CN102614493B - Liquid pharmaceutical composition containing echinocandin antifungal agent caspofungin - Google Patents
Liquid pharmaceutical composition containing echinocandin antifungal agent caspofungin Download PDFInfo
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- CN102614493B CN102614493B CN2011100342522A CN201110034252A CN102614493B CN 102614493 B CN102614493 B CN 102614493B CN 2011100342522 A CN2011100342522 A CN 2011100342522A CN 201110034252 A CN201110034252 A CN 201110034252A CN 102614493 B CN102614493 B CN 102614493B
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Abstract
The invention discloses a liquid pharmaceutical composition containing echinocandin antifungal agent caspofungin, wherein the pharmaceutical composition containing carbohydrate as a stabilizer. The pharmaceutical composition provided by the invention has good stability.
Description
Technical field
The present invention relates to treat and/or prevent the liquid pharmaceutical composition of fungal infection.More particularly, the present invention relates to Caspofungin or its pharmaceutically acceptable salt, and the stabilizing agent of pharmaceutically acceptable amount, as monosaccharide, disaccharide or polysaccharide, or its compositions.It is fluid composition.
Background technology
Echinocandin, claim again echinocandin, is the novel antifungal agent of a class, belongs to acetyl six lopps, is glucan synthase inhibitors, noncompetitive ground Antifungi cell wall-β (1,3)-D-glucosan synthetic and performance bactericidal action.Glucosan is a kind of fungal cell wall polysaccharide, is the important component of cell wall, and it can make cell wall keep integrity and make its osmotic pressure keep stable.
Caspofungin (caspofungin) (Cancidas, Merck & Co., Inc.) is the product of first listing of echinocandin antifungal agent, and its structure is suc as formula I,
It has broad-spectrum antifungal activity, and the fungus of Candida albicans, non-Candida albicans and aspergillus is all had to good antifungal activity, and the candidiasis of anti-fluconazol, amphotericin B or flucytosine, aspergillosis etc. are also had to antibacterial activity in vitro.With azole or polyenoid class, without crossing drug resistant, the candidiasis separated strain, also without natural drug resistance, is applicable to the invalid Aspergillosis that maybe can not tolerate of other treatment.U.S. Pat 2010/0137197 discloses containing Caspofungin, one or more glass transition temperatures as the sugar more than 90 ℃ and a kind of freeze-dried composition of the acetate buffer system of pH5-7 effectively is provided, its stability will be significantly better than the product Cancidas (Cancidas) that goes on the market, can under 5 ℃, preserve the longer time, or even at room temperature be preserved.
Yet above-mentioned composition is all freeze-dried products, its manufacturing process is comparatively complicated, and energy consumption is higher, and the freeze-drying process energy consumption is higher, and the production cycle is long, and the limited factors such as lyophilizing area of freeze dryer have all directly affected production efficiency, have increased production cost.And in the medication process, need to redissolve, inconvenient operation not only, and increased the risk of medication.Therefore, be necessary very much to develop a kind of manufacturing process simple, the Pharmaceutical composition that energy consumption is low and stable.
Compositions provided by the invention provides a kind of safety, and stable, reproducible liquid preparation, can be directly used in treatment/prevent fungal infections.
Summary of the invention
The unexpected discovery of the inventor comprises pharmaceutically acceptable echinocandin class antifungal compound, stabilizing agent as Caspofungin or its pharmaceutically acceptable salt and pharmaceutically acceptable amount, as monosaccharide, disaccharide or polysaccharide, or unexpected the stablizing of the liquid pharmaceutical composition of its compositions, its stability even is better than lyophilized formulations.
The invention provides a kind of pharmaceutical composition, it comprises:
A) echinocandin class antifungal compound shown in formula I or its pharmaceutically acceptable salt, and
B) stabilizing agent of pharmaceutically acceptable amount, as monosaccharide, disaccharide or polysaccharide, or its compositions.
Compositions of the present invention is liquid preparation.
The stabilizing agent comprised in compositions of the present invention is monosaccharide, disaccharide or polysaccharide, or its compositions, is preferably trehalose, sucrose or its compositions.The preferred 10-500mg/ml of concentration, more preferably 20-400mg/ml.
In compositions of the present invention, containing formula I compound concentration, be 1-150mg/ml, preferred 5-100mg/ml.
In one embodiment, the stabilizing agent trehalose that pharmaceutical composition of the present invention comprises pharmaceutically acceptable salt as the formula I compound Caspofungin of medicine activity component, suitable pharmaceutically acceptable amount.
In another embodiment, the stabilizing agent sucrose that pharmaceutical composition of the present invention comprises pharmaceutically acceptable salt as the formula I compound Caspofungin of medicine activity component, suitable pharmaceutically acceptable amount.
In another embodiment, the stabilizing agent trehalose that pharmaceutical composition of the present invention comprises pharmaceutically acceptable salt as the formula I compound Caspofungin of medicine activity component, suitable pharmaceutically acceptable amount and the compositions of sucrose.
Pharmaceutical composition provided by the invention can also contain extra pH adjusting agent, as pharmaceutically acceptable pH adjusting agents such as phosphate buffer, acetate buffer, citrate buffer agents.The preferred 5-7 of pH scope of buffer agent, more preferably 5.5-6.5.
Compositions of the present invention can also further comprise another kind, one or more pharmaceutically acceptable stabilizing agents for example, comprise diluent or carrier as known in the art, they are suitable for expection for the compositions of parenteral administration, such as the injectable formulation for intramuscular, subcutaneous, intravenous, intraperitoneal or intramuscular administration.This class stabilizing agent can comprise, such as antioxidant, a skin agent, antiseptic, carbohydrate, wax, water solublity and/or polymers capable of swelling, hydrophilic or hydrophobic material, gelatin, oil, solvent, water etc.
The present invention further provides the present composition for the preparation of preventing and/or treating mammal, the fungal infection that preferably people causes because of candida mycoderma species and/or aspergillus species and/or Jie Shi lung sac worm or the medicine of disease, the preferred purposes in intravenous drug.
Term used herein " Caspofungin " means the Caspofungin free alkali.For example, the pharmaceutically acceptable salt of Caspofungin is described in EP0620232.The present invention also comprises its solvate and/or hydrate.
Term used herein " pharmaceutically acceptable salt of Caspofungin " means the non-toxic salts of Caspofungin, preferably the pharmaceutically acceptable salt of Caspofungin is and the organic acid acid-addition salts that described organic acid is selected from acetic acid, citric acid, tartaric acid, propanoic acid, oxalic acid, malic acid, maleic acid, lactic acid, glutamic acid.Most preferably the pharmaceutically acceptable salt of Caspofungin is the Caspofungin diacetin.
The accompanying drawing explanation
Fig. 1 is formula 1 in embodiment under the 40 ℃ HPLC collection of illustrative plates of 8 weeks.
Fig. 2 is formula 5 in embodiment under the 40 ℃ HPLC collection of illustrative plates of 8 weeks.
Fig. 3 is formula 1 in embodiment under the 30 ℃ HPLC collection of illustrative plates of 8 weeks.
Fig. 4 is formula 5 in embodiment under the 30 ℃ HPLC collection of illustrative plates of 8 weeks.
The specific embodiment
Caspofungin HPLC analytical method:
Analytical column: YMC-Pack ODS-A post, specification: 250 * 4.6mm, S-5um, 1.2nm
Column temperature: 35 ℃
Detect wavelength: 220nm
The perchloric acid of mobile phase: A:0.1% and 0.075 sodium chloride solution (get perchloric acid 1.0ml and sodium chloride 0.75g, be dissolved in water and be diluted to 1000ml);
B: acetonitrile.
Gradient condition is as shown in the table:
| Time (minute) | Flow | A％ | B％ |
| Initially | 1ml/min | 65.5 | 34.5 |
| 14.5 | 1ml/min | 65.5 | 34.5 |
| 35 | 1ml/min | 50 | 50 |
| 45 | 1ml/min | 35 | 65 |
| 50 | 1ml/ |
20 | 80 |
| 52 | 1ml/ |
20 | 80 |
| 53 | 1ml/min | 65.5 | 34.5 |
| 66 | 1ml/min | 65.5 | 34.5 |
Embodiment raw material used all originates from Shanghai Tianwei Biological Pharmaceutical Corp..
Comparative Examples 1
Caspofungin acetate (by base) 40mg/ml
Trehalose 240mg/ml
Glacial acetic acid 1.5mg/ml
Sodium hydroxide is adjusted to pH6.0
The solution prepared divides in the antibiotic bottle that is filled to 2mL by the 0.5mL/ bottle, uses the plug spent the night through 110 ℃ of bakings partly to jump a queue, and sabot is put into freezer dryer and carried out lyophilization, and the lyophilization program is as follows:
A, shelf temperature are down to-40 ℃ with the speed of 0.2 ℃/min;
B, shelf temperature maintain 120min under-40 ℃;
C, unlatching cold-trap, condenser temperature is down to below-45 ℃;
D, unlatching vacuum, vacuum is down to below 80mTor;
E, shelf temperature rise to-20 ℃ with the speed of 0.1 ℃/min;
F, shelf temperature maintain 3000min under-20 ℃;
G, shelf temperature rise to-15 ℃ with the speed of 0.1 ℃/min;
H, shelf temperature maintain 900min under-15 ℃;
I, shelf temperature rise to-10 ℃ with the speed of 0.1 ℃/min;
J, shelf temperature maintain 400min under-10 ℃;
K, shelf temperature rise to-5 ℃ with the speed of 0.1 ℃/min;
L, shelf temperature maintain 400min under-5 ℃;
M, shelf temperature rise to 15 ℃ with the speed of 0.1 ℃/min;
N, shelf temperature maintain 7200min under 15 ℃;
O, shelf temperature rise to 25 ℃ with the speed of 0.1 ℃/min;
P, shelf temperature maintain 240min under 25 ℃;
Tamponade after q, the dry end, outlet, roll lid.
Freeze-dried products is positioned over respectively under 40 ℃, 75%RH and 30 ℃, 65%RH condition and carries out study on the stability, and carries out the HPLC analysis respectively at sampling after 8 weeks.
Getting trehalose 1.20g is dissolved in 3ml water, the glacial acetic acid that adds afterwards 7.5 μ l, be adjusted to pH5.1 with the sodium hydroxide of 1M, add again caspofungin acetate 0.223g, stirring and dissolving gently, and be adjusted to pH6.0 with the sodium hydroxide of 1M, add the water standardize solution to 5mL, 0.22 μ m membrane filtration, the table composed as follows of compositions (filling a prescription 2):
Caspofungin acetate (by base) 40mg/ml
Trehalose 240mg/ml
Glacial acetic acid 1.5mg/ml
Sodium hydroxide is adjusted to pH6.0
The solution prepared divides in the antibiotic bottle that is filled to 2mL by the 0.5mL/ bottle, with plug, entirely jumps a queue, and rolls lid, and is positioned over respectively under 40 ℃, 75%RH and 30 ℃, 65%RH condition and carries out study on the stability, and carries out the HPLC analysis respectively at sampling after 8 weeks.
Process for preparation is similar to embodiment 2, difference is in process for preparation, stabilizing agent is selected between the compositions of trehalose, sucrose or trehalose and sucrose, pH adjusting agent used is selected between acetate, phosphate or citrate, or even do not add any extra pH adjusting agent, obtain thus different formulas, the table composed as follows of each composite formula:
The compositions of each formula, carry out the study on the stability described in embodiment 2 equally.
The sample of Comparative Examples 1, embodiment 2 and embodiment 3 is analyzed active substance with HPLC after carrying out study on the stability respectively.
40 ℃ of stability test results are as shown in the table:
| Formula number | Temperature/℃ | Time/week | Caspofungin/% |
| 1 | 40 | 8 | 72.98 |
| 2 | 40 | 8 | 73.06 |
| 3 | 40 | 8 | 81.66 |
| 4 | 40 | 8 | 86.41 |
| 5 | 40 | 8 | 90.88 |
| 6 | 40 | 8 | 82.21 |
| 7 | 40 | 8 | 71.37 |
| 8 | 40 | 8 | 85.33 |
30 ℃ of stability test results are as shown in the table:
| Formula number | Temperature/℃ | Time/week | Caspofungin/% |
| 1 | 30 | 8 | 84.90 |
| 2 | 30 | 8 | 84.91 |
| 3 | 30 | 8 | 91.51 |
| 4 | 30 | 8 | 92.47 |
| 5 | 30 | 8 | 94.11 |
| 6 | 30 | 8 | 91.87 |
| 7 | 30 | 8 | 82.63 |
| 8 | 30 | 8 | 87.72 |
By the data in above table, can find out, the liquid combination composition formula is especially when the content of stabilizing agent reaches finite concentration, and its stability obviously is better than the freeze-dried composition of formula 1.Accompanying drawing 1～4 is shown in by HPLC collection of illustrative plates after the study on the stability of formula 1 and formula 5.
Claims (5)
1. for the antifungal Pharmaceutical composition, it is characterized in that, described compositions comprises:
A) the formula I compound of medicinal effective dose or its pharmaceutically acceptable salt; With
B) stabilizing agent of pharmaceutically acceptable amount, wherein said stabilizing agent is selected from trehalose, sucrose or its compositions;
Wherein, the formula I compound that comprises 1-150mg/ml in described compositions or its pharmaceutically acceptable salt; The stabilizing agent that comprises 10-500mg/ml in compositions;
Described compositions is liquid.
2. Pharmaceutical composition as claimed in claim 1, is characterized in that, wherein said formula I compound pharmaceutically acceptable salt is the organic acid acid-addition salts.
3. Pharmaceutical composition as claimed in claim 1, is characterized in that, comprises formula I compound or its pharmaceutically acceptable salt of 5-100mg/ml in compositions.
4. Pharmaceutical composition as claimed in claim 1, is characterized in that, comprises the stabilizing agent of 20-400mg/ml in compositions.
5. as the purposes of the arbitrary described Pharmaceutical composition of claim 1-4, it is characterized in that, for the preparation of preventing and/or treating the fungal infections in mannals medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100342522A CN102614493B (en) | 2011-01-31 | 2011-01-31 | Liquid pharmaceutical composition containing echinocandin antifungal agent caspofungin |
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| CN2011100342522A CN102614493B (en) | 2011-01-31 | 2011-01-31 | Liquid pharmaceutical composition containing echinocandin antifungal agent caspofungin |
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| CN102614493B true CN102614493B (en) | 2013-12-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4364566A1 (en) * | 2022-11-04 | 2024-05-08 | B. Braun Melsungen AG | Anti-fungal composition |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103071146A (en) * | 2012-12-27 | 2013-05-01 | 北京济圣康泰国际医药科技有限公司 | Caspofungin acetate composition and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222082A (en) * | 1996-04-19 | 1999-07-07 | 麦克公司 | Compsns. comprising antifungal agent and acetate buffer |
| CN101516387A (en) * | 2006-07-26 | 2009-08-26 | 桑多斯股份公司 | Caspofungin formulations |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5537425B2 (en) * | 2007-06-26 | 2014-07-02 | メルク・シャープ・アンド・ドーム・コーポレーション | Lyophilized antifungal composition |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222082A (en) * | 1996-04-19 | 1999-07-07 | 麦克公司 | Compsns. comprising antifungal agent and acetate buffer |
| CN101516387A (en) * | 2006-07-26 | 2009-08-26 | 桑多斯股份公司 | Caspofungin formulations |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4364566A1 (en) * | 2022-11-04 | 2024-05-08 | B. Braun Melsungen AG | Anti-fungal composition |
| WO2024094896A1 (en) * | 2022-11-04 | 2024-05-10 | B. Braun Melsungen Ag | Anti-fungal composition |
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