CN103142997A - Medical composition containing antifungal agent and succinate buffer liquid - Google Patents

Abstract

The invention relates to a medical composition which comprises a) caspofungin in medical effective quantity or pharmaceutically acceptable salt, b) a pharmaceutically acceptable amount of succinate buffer liquid with the pH value of 4-7 and c) a pharmaceutically acceptable amount of excipient. The medical composition provided by the invention is high in stability, good in safety, convenient to use, simple in preparation process and suitable for industrial production.

Description

The pharmaceutical composition that contains antifungal and succinate buffer

Technical field:

The invention belongs to medical technical field, be specifically related to contain the pharmaceutical composition of antifungal Caspofungin and succinate buffer.

Background of invention:

Caspofungin (Caspofungin) is the echinocandin class antifungal compound by the first listing of Merck ﹠ Co., Inc.'s release, Caspofungin has broad-spectrum antifungal activity, fungus to Candida albicans, non-Candida albicans and aspergillus has good antibacterial activity, with azole or polyenoid class without crossing drug resistant, the candidiasis separated strain also without natural drug resistance, is applicable to the Aspergillosis that other is failed to respond to any medical treatment and maybe can not tolerate.

Caspofungin itself is highly unstable, can degrade with various forms such as hydrolysis, oxidation, dimerization.Pharmaceutically improve the stability of medicine by the method for adding sugar part and buffer salt.European patent EP 0620232A discloses Caspofungin and preparation method thereof first.The acetate buffer system that Chinese patent CN1132624C discloses the excipient that contains Caspofungin, pharmaceutically acceptable amount and pharmaceutically acceptable amount to be forming the pharmaceutical composition of pH value as 4～7, and said composition is selected acetate buffer rather than tartrate buffer and is considered to have the stability of enhancing.US Patent No. 20100137197 discloses and has contained Caspofungin, one or more glass transition temperatures for the sugar more than 90 ℃ and a kind of freeze-dried composition of the acetate buffer of pH5～7 effectively is provided, it can preserving the longer time below 5 ℃, even can at room temperature be preserved.Yet, stability data under the disclosed high temperature of this patent shows, its at high temperature stable unsatisfactory, the trehalose formula of low ratio occurs sharply to degrade within a short period of time, even the stability trehalose formula of height ratio preferably also has larger degraded within a short period of time, can't accomplish at room temperature to preserve for a long time.Chinese patent CN101516387A also discloses a kind of pharmaceutical composition that contains Caspofungin, and it thinks that described pharmaceutical composition has stability preferably because of the acetate buffer that contains extra small amount.This patent only discloses the stability data under low temperature environment, only proves that these formulas have good stability at a lower temperature.For the ease of transportation and the storage of medicine, be badly in need of obtaining a kind of more stable formula, make this pharmaceutical composition have higher stability.

The inventor is through a large amount of experimentatioies, pleasantly surprised discovery, the Caspofungin pharmaceutical composition of selecting the succinate buffer to prepare, than the pH adjusting agent of selecting other kind, acetate buffer for example, have higher stability, and said composition preparation technology is simple, is fit to very much suitability for industrialized production.

Summary of the invention:

The invention provides a kind of pharmaceutical composition, it comprises:

A) Caspofungin or its pharmaceutically acceptable salt;

B) effectively form the excipient of the pharmaceutically acceptable amount of lyophilized cake; With

C) the succinate buffer of pharmaceutically acceptable amount is to obtain pharmaceutically acceptable pH, and this pH value is 4～7.

In a specific technical scheme, compositions of the present invention comprises Caspofungin or its pharmaceutically acceptable salt of 10～100mg/ml, the filler of 10～200mg/ml, the succinate buffer of 10～200mM, and water for injection.Preferably, compositions of the present invention comprises Caspofungin or its pharmaceutically acceptable salt of 40～60mg/ml, the filler of 35～150mg/ml, the succinate buffer of 25～50mM, and water for injection.

Term used herein " Caspofungin " refers to the Caspofungin free alkali, and this compound is described in EP0620232A.The present invention also comprises its solvate and/or its hydrate.

Term used herein " pharmaceutically acceptable salt " refers to the non-toxic salts of active component, be preferably and the organic acid acid-addition salts, described organic acid includes but not limited to acetic acid, citric acid, tartaric acid, propanoic acid, oxalic acid, malic acid, maleic acid, lactic acid and glutamic acid.In the present invention, the more preferably acetate of Caspofungin of pharmaceutically acceptable salt.The Caspofungin that compositions of the present invention comprises or the concentration range of its pharmaceutically acceptable salt are 10～100mg/ml, preferred 40～60mg/ml.

Term used herein " effectively forms the excipient of lyophilized cake " and is interpreted as this excipient is added in compositions in a large number, produces the cake of good form in freeze-drying process.This class excipient is preferably the filler of effective formation lyophilized cake, and this class filler can also be as stabilizing agent, because it also has Stabilization.Suitable filler includes but not limited to the polyhydroxy sugar alcohols, and for example trihydroxy or higher alcohols are such as glycerol, xylitol, sorbitol and mannitol; Lactose, sucrose, trehalose, glucose, glucosan, hetastarch, gelatin or its mixture.The preferred filler of the excipient of compositions of the present invention, its content range are 10～200mg/ml, preferred 35～150mg/ml.

Compositions of the present invention comprises the succinate buffer of effective dose so that pharmaceutically acceptable pH to be provided, and this pH value is 4～7, preferred 6～7.To obtain required pH, can use the sodium succinate of appropriate amount and succinic acid and the sodium hydroxide of succinic acid or appropriate amount for succinate buffer that effective dose is provided.Succinate buffer content range is 10～200mM, preferred 25～50mM.

In a preferred technical scheme, compositions of the present invention comprises: a) caspofungin acetate of 42mg/ml; B) mannitol of 10mg/ml, the sucrose of 60mg/ml; C) the succinate buffer of 35mM.

In a preferred technical scheme, compositions of the present invention comprises: a) caspofungin acetate of 42mg/ml; B) mannitol of 10mg/ml, the sucrose of 80mg/ml; C) the succinate buffer of 50mM.

In a preferred technical scheme, compositions of the present invention comprises: a) caspofungin acetate of 42mg/ml; B) mannitol of 10mg/ml, the sucrose of 60mg/ml; C) the succinate buffer of 50mM.

In a preferred technical scheme, compositions of the present invention comprises: a) caspofungin acetate of 42mg/ml; B) mannitol of 10mg/ml, the sucrose of 80mg/ml; C) the succinate buffer of 35mM.

In a preferred technical scheme, compositions of the present invention comprises: a) caspofungin acetate of 42mg/ml; B) sucrose of 80mg/ml; C) the succinate buffer of 35mM.

Pharmaceutical composition of the present invention can also comprise another kind, one or more pharmaceutically acceptable excipient for example, comprise diluent or carrier as known in the art, they are suitable for preparing the pharmaceutical composition that non-intestinal is used, such as the ejection preparation that is used for intramuscular injection, subcutaneous injection, intravenous injection or lumbar injection.This class excipient comprises antioxidant, antiseptic, carbohydrate, wax, water solublity and/or swellable polymer, hydrophilic or hydrophobic material, gelatin and water.

The present invention also provides pharmaceutical composition of the present invention for the preparation of the purposes in the medicine that prevents and/or treats fungal infection.The infection that described fungal infection is preferably caused by Candida and/or aspergillus and/or Pneumocystis carinii.

The present invention also provides a kind of method for preparing the pharmaceutical composition that contains Caspofungin, comprising:

A) excipient with 10～200mg/ml is dissolved in water for injection;

B) add 10～200mM succinic acid;

C) add the Caspofungin of 10～100mg/ml or its pharmaceutically acceptable salt and stirring to make its dissolving, then with sodium hydroxide adjust pH to 4～7;

D) filtration step c) gained solution, and with the filtrate packing, be filled in the lyophilizing bottle;

E) freezing steps d) gained contains the lyophilizing bottle of filtrate to-40 ℃;

F) prior to 10～0 ℃ of lyophilizations, then in 15 ℃ of vacuum drying step e) the obtained freeze-drying bottle, thus obtain containing the pharmaceutical composition of Caspofungin or its pharmaceutically acceptable salt.

Pharmaceutical composition of the present invention compared with prior art demonstrates higher stability and safety, and preparation technology is simple, is fit to suitability for industrialized production fully.

The specific embodiment

The present invention is described in detail by the following examples, must be pointed out, following examples are for explanation

The present invention, and should not be construed as limitation of the present invention.

Embodiment 1

The present embodiment carries out screening study to several known pH adjusting agents, and the design prescription is as follows:

?	Excipient	Active component	PH adjusting agent
				Prescription 1	Sucrose, 30mg/ml; Twenty reveals alcohol, 20mg/ml	Caspofungin acetate, 42mg/ml	Succinic acid, 25mM
Prescription 2	Sucrose, 30mg/ml; Mannitol, 20mg/ml	Caspofungin acetate, 42mg/ml	Acetic acid, 25mM
				Prescription 3	Sucrose, 30mg/ml; Mannitol, 20mg/ml	Caspofungin acetate, 42mg/ml	Citric acid, 25mM
Prescription 4	Sucrose, 30mg/ml; Mannitol, 20mg/ml	Caspofungin acetate, 42mg/ml	Lactic acid, 25mM
				Prescription 5	Sucrose, 30mg/ml; Mannitol, 20mg/ml	Caspofungin acetate, 42mg/ml	Maleic acid, 25mM
Prescription 6	Sucrose, 30mg/ml; Twenty reveals alcohol, 20mg/ml	Caspofungin acetate, 42mg/ml	Glutamic acid, 25mM
				Prescription 7	Sucrose, 30mg/ml; Mannitol, 20mg/ml	Caspofungin acetate, 42mg/ml	MES，25mM
Prescription 8	Sucrose, 30mg/ml; Mannitol, 20mg/ml	Caspofungin acetate, 42mg/ml	Aspartic Acid, 25mM

Above-mentioned prescription 1～8 is carried out 40 ℃ of Study on influencing factors, and it the results are shown in following table:

?	Total assorted (40 ℃, 0 day)	Total assorted (40 ℃, 5 days)	Total assorted (40 ℃, 10 days)
				Prescription 1	0.93％	2.60％	4.21％
Prescription 2	0.82％	3.75％	5.68％
				Prescription 3	0.78％	3.93％	6.43％
Prescription 4	0.80％	4.12％	8.36％
				Prescription 5	0.83％	4.53％	10.02％
Prescription 6	0.88％	4.63％	9.93％
				Prescription 7	0.85％	4.26％	9.60％
Prescription 8	1.05％	5.21％	12.46％

Result shows, the pharmaceutical composition of selecting the succinate buffer to prepare than the pH adjusting agent of selecting other kind, demonstrates higher stability.

Embodiment 2

Prescription:

Supplementary material

Concentration

Caspofungin acetate	42mg/ml
		Sucrose	60mg/ml
Mannitol	10mg/ml
		Succinic acid	35mM
Sodium hydroxide	In right amount, regulate pH to 6.0～6.5
		Water for injection	In right amount

Sucrose and the mannitol of recipe quantity are dissolved in water for injection, the succinic acid that adds recipe quantity, then add caspofungin acetate and the stirring of recipe quantity to make its dissolving, then drip 10% sodium hydroxide solution regulator solution pH to 6.0～6.5, filter, gained filtrate is divided be filled in the lyophilizing bottle, and lyophilizing at 40 ℃ of temperature, follow in 10 ℃ of lyophilizations, then in 15 ℃ of vacuum dryings, obtain the lyophilized powder of pharmaceutical composition.Finished product is in 5 ℃ of stored refrigerated.

Preparation contains other compositions (each compositions is according to the solution preparation of 42mg/ml active component concentration) of following component according to the method for embodiment 2:

Embodiment	Buffer	Excipient
			Embodiment 3	Succinic acid, 25mM	Mannitol, 20mg/mL; Sucrose, 30mg/ml
Embodiment 4	Succinic acid, 35mM	Mannitol, 20mg/mL; Sucrose, 30mg/ml
			Embodiment 5	Succinic acid, 50mM	Mannitol, 20mg/mL; Sucrose, 30mg/ml
Embodiment 6	Succinic acid, 75mM	Mannitol, 20mg/mL; Sucrose, 30mg/ml
			Embodiment 7	Succinic acid, 35mM	Mannitol, 10mg/ml; Sucrose 30mg/ml
Embodiment 8	Succinic acid, 50mM	Mannitol, 10mg/mL; Sucrose, 80mg/ml
			Embodiment 9	Succinic acid, 35mM	Mannitol, 40mg/mL; Sucrose, 30mg/ml
Embodiment 10	Succinic acid, 35mM	Mannitol, 60mg/mL; Sucrose, 30mg/ml
			Embodiment 11	Succinic acid, 35mM	Mannitol, 20mg/mL; Sucrose, 15mg/ml
Embodiment 12	Succinic acid, 35mM	Mannitol, 20mg/mL; Sucrose, 30mg/ml
			Embodiment 13	Succinic acid, 35mM	Mannitol, 20mg/mL; Sucrose, 60mg/ml
Embodiment 14	Succinic acid, 50mM	Mannitol, 10mg/mL; Sucrose, 60mg/ml
			Embodiment 15	Succinic acid, 35mM	Mannitol, 10mg/mL; Sucrose, 80mg/ml
Embodiment 16	Succinic acid, 35mM	Sucrose, 80mg/ml

The form of the above-mentioned compositions for preparing with lyophilizing stored under 5 ℃, test every other month its stability.Measure the formation of its stability and degradation product through gradient HPLC with well known to a person skilled in the art standard method.Result shows, embodiment 2,8, and 14,15,16 compositionss that prepare are more stable than the formula of other compositions, and shows significantly few unwanted degradation impurity.

Claims (10)

1. pharmaceutical composition, described compositions comprises:

A) Caspofungin or its pharmaceutically acceptable salt;

B) effectively form the excipient of the pharmaceutically acceptable amount of lyophilized cake; With

C) the succinate buffer of pharmaceutically acceptable amount is to obtain pharmaceutically acceptable pH, and this pH value is 4～7.

2. pharmaceutical composition according to claim 1, it comprises:

A) Caspofungin of 10～100mg/ml or its pharmaceutically acceptable salt;

B) filler of 10～200mg/ml;

C) the succinate buffer of 10～200mM.

3. pharmaceutical composition according to claim 2, it comprises:

A) Caspofungin of 40～60mg/ml or its pharmaceutically acceptable salt;

B) filler of 35～150mg/ml;

C) the succinate buffer of 25～50mM.

4. pharmaceutical composition according to claim 3, it comprises:

A) caspofungin acetate of 42mg/ml;

B) mannitol of 10mg/ml, the sucrose of 60mg/ml;

C) the succinate buffer of 35mM.

5. pharmaceutical composition according to claim 3, it comprises:

A) caspofungin acetate of 42mg/ml;

B) mannitol of 10mg/ml, the sucrose of 80mg/ml;

C) the succinate buffer of 50mM.

6. pharmaceutical composition according to claim 3, it comprises:

A) caspofungin acetate of 42mg/ml;

B) mannitol of 10mg/ml, the sucrose of 60mg/ml;

C) the succinate buffer of 50mM.

7. pharmaceutical composition according to claim 3, it comprises:

A) caspofungin acetate of 42mg/ml;

B) mannitol of 10mg/ml, the sucrose of 80mg/ml;

C) the succinate buffer of 35mM.

8. pharmaceutical composition according to claim 3, it comprises:

A) caspofungin acetate of 42mg/ml;

B) sucrose of 80mg/ml;

C) the succinate buffer of 35mM.

9. the described pharmaceutical composition of claim 1～8 any one is for the preparation of the purposes in the medicine that prevents and/or treats fungal infection.

10. method for preparing the pharmaceutical composition that contains Caspofungin or its pharmaceutically acceptable salt, described method comprises:

A) excipient with 10～200mg/ml is dissolved in water for injection;

B) add the succinic acid of 10～200mM;

C) add the Caspofungin of 10～100mg/ml or its pharmaceutically acceptable salt to make its dissolving, then with sodium hydroxide adjust pH to 4～7;

D) filtration step c) gained solution, and with the filtrate packing, be filled in the lyophilizing bottle;

E) freezing steps d) gained contains the lyophilizing bottle of filtrate to-40 ℃;

F) prior to 10～0 ℃ of lyophilizations, then in 15 ℃ of vacuum drying step e) the obtained freeze-drying bottle, thus obtain containing the pharmaceutical composition of Caspofungin or its pharmaceutically acceptable salt.