrane is used, to form lyophilized preceding solution；C) then by step
A) resulting composition (or being lyophilized preceding solution) freeze-drying.
Further, the step c) freeze-dryings are divided into the following three stage：I) the pre-freeze phase：Lyophilized preceding solution is kept
In -20 DEG C~-10 DEG C at least 1h, the ice crystal of the sample freezed is presented chimney-like in vertical direction, not freezed in drug substance surface
Enriched layer, and the structural homogeneity of whole medicine is fine；Ii) distil the phase：Vavuum pump is opened, frozen soln is slowly adjusted into temperature
First freeze-drying temperature of -50 DEG C~-40 DEG C of angle value, keeping temperature at least 10-50h, it is 150~200 μ during which to maintain vacuum
Bar (millibar)；Iii the phase) is dried：Freeze-drying temperature is slowly adjusted to -30 DEG C~-10 DEG C, keeping temperature about 5-20h, extremely
Ice heading line off, holding vacuum is 150~200 μ bar (millibar), to form freeze-dried composition.
Further, the content containing impurity 3 is less than 0.1% in foregoing obtained freeze-drying composition, can for 0.1,0.09,
0.08th, 0.07,0.06,0.05,0.04,0.03,0.02,0.01% or lower；The content of impurity 4 is less than 0.40%, Ke Yiwei
0.40、0.39、0.38、0.37、0.36、0.35、0.34、0.33、0.32、0.31、0.30、0.29、0.25、0.22、0.21、
0.18th, 0.16,0.14,0.12,0.10,0.08,0.06,0.04,0.02 or lower；The content of impurity 5 is less than 0.2%, can be with
For 0.2,0.19,0.18,0.17,0.16,0.15,0.14,0.13,0.12,0.11,0.1,0.09,0.08,0.07,0.06,
0.05th, 0.04,0.03,0.02,0.01% or lower；The content of impurity 6 is less than 0.2%, can for 0.2,0.19,0.18,
0.17、0.16、0.15、0.14、0.13、0.12、0.11、0.1、0.09、0.08、0.07、0.06、0.05、0.04、0.03、
0.02nd, 0.01% or lower；The content of impurity 7 is less than 0.1%, can for 0.1,0.09,0.08,0.07,0.06,0.05,
0.04th, 0.03,0.02,0.01% or lower.Further, total miscellaneous content is less than 1.5% in the freeze-dried composition, can be with
For 1.5,1.4,1.3,1.2,1.1,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1 or smaller.
Meanwhile, residual solvent t butanol content is less than 0.05% in freeze-dried composition of the present invention, can for 0.05,
0.04th, 0.03,0.02,0.01%, comply fully with ICH Q3c residual solvent guidelines.
Moisture is not higher than 1% in freeze-dried composition of the present invention, can be less than or equal to 0.02,0.04,0.06,
0.08th, 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0% or lower, moisture is low in freeze-dried composition has
Beneficial to stability in placement process, the generation of degradation impurity is reduced.
Take freeze-dried composition appropriate, it is accurately weighed；Placed in -20 DEG C after June, be measured by sampling and investigate freeze-dried composition stabilization
Implementations, as a result show：Freeze-dried composition shows excellent stability, is easy to long term storage.
In some embodiments, pharmaceutical composition is placed June in -20 DEG C, and wherein the content of impurity 3 is less than 0.1%, can
Think 0.1,0.09,0.08,0.07,0.06,0.05,0.04,0.03,0.02,0.01% or lower；The content of impurity 4 is less than
0.40%, can for 0.40,0.39,0.38,0.37,0.36,0.35,0.34,0.33,0.32,0.31,0.30,0.29,
0.25th, 0.22,0.21,0.18,0.16,0.14,0.12,0.10,0.08,0.06,0.04,0.02 or lower；The content of impurity 5
Less than 0.3%, can for 0.3,0.28,0.26,0.24,0.22,0.20,0.18,0.16,0.14,0.12,0.1,0.09,
0.08th, 0.07,0.06,0.05,0.04,0.03,0.02,0.01% or lower；The content of impurity 6 is less than 0.2%, Ke Yiwei
0.2、0.19、0.18、0.17、0.16、0.15、0.14、0.13、0.12、0.11、0.1、0.09、0.08、0.07、0.06、
0.05th, 0.04,0.03,0.02,0.01% or lower；The content of impurity 7 is less than 0.2%, can for 0.2,0.19,0.18,
0.17、0.16、0.15、0.14、0.13、0.12、0.11、0.1、0.09、0.08、0.07、0.06、0.05、0.04、0.03、
0.02nd, 0.01% or lower.
Term " Caspofungin " used herein means Caspofungin free alkali." Caspofungin officinal salt " is fragrant for card pool
Only with the acid-addition salts of organic acid, further, Caspofungin officinal salt is caspofungin acetate, also known as Caspofungin two
Acetate.Caspofungin acetate of the present invention is obtained by WO2012146099 methods describeds, and other reagents used can lead to
Outsourcing mode is crossed to obtain.
Caspofungin acetate bulk drug quality used of the invention is as follows：
" purity or relevant material " of the present invention is determined by HPLC methods, and its detection method is with reference to high performance liquid chromatography
Method (two annex V D of Chinese Pharmacopoeia version in 2010)：Chromatographic column Waters Symmetry-C18 posts；With perchloric acid and sodium chloride
Mixed solution/acetonitrile is mobile phase, gradient elution.
Determination of moisture method of the present invention：The first methods of the M A of two annex of Chinese Pharmacopoeia version in 2010 VIII
Operating method：Appropriate absolute methanol is injected in titration bottle, with the titration of Ka Erfeixiushi test solutions to terminal.It is rapid to claim
Take about 0.1g test sample, inject a sample into titration bottle, make sample in methyl alcohol fully dissolve after, start determine, need to do parallel
Sample.
This product moisture is calculated as follows：
In formula：V is that test sample consumes the volume for taking Xiu Shi test solutions, ml；
F is to take quality of the Xiu Shi test solutions equivalent to water, mg/ml per 1ml；
W is the quality of test sample, mg.
Residual solvent detection method of the present invention：The second methods of P of two annex of Chinese Pharmacopoeia version in 2010 VIII are determined.
Chromatographic condition and system suitability：
Chromatographic column：Using the dimethyl polysiloxane of 6% cyanogen propyl group phenyl -94% as fixer
Heating schedule：It is 40 DEG C to originate column temperature, is maintained 5 minutes, and 100 DEG C are warming up to 20 DEG C per minute of speed, maintains 2
Minute, 180 DEG C are warming up to 80 DEG C per minute of speed, is maintained 2 minutes
Carrier gas：Carrier gas is nitrogen；Flow velocity：4.0ml/min；Split ratio：10:1；Injector temperature：160℃
The amount of residual solvent is calculated with external standard method as follows：
In formula：AiSolvent peak area to be measured in-test solution
Mi- test sample is weighed
AsSolvent peak area to be measured in-contrast solution
Ms- solvent control product to be measured are weighed
Embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate the skill of the present invention
Art scheme, and non-limiting essence of the invention.
Embodiment 1：Prepare caspofungin acetate composition
Prescription
Preparation technology：
1) 2g sucrose, 1.3g mannitol, 2.5g caspofungin acetate (lot numbers are taken；801) methanol/ethanol (70ml/ is added
In mixed solution 20ml), after stirring and dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=6.1 are added, tert-butyl alcohol 10ml is added.
Embodiment 2：Prepare caspofungin acetate composition
Prescription
Preparation technology：
1) 3.1g sucrose, 2g mannitol, 4.0g caspofungin acetate (lot numbers are taken；801) methanol/ethanol (75ml/ is added
In mixed solution 5ml), after stirring and dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=5.9 are added, tert-butyl alcohol 20ml is added.
Embodiment 3：Prepare caspofungin acetate composition
Prescription
Preparation technology：
1) 4.7g sucrose, 3.1g mannitol, 6.0g caspofungin acetate (lot numbers are taken；801) methanol/ethanol (80ml/ is added
In mixed solution 20ml), after stirring and dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=6.5 are added.
Embodiment 4：Prepare caspofungin acetate composition
Prescription
Preparation technology：
1) 7.8g sucrose, 5.2g mannitol, 10.0g caspofungin acetate (lot numbers are taken；801) methanol/ethanol is added
In the mixed solution of (55ml/45ml), after stirring and dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=6.2 are added.
Embodiment 5：Prepare caspofungin acetate composition
Prescription
Preparation technology：
1) 11.6g sucrose, 7.7g mannitol, 15.0g caspofungin acetate (lot numbers are taken；901) add in methanol (80ml),
After stirring and dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=5~7 are added, tert-butyl alcohol 20ml is added.
Embodiment 6：Prepare caspofungin acetate composition
Prescription
Preparation technology：
1) 3.9g sucrose, 2.6g mannitol, 5.0g caspofungin acetate (lot numbers are taken；901) add in ethanol (80ml), stir
Mix after dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=6.0 are added, tert-butyl alcohol 20ml is added.
Embodiment 7：Prepare caspofungin acetate composition
Prescription
Caspofungin acetate (based on Caspofungin alkali, similarly hereinafter) 50mg/ml
Sodium acetate 10mg/ml
Preparation technology：
1) 5.0g caspofungin acetate (lot numbers are taken；901) add in water (80ml), after stirring and dissolving；
2) proper amount of acetic acid sodium regulation pH value of solution=6.0 are added.
Embodiment 8：Composition is prepared according to CN103315969 comparative example 3
Prescription
Caspofungin acetate (based on Caspofungin alkali, similarly hereinafter) 50mg/ml
Sucrose 40mg/ml
Mannitol 26mg/ml
Preparation technology：Take mannitol 0.5g, sucrose 0.75g to be dissolved in 20ml water, 1.17g caspofungin acetates are added afterwards
(lot number；901), pH6.2 is adjusted with 1M sodium hydroxide, hydrochloric acid.
Embodiment 9：Composition is prepared according to CN103315969 comparative example 2
Prescription
Preparation technology：Trehalose 1.20g is dissolved in 3ml water, and 7.5 μ l glacial acetic acid is added afterwards, with 1M sodium hydroxide
PH5.1 is adjusted to, 0.223g caspofungin acetate (lot numbers are added；901), it is gently mixed dissolving, and with 1M sodium hydroxide, salt
Acid is adjusted to pH6.0, and the constant volume that adds water is to 5mL, and 0.22 μm of membrane filtration is produced.
Embodiment 10：2~8 DEG C of shelf-stability experiments
Using previous embodiment 1-9 pharmaceutical compositions as test sample, 3 days stability datas are placed in 2~8 DEG C as follows：
Table 1 places 3 days stability in 2~8 DEG C
Conclusion：In the tert-butyl alcohol/C1-3 alcoholic solution systems, each prescription is all highly stable under the conditions of 2~8 DEG C, places
Caspofungin content is not reduced significantly after 3d, and the prescription in aqueous solution system is poor in 2~8 DEG C of condition stability inferiors,
Composition reclaimed water can promote the degraded of Caspofungin to produce impurity 3,4, can influence the quality of follow-up freeze-dried composition.
Embodiment 11：Pharmaceutical composition obtained by embodiment 1-9 is prepared into freeze-dried composition
Preparation technology：
I) embodiment 1-9 pharmaceutical composition (solvent before lyophilized) is maintained at -20 DEG C~-10 DEG C at least 1h respectively, frozen
Chimney-like is presented in vertical direction in the ice crystal of the sample of knot, and Freeze concentration layer, and the knot of whole medicine are not formed on surface
Structure homogeneity is fine；Ii vavuum pump) is opened, frozen soln is slowly adjusted to the first freeze-drying of -50 DEG C~-40 DEG C of temperature value
Temperature, keeping temperature at least 10-50h, it is 150~200 μ bar (millibar) during which to maintain vacuum；Iii) freeze-drying temperature is delayed
Slow regulation is to -30 DEG C~-10 DEG C, keeping temperature about 5-20h, to ice heading line off, holdings vacuum for 150~200 μ bar (in the least
Bar), to form freeze-dried composition.
The relevant material of the embodiment 1-9 freeze-dried compositions of table 2
Embodiment 12：Embodiment 1-9 freeze-dried compositions are positioned over -20 DEG C, 2~8 DEG C of investigation stability, specific stability
Data are as follows：
Table 3 is in -20 DEG C of condition shelf-stability data
Table 4 is in 2-8 DEG C of condition shelf-stability data
Conclusion：The lyophilized system of the tert-butyl alcohol is more stable under the conditions of 2~8 DEG C beneficial to each prescription, places Caspofungin after June
Content is not reduced significantly, still in tolerance interval.Further, the tert-butyl alcohol freeze in system ethanol or methanol ratio compared with
Freeze concentration layer occurs in drug substance surface in Gao Shi, the more difficult solidification in step of freeze drying i) of the present invention, and homogeneity is bad,
Influence follow-up step of freeze drying, and obtained freeze-drying composition structure heterogeneity, it may appear that slightly lump, such as the sample knot of embodiment 3 or 4
Structure heterogeneity, there is caking phenomenon, stability number value difference is in than other samples.
Embodiment 13：The redissolution time of embodiment 1-9 freeze-dried compositions
Embodiment 1-9 freeze-dried compositions are blent into dilution with 0.9% physiological saline respectively, the redissolution of freeze-dried composition is investigated
Time.
Table 5
Conclusion：During caspofungin acetate freeze-dried composition is prepared, carried out with containing less than 10% t-butanol solution
It is lyophilized, it is easy to occur collapsing or caking phenomenon in gained sample, directly affects obtained freeze-drying composition and redissolve the time.Do not freezing
In the case of dry protective agent or filler, it is in pie to be carried out using water lyophilized obtained freeze-drying composition more, and it is longer that it redissolves time, and
Water content is higher in obtained freeze-drying composition, and long-time stability can be poor.In addition, when aqueous high in freeze-dried composition, even if containing
Mannitol, redissolves the time also longer.
Embodiment 14：Lyophilized technique is investigated
Prescription described in embodiment 2 is subjected to lyophilized experiment, optimal lyophilized parameter is investigated
Table 6
| The pre-freeze phase | The distillation phase | The phase of drying | |
| Experimental example 1 | -20℃ | - 50 DEG C, 180 μ bar | - 30 DEG C, 150 μ bar |
| Experimental example 2 | -10℃ | - 40 DEG C, 200 μ bar | - 20 DEG C, 150 μ bar |
| Experimental example 3 | -40℃ | - 50 DEG C, 180 μ bar | - 30 DEG C, 180 μ bar |
| Experimental example 4 | -60℃ | - 50 DEG C, 180 μ bar | - 20 DEG C, 150 μ bar |
Table 7
Note：The loose shape of usual freeze-dried powder is better than shrunk better than caking shape, caking shape.
Conclusion：Pressure and temperature has large effect to the outward appearance and quality of freeze-dried composition in freeze-drying process, works as pre-freeze
Phase stablizes too low, and solvent will be because of rapid freeze-drying in drug substance surface formation Freeze concentration layer, and internal structure ice crystal before freezing
Size differs, and homogeneity is bad, influences the molding effect of freeze-dried composition, freeze-dried powder structure heterogeneity, surface irregularity.
Claims (10)
1. a kind of pharmaceutical composition, containing Caspofungin or its officinal salt, buffer salt and the tert-butyl alcohol/C1-C3Alcoholic solution, it is described
Moisture is not higher than 1% in pharmaceutical composition pH=5~7, preferably described pharmaceutical composition.
2. pharmaceutical composition according to claim 1, it is characterised in that the concentration of the Caspofungin or its officinal salt
For 3mg/ml~200mg/ml, preferably 10mg/ml~150mg/ml.
3. pharmaceutical composition according to claim 1 or 2, it is characterised in that the C1-C3Alcohol is selected from methanol, ethanol, just
At least one of propyl alcohol, isopropanol or n-butanol, preferably methanol, ethanol or its combination.
4. pharmaceutical composition according to claim 3, it is characterised in that the C1-C3Volume ratio (the v/ of alcohol and the tert-butyl alcohol
V) it is 95:5~60:40, preferably 90:10~80:20.
5. the pharmaceutical composition according to claim any one of 1-4, it is characterised in that the buffer salt is sodium acetate, preferably
The concentration of the sodium acetate is 0.5~20mg/ml, preferably 1~10mg/ml.
6. the pharmaceutical composition according to claim any one of 1-5, it is characterised in that described pharmaceutical composition is in 2~8 DEG C
72h is placed, the wherein content of impurity 3 is less than 0.1%, and the content of impurity 4 is less than 0.40%,
7. a kind of freeze-dried composition, is freeze-dried by any one of claim 1-6 described pharmaceutical composition and obtained, described lyophilized group
The content of impurity 3 is less than 0.1% in compound, and the content of impurity 4 is less than 0.40%.
8. freeze-dried composition according to claim 7, it is characterised in that the freeze-dried composition places June in -20 DEG C,
Wherein the content of impurity 3 is less than 0.1%, and the content of impurity 4 is less than 0.40%.
9. a kind of method for preparing freeze-dried composition described in claim 7-8, including：
A) buffer salt in Caspofungin or its officinal salt t-butanol solution, will be gradually added into, pH=5~7 are adjusted；
B) 0.22um filtering with microporous membrane is used, to form lyophilized preceding solution；
C) will lyophilized preceding solution freeze-drying.
10. preparation method according to claim 9, wherein step c) includes：
I) solution is maintained at -20 DEG C~-10 DEG C at least 1h before will be lyophilized；
Ii vavuum pump) is opened, frozen soln is slowly adjusted to the first freeze-drying temperature of -50 DEG C~-40 DEG C of temperature value, kept
Temperature at least 10-50h, it is 150~200 μ bar (millibar) during which to maintain vacuum；
Iii) freeze-drying temperature is slowly adjusted to -30 DEG C~-10 DEG C, keeping temperature about 5-20h, to ice heading line off, is kept
Vacuum is 150~200 μ bar (millibar), to form freeze-dried composition.
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