CN101516387A

CN101516387A - Caspofungin formulations

Info

Publication number: CN101516387A
Application number: CNA2007800349909A
Authority: CN
Inventors: C·韦尔茨; G·斯蒂鲍尔; A·施马尔达; H·延内魏因; I·马赫尔; J·卢德谢尔
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 2006-07-26
Filing date: 2007-07-24
Publication date: 2009-08-26
Anticipated expiration: 2027-07-24
Also published as: CN101516387B

Abstract

The present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable salt of caspofungin as active ingredient being useful for the prevention and/or treatment of fungal infections. Said compositions additionally comprise specific bulking agents and small amounts or no amounts of an additional pH modifier and may be in a liquid or solid form, e.g. may be lyophilized compositions. Said compositions show good stability and reduced amounts of sub-visible particulate matter formed in solutions which are reconstituted from the lyophilized product.

Description

Caspofungin formulations

Invention field

The present invention relates to comprise medicine activity component be used to prevent and/or treat fungal infection and/or the pharmaceutical composition of the disease that produces by described infection.More particularly, the present invention relates to comprise chemical compound Caspofungin as active component, concrete filler and a small amount of or do not have the compositions of extra pH regulator agent, it is liquid or solid compositions, for example freeze-dried composition.

Background of invention

Compositions of the present invention is included as the Caspofungin free alkali as medicine activity component of formula I chemical compound:

Known its is effective antifungal agent and antiprotozoal.The azacyclo-hexapeptide compounds Caspofungin that belongs to echinocandin family has CAS registration number 162808-62-0 and CAS name 1-[(4R, 5S)-the 5-[(2-amino-ethyl) amino-N ²-(10,12-dimethyl-1-oxo myristyl-4-hydroxyl-L-ornithine]-5-[(3R)-3-hydroxyl-L-ornithine]-lung reads and to decide B ₀(Merck Index online, 2001-2005 version, Merck ﹠amp; Co., Inc., Whitehouse Station, NJ, USA).Caspofungin exists with the form of various pharmaceutically acceptable salts, such as, for example at the oxalic acid Caspofungin described in European patent EP 0 904 098 B1.Caspofungin and preparation method thereof for example is described among the WO94/21677 and EP 620232, disclosed the Caspofungin that in many other azacyclo-hexapeptide compounds and pharmaceutically acceptable salt thereof, is used in particular for controlling the mycosis infection in these documents especially, such as hydrochlorate, sulfate, citrate or other acid-addition salts.Caspofungin (tris)-trifluoroacetate and (tris)-hydrochlorate has been described.Disclosed other method of preparation Caspofungin and particularly Caspofungin diacetin among the WO96/24613.Caspofungin can effectively prevent and/or treat because of filamentous fungi and yeast, the infection that causes such as the kind (Candida sp.) of the kind (Blastomyces sp.) of the kind (Coccidioides sp.) of the kind (Aspergillus sp.) of Eurotium, ball spore Pseudomonas, Blastomyces and/or mycocandida, and be used for prevention and/or control and/or this class of treatment such as the pneumonia that causes because of Jie Shi lung sac worm (Pneumocystis jiroveci) (being categorized as Pneumocystis carinii (Pneumocystiscarinii) in the past) and infect.Can pass through parenteral,, use to the compositions of lyophilizing or liquid preparation and use Caspofungin for example through intravenous.

Disclosed in European patent EP 0 904 098 B1 or the U.S. Pat 5,952,300 and comprised the extra acetate buffer of Caspofungin, 25mM-50mM and the lyophilized formulations of filler such as sucrose and/or mannitol or its mixture.Think that described preparation has enhanced chemical stability because of having used acetate buffer rather than tartrate buffer agent.Changing over acetate buffer according to reports causes less catabolite and generation to have the more stable lyophilized formulations that prolongs the shelf life.The preparation that is lyophilized into the liquid preparation that is used for the finished product that parenteral, particularly intravenous use is consuming time and complicated operation, needs 2 step pH regulator thus.

In addition, use carrier solution according to reports, such as, water for injection for example, or normal saline or 5% D/W dissolve this class freeze-drying medicinal composition again and may cause forming in solution visible and/or be lower than visible granule, as described in WO 02/41919 A1 that relates to pantoprazole injection.Injectable solution, such as by aseptic, for example the dissolved again solution of lyophilized solid generally should be substantially free of and can use the observed granule of vision.For patient's safety, also need this class Injectable solution to have the visible granule of being lower than of low quantity.This class granule can be external granule, for example derives from the vial that comprises freeze-drying prods.This class is lower than visible granule and for example can causes intravenous to accept the risk increase of patient's thromboembolism of dissolved product again.Known ethylenediaminetetraacetic acid (EDTA) or its sodium salt generally are used for reducing the granule formation that expection is used for the conventional medicine preparation of parenteral administration, for example dissolved again lyophilized solid or ready-to-use liquid-liquid preparation, such as, for example as among the WO 02/41919A1 to as described in the Protonix and US 6, described among 900,184 B2 to the compositions of recipe comprising piperacillin Tazobactam Sodium.

Expectation provides liquid or the freeze-dried composition that comprises Caspofungin, it have reduce quantity be lower than visible granule so that even under the situation of not adding any extra EDTA or related substances, increase patient's safety.In addition, expect this based composition have good stable and long shelf life and can by easy and fast method produce.

In addition, other salt of expectation Caspofungin provides the probability of the salt form selected that uses Caspofungin for those skilled in the art.Described new salt should be stable, should be able to carry out mass preparation and should be easy to when preparation comprises the pharmaceutical composition of Caspofungin salt handling.

Summary of the invention

The inventor finds at present to comprise the pharmaceutically acceptable salt of Caspofungin and pharmaceutically acceptable excipient unexpectedly, a small amount of pH regulator agent is only being arranged and even in the presence of basically without any extra pH regulator agent or buffer agent, for example without any extra acetate buffer or other is known as buffer agent and/or has in the presence of the material of buffer capacity and stablizes unexpectedly arbitrarily such as the pharmaceutical composition of the filler that is suitable for forming lyophilized cake.

The inventor has been found that and only adds a small amount of pH regulator agent, is enough to obtain stable formulation such as adding the acetic acid that consumption is lower than the described Caspofungin salt of 0.3 molar equivalent.The inventor finds that further if use the pharmaceutically acceptable salt of Caspofungin, for example the oxalic acid Caspofungin adds the pH regulator agent so and not even necessarily do not obtain stable formulation.

In addition, the inventor has been found that when compositions of the present invention is dissolved with solvent after lyophilizing again, although do not have EDTA or related compound, still shows the visible granule of being lower than of remarkable minimizing quantity.Even more unexpectedly, compositions of the present invention is compared with the compositions that comprises EDTA sodium and is shown the granule that more reduces quantity.

Therefore, the invention provides pharmaceutical composition, it comprises:

A) pharmaceutically acceptable salt of Caspofungin,

B) consumption be lower than 0.3 molar equivalent described Caspofungin salt extra pH regulator agent and

C) but effectively form the excipient of the pharmacy receiving amount of lyophilized cake, preferred filler.

The pharmaceutically acceptable salt of preferred Caspofungin is the oxalic acid Caspofungin, and filler preferably is made up of one or more filleies, is also referred to as the filling saccharide in this article, preferably mannitol, sucrose or its combination.

In another aspect of the present invention, compositions of the present invention is substantially free of any extra pH regulator agent.

In addition, the invention provides can be by the lyophilized powder of the aforesaid pharmaceutical composition acquisition of the present invention of lyophilizing.This lyophilized powder is suitable for being dissolved into the fluid composition that parenteral, preferred intravenous are used again.In addition, the invention provides can be by dissolving the pharmaceutical composition that described lyophilized powder obtains again with aqueous solution, preferred distilled water of described aqueous solution and/or sterile water for injection, the optional bacteriostatic water for injection that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution, and/or ringer lactate solution.

The present invention further provides the present composition and be used to prevent and/or treat mammal, the fungal infection that preferred people causes because of candida mycoderma species and/or aspergillus species and/or Jie Shi lung sac worm or the medicine of disease, the purposes in the preferred intravenous drug in preparation.

The present invention also provides the method for preparing the pharmaceutical composition of the pharmaceutically acceptable salt that contains Caspofungin, and this method comprises the following steps:

1) combination of filler or filler is water-soluble;

2) join the pharmaceutically acceptable salt of Caspofungin in the solution that obtains in the step 1) and dissolve it;

3) adding is lower than the extra pH regulator agent of the described Caspofungin salt of 0.3 molar equivalent;

4) filtration step 3) the middle solution that obtains;

5) solution that obtains in the freezing step 4), and

6) the refrigerated solution of lyophilization.

The present invention provides the method for preparing the pharmaceutical composition of the pharmaceutically acceptable salt that contains Caspofungin according to the method described above in one aspect of the method, does not wherein comprise step 3).

In addition, the invention provides can be by the compositions of said method acquisition.

Pharmaceutical composition of the present invention is stable unexpectedly, promptly they comprise with the conventional composition that comprises extra a large amount of acetic acid or acetate buffer in observed very nearly the same and even be lower than the overall impurity of their low quantity.In addition, compositions of the present invention and the buffered conventional formulation of acetate and/or the preparation that contains EDTA are compared and are shown the visible granule that is lower than that reduces quantity.Advantageously, compositions of the present invention can directly be passed through the method production more easier than the method for prior art.

The accompanying drawing summary

Fig. 1Demonstration uses ultra-pure water to dissolve the total impurities of back freeze-dried composition 1-5 again according to method described in the embodiment 6.Ultra-pure water is available from the ultra-pure water purification system, for example has the water of the Millipore Gradient A10 of UV-lamp and ultrafiltration.Ultra-pure water has the characteristic very nearly the same with the water for injection of USP and Ph.Eur..

According to embodiment 1 preparation compositions 1.Said composition comprises a large amount of extra acetate buffers and according to embodiment 1 preparation of EP 0 904 098 B1.According to embodiment 2 production compositionss 2.Use small amount of acetic acid that pH is adjusted to pH 6.0, after this lyophilizing.According to embodiment 3 production compositionss 3.Use extremely low amount acetic acid that pH is adjusted to pH 6.5, after this lyophilizing.According to embodiment 4 production compositionss 4.The oxalic acid Caspofungin is dissolved in the aqueous solution of mannitol and sucrose.Not carrying out further pH adjusts.According to embodiment 5 production compositionss 5.Adding EDTA sodium dihydrate to final concentration is 0.8mg/ml, after this lyophilizing.In Fig. 1, the Y-axle is represented the total impurities in the relative peak area of % measured by HPLC.All numbers shown in the X-axle is represented corresponding freeze-dried composition stored under 5 ℃.

Fig. 2The measurement result that shows Caspofungin.Under 2-8 ℃, freeze-dried composition stored behind all numbers shown in the X-axle according to defined compositions 1-5 among the method indirect determination described in the embodiment 7 such as Fig. 1.The Y-axle is illustrated in the Caspofungin amount that the relative peak area in the % that measures by HPLC measured in this algoscopy is represented.

Fig. 3Show every bottle to have＞10 μ m sizes as the visible particulate amount of being lower than of defined compositions 1-5 among Fig. 1.After under about 5 ℃ freeze-dried composition being stored all numbers shown in the X-axle according to the method indirect determination amounts of particles described in the embodiment 11.Directly carrying out granule after dissolving the lyophilizing sample again measures.The Y-axle represents in every bottle of granule＞10 μ m be lower than visible amounts of particles.

Fig. 4Show every bottle to have＞the compositions 1-5 as shown in Figure 1 of 25 μ m sizes be lower than visible particulate amount.After under 2-8 ℃ freeze-dried composition being stored all numbers shown in the X-axle, measure amounts of particles according to the method described in the embodiment 11.Directly carrying out granule after dissolving the lyophilizing sample again measures.The Y-axle represents in every bottle of granule＞25 μ m be lower than visible amounts of particles.In Fig. 1-4,0 value on the X-axle means after lyophilizing directly to be analyzed.

Fig. 5The crystalline X-ray powder diffraction of propanoic acid Caspofungin (XRPD) figure that shows preparation as described in example 17 above.

Fig. 6X-ray powder diffraction (XRPD) figure that shows the amorphous propanoic acid Caspofungin that comprises in the pharmaceutical composition of preparation as described in example 21 above.

In Fig. 5 and 6, abscissa is represented the θ/2 θ values (CuK α-emission) in degree, and vertical coordinate is represented the counting (cps) of per second.

Detailed Description Of The Invention

In one embodiment, pharmaceutical composition of the present invention comprise pharmaceutically acceptable salt, preferable amount that the pharmaceutically acceptable salt as the Caspofungin of medicine activity component, pharmaceutically acceptable excipient suitable and/or that effectively form lyophilized cake and consumption be lower than the described Caspofungin of 0.3 molar equivalent be lower than 0.2 molar equivalent, more preferably less than the extra pH adjusting agent of 0.1 molar equivalent.

In another embodiment, pharmaceutical composition of the present invention comprises as the pharmaceutically acceptable salt of the Caspofungin of medicine activity component and pharmaceutically acceptable excipient suitable and/or that effectively form lyophilized cake, and wherein said composition is substantially free of or does not contain extra pH adjusting agent fully. " being substantially free of " used herein or " not containing fully " be interpreted as meaning not add the pH adjusting agent of additional quantity, for example acetic acid or acetate buffer are in order to form composition of the present invention. Should understand the buffer that pharmaceutical composition of the present invention does not also contain any extra interpolation.

Term used herein " Caspofungin " means suc as formula the Caspofungin free alkali shown in the I compound. For example, the pharmaceutically acceptable salt of Caspofungin is described among the EP 0 620 232. The pharmaceutically acceptable salt of Caspofungin is the medicine activity component that is included in the present composition. 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, and comprises usually one, the two and three sour forms that free alkali and suitable organic or inorganic acid reaction by Caspofungin prepare. Be suitable for as acid-addition salts and provide the pharmaceutically acceptable salt of the anion of quaternary ammonium salt to serve as reasons acid forms those, the all example hydrochloric acids of described acid, hydrobromic acid, phosphoric acid, sulfuric acid, lactic acid, maleic acid, acetic acid, citric acid, tartaric acid, propionic acid, butanedioic acid, oxalic acid, malic acid, glutamic acid, pounce on acid etc., and comprise the S.M. with Berge, Bighley L.D., Monkhouse D.C.: " Pharmaceutical Salts ", Journal of Pharmaceutical Sciences, 66 (1), 1977, other relevant acid of listed pharmaceutically acceptable salt among the pp.1-19, and Strickley R. G.: " Parenteral Formulations of Small Molecules Therapeutics Marketed in the United States (1999)-Part I "; PDA Journal of Pharmaceutical Science ﹠ Technology, 53 (6), the acid that the counter ion counterionsl gegenions among 1999, the 324-349 in the listed salt form are relevant.

The pharmaceutically acceptable salt of preferred Caspofungin is and the organic acid acid-addition salts that described organic acid is selected from acetic acid, citric acid, tartaric acid, propionic acid, butanedioic acid, oxalic acid, malic acid, maleic acid, lactic acid, glutamic acid, pounces on acid. Most preferably the pharmaceutically acceptable salt of Caspofungin is Caspofungin diacetin, propionate or lactate.

The excipient that comprises in the present composition is preferably the filler of effective formation lyophilized cake. Term used herein " effectively forms the filler of lyophilized cake " and is interpreted as meaning this filler and adds in a large number in preparation or the composition, produces the good pie that forms when freeze drying is freeze-drying. This class filler can also be called stable reagent or stabilizing agent, because it also has stabilization and makes freeze-drying prods or composition has certain amount. Suitable filler comprises, but is limited to never in any form the polyhydroxy glycitols, and for example trihydroxy or higher alcohols are such as glycerine, erythrite, arabite, xylitol, sorbierite and mannitol; Lactose, sucrose, trehalose, glucose, glucan, HES, sugarcane glycan or gelatin or its mixture etc. Preferred filler is mannitol and sucrose or its mixture.

Composition of the present invention can further comprise another kind, one or more pharmaceutically acceptable excipient for example, comprise diluent or carrier as known in the art, they are suitable for expecting the composition for parenteral administration, such as being used in intramuscular, subcutaneous, intravenous, the peritonaeum or the injectable formulation of intramuscular administration. This class excipient can comprise, such as antioxidant, tonicity agent, anticorrisive agent, carbohydrate, wax, water-soluble and/or polymers capable of swelling, hydrophily or hydrophobic material, gelatin, oil, solvent, water etc.

Suitable solvent or diluent comprise, but be not limited to aqueous solvent, preferred water, for example distilled water and/or sterile water for injection, the optional bacteriostatic water for injection that comprises methyl p-hydroxybenzoate and/or propylparaben and/or 0.9% benzylalcohol, or physiological saline (normal saline) or physiological saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution, and/or ringer lactate solution, wherein % is weight percentage. These solvents and/or diluent can also be used for the present composition of dissolved freeze-dried powder form again and/or be used for the further thus obtained again solvent soln of dilution.

Term pH adjusting agent used herein is interpreted as meaning to be suitable for fluid composition, and for example the pH of solution is adjusted to desirable value, and such as to pharmaceutically acceptable pH value, for example extremely about 5-is about 8, for example compound or the material of the pH value of about 5-about 7.5. PH adjusting agent is understood to include buffer or " buffer solution " or " buffer system ". Term used herein " buffer " or " buffer solution " or " buffer system " are interpreted as being used interchangeably and mean one or more pharmaceutically acceptable excipient, they help fluid composition, and for example the pH value of solution maintains in the specific scope of buffer system. Term " pharmaceutically acceptable excipient " is interpreted as meaning avirulent excipient. Therefore, the pH adjusting agent that comprises in the present composition comprises, but be not limited to any side: relevant organic acid or the inorganic acid of the pharmaceutically acceptable salt with forming Caspofungin as described herein, all example hydrochloric acids, hydrobromic acid, phosphoric acid, sulfuric acid, lactic acid, maleic acid, acetic acid, citric acid, tartaric acid, propionic acid, butanedioic acid, oxalic acid, malic acid, glutamic acid, pounce on acid etc., with Berge S.M. etc., other relevant acid of listed pharmaceutically acceptable salt in 1977 (referring to above); With Strickley R.G., the acid that the counter ion counterionsl gegenions in the listed salt form of 1999 (referring to above) are relevant; Organic or inorganic alkali, such as NaOH, potassium hydroxide, ammonia, three (hydroxymethyl)-aminomethane or buffer, such as acetate, lactate, tartrate, citrate, phosphate, succinate, amino acid etc. or such as Strickley R.G., listed those in 1999 (referring to above).

Composition of the present invention preferably comprises the Caspofungin that calculates with Caspofungin alkali, its concentration is about the about 500mg/ml of 0.1mg/ml-, the about 200mg/ml of all according to appointment 10mg/ml-, the preferred about 60mg/ml of about 20 mg/ml-, 42mg/ml most preferably, be in the situation of fluid composition in said composition, namely also comprise for example water.

Excipient is preferably filler, the about 200mg/ml of the about 10mg/ml-of its amount, the about 60mg/ml of the about 40mg/ml-of preferable amount, the more preferably about 50mg/ml of consumption. Preferred composition of the present invention comprises the mixture of mannitol and sucrose, the about 200mg/ml of the about 10mg/ml-of the amount of mannitol wherein, the preferred about 30mg/ml of about 10mg/ml-, 20mg/ml most preferably from about, and the about 200mg/ml of the about 10mg/ml-of the amount of sucrose, the preferred about 40mg/ml of about 20mg/ml-, most preferably from about 30mg/ml. Above-mentioned concentration in mg/ml relates to the present composition of liquid form, namely also comprises for example water.

The pH adjusting agent that comprises in a preferred embodiment of the present composition is preferably used with pharmaceutically acceptable amount, this amount is adjusted to about 5-about 7 with the pH value of the present composition of liquid form before to freeze-drying, preferred about 5.5-is about 6.5, more preferably extremely about 6.0 is absolutely necessary. With regard to the present composition that is lyophilized as described below, pH adjusting agent is preferably with about 5-in the effective supply fluid composition about 8, the amount of the pH value of preferred about 6-about 7.5 is used, and described fluid composition is using solvent, and for example water obtains after dissolving freeze-dried composition again. The preferred pH adjusting agent that consists of the present composition is acetic acid or hydrochloric acid. In preferred embodiment of the present invention, said composition comprises the extra pH adjusting agent of pharmaceutically acceptable described salt that consumption is lower than the Caspofungin of 0.3 molar equivalent. The mol ratio of Caspofungin salt and extra pH adjusting agent is preferably greater than 2: 1, such as greater than 3: 1, is preferably greater than 4: 1, and 5: 1,8: 1 or 10: 1, particularly greater than 25: 1.

Therefore, one preferred aspect in, pharmaceutical composition of the present invention comprises:

A) the about 500mg/ml of about 0.1mg/ml-, for example about 200mg/ml of about 10mg/ml-, the preferably about 60mg/ml of about 20mg/ml-, the more preferably from about Caspofungin with the calculating of Caspofungin alkali of 42mg/ml;

B) but the pH adjusting agent of pharmacy receiving amount, preferred acetic acid, but the about 5-of its effective supply is about 7, preferably about 5.5-is about 6.5, more preferably from about 6.0 pH value;

C) the about 200mg/ml of about 10mg/ml-, the preferred about 60mg/ml of about 40mg/ml-, the excipient of 50mg/ml more preferably from about, it is filler, preferred filler and/or fill the mixture of sugar, it can effectively form lyophilized cake;

And water.

Preferred mixture of filling sugar is by the compositions of mixtures of the sucrose of the mannitol of 20mg/ml and 30mg/ml.

Preferred composition of the present invention comprises the oxalic acid Caspofungin that consumption is 46.6mg/ml, is equivalent to the Caspofungin with the 42mg/ml of alkali calculating. The mol ratio of Caspofungin salt and extra pH adjusting agent is preferably greater than 2: 1, such as greater than 3: 1, is preferably greater than 4: 1, and 5: 1,8: 1 or 10: 1, particularly greater than 25: 1.

In another preferred embodiment, composition of the present invention comprise mentioned component a), c) and water, but be substantially free of or do not contain extra pH adjusting agent fully.

The pH value of aforesaid liquid composition is about 7 for about 5-, and preferably about 5.5-is about 6.5, and more preferably from about 6.0.

Preferably with aforesaid pharmaceutical composition of the present invention, i.e. its liquid form, for example the aqueous solution form is with the about 3ml of about 1ml-, and more preferably from about the consumption of 1.25ml or about 1.75ml/ bottle is filled into bottle.

Aforesaid pharmaceutical composition of the present invention is suitable for lyophilizing, for example can be preferably according to following method lyophilizing at above-mentioned bottle, for example in the vial, so that obtain lyophilized powder.The composition of the preferred embodiment of the described lyophilized powder in this class bottle that the mixture of Caspofungin, the preferred acetic acid of pH regulator agent (if having the extra pH regulator agent of this class) and preferred mannitol of filler and sucrose that to be unit with mg calculate with alkali is represented is easy to by mg/ml concentration as implied above being multiply by 1.25 or selectively multiply by 1.75 and calculate.Therefore, the present invention also provides the lyophilized powder that can obtain by the lyophilizing aforementioned pharmaceutical compositions, and described pharmaceutical composition is suitable for being dissolved into again and is used for the fluid composition that parenteral, preferred intravenous are used.

The preferred embodiment of the pharmaceutical composition of the present invention of lyophilized powder form comprises and preferably is made up of following component:

I) be equivalent to the 58.28mg oxalic acid Caspofungin of 52.5mg Caspofungin alkali, the mannitol of about 25mg, the sucrose of about 37.5mg and extra pact be 0.1mg-1.4mg for example, and the about 0.7mg of preferably about 0.1mg-is used for the acetic acid of pH regulator; Or

The 58.28mg oxalic acid Caspofungin that ii) is equivalent to 52.5mg Caspofungin alkali, the mannitol of about 25mg and the sucrose of about 37.5mg; Or

The oxalic acid Caspofungin that iii) is equivalent to the 81.59mg of 73.5mg Caspofungin alkali, the mannitol of about 43.75mg, the sucrose of about 52.5mg and extra pact be the about 2mg of 0.16mg-for example, and the about 1mg of preferably about 0.16mg-is used for the acetic acid of pH regulator; Or

The 81.59mg oxalic acid Caspofungin that iv) is equivalent to 73.5mg Caspofungin alkali, the mannitol of about 43.75mg and the sucrose of about 52.5mg.

When dissolving above-mentioned lyophilized powder again with about 10.5ml aqueous solvent as described herein or diluent, be present in preferred embodiment i) and iii) in and for the extra acetic acid of aforesaid pH regulator agent about 8 with the about 5-of effective acquisition, the amount existence of the pH value of preferably about 6-about 7.5.

Pharmaceutical composition of the present invention can be solid form thus, powder type for example, such as the lyophilized powder form, lyophilized cake form for example, be suitable for preparing the liquid that is used for parenteral administration, the injectable formulation of, intravenous subcutaneous, intraperitoneal or intramuscular administration such as being used for.

Therefore, can be by adding compatibility diluent as herein described and/or solvent before parenteral administration, for example by adding aqueous solution, preferred distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution, for example, an amount of described solvent or diluent be used for freeze dried bottle by directly being joined, for example in the vial, dissolve described lyophilized powder or cake (preferably can obtain) again by lyophilizing aforesaid liquid pharmaceutical composition.

The present invention thus one preferred aspect in provide can be by using the 10.5ml aqueous solution, preferred distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution dissolve the pharmaceutical composition that lyophilized powder of the present invention obtains again.The present invention one preferred aspect in the pharmaceutical composition that can obtain by the lyophilized powder of the present invention that dissolves above-mentioned preferred embodiment with the aforesaid aqueous solution of 10.5ml again is provided.With regard to described preferred pharmaceutical compositions, what wherein comprise is Caspofungin and mannitol, sucrose and the extra pH regulator agent of calculating with Caspofungin alkali of unit with mg/ml, and the concentration of preferred acetic acid (if existence) is easy to calculate divided by 10.5 by the amount of the lyophilized powder of the invention described above preferred embodiment that will represent with mg.

The present invention also provides thus and has been suitable for parenteral, and the present invention that preferred intravenous is used is the aqueous solution of dissolved freeze-dried composition again.

Preferably to have about 5-about 8 dissolving the pharmaceutical composition that obtains after the aforesaid lyophilized cake again, the pH value of preferably about 6.0-about 7.5.

Perhaps, comprise as mentioned above composition a), c) and optional b) and the present composition of water can exist with liquid form, for example, for example be not lyophilizing first and dissolved more subsequently as the instant available liquid form that is used for parenteral administration.

Pharmaceutical composition of the present invention be stable formulation and with regard to them for liquid preparation, such as showing the visible granule that is lower than that reduces quantity with regard to the form of dissolved freeze-dried powder more as described herein.The pharmaceutical composition of the present invention of preferred described liquid form has and is less than 500, preferably be less than 300 and be lower than visible granule/bottle, described granule has the size greater than 10 μ m, particulate quantity is according to USP27,＜788〉" using the particulate matter in the injection of photoresistance grain count test " in measures.

In a preferred embodiment, prepare compositions of the present invention by the method that comprises the following steps:

It is 1) combination of filler or filler is water-soluble,

2) add the pharmaceutically acceptable salt of Caspofungin in the solution that in step 1), obtains and with its dissolving,

3) add extra pH regulator agent with the consumption that is lower than the described Caspofungin salt of 0.3 molar equivalent, preferred acetic acid or sodium hydroxide are so that with step 2) in the pH value of the solution that obtains to be adjusted to about 5-about 7, preferably about 5.5-is about 6.5, and is more preferably extremely about 6.0,

4) filtration step 3) the middle solution that obtains, filtering filled with solution is gone into bottle, preferably be filled into the lyophilizing bottle, and give part bottle stopper beyond the Great Wall,

5) with freeze dryer by storage temperature is adjusted to approximately in the bottle that obtains in-50 ℃ of freezing step 4) solution and

6) by storage temperature being adjusted to approximately-40 ℃ and by regulating suitable pressure to guarantee the water refrigerated solution of lyophilization that from frozen soln, distils.

In another preferred embodiment, prepare compositions of the present invention, but omitted step 3) and omitted thus and added extra pH regulator agent by the method that comprises identical with said method basically step.In this second method of the present invention, step 2) solution that obtains in, promptly the combination of filler or filler is water-soluble and the pharmaceutically acceptable salt of Caspofungin added to gained solution and with its dissolving after, the described solution of Direct Filtration and it is filled into bottle and further processes described in step 4), step 5) and the step 6) as mentioned above.The pharmaceutically acceptable salt of preferred Caspofungin is the oxalic acid Caspofungin.

The acetic acid that uses in the step 3) is 1.25N acetic acid suitably.Optional water can be joined above-mentioned first method step 3) or second method step 2) in the solution that obtains so that adjust the required cumulative volume of described solution.

According to or filter with the similar mode of known method, for example can use to have the pharmaceutically acceptable filter membrane that is no more than 0.22 μ m aperture and filter.

Further procedure of processing 6) in the freeze-drying solution that obtains so that obtain to be used for the pharmaceutical composition of parenteral administration.This class processing preferably includes the following step: jam-pack contains the bottle of freeze-dried composition of the present invention and at about 2 ℃-Yue 8 ℃, stores under for example about 5 ℃ temperature or under other suitable condition of storage fully after finishing lyophilization.

According to or carry out lyophilizing or lyophilization with the similar mode of known method.Preferably freeze drying comprises preliminary and redrying, and wherein preliminarily dried carries out under-40 ℃ storage temperature approximately and redrying is carried out under about 15 ℃ storage temperature.The bone dry circulation needs about 15-18 hour.Can the Virtis freeze dryer for example among the Virtis Advantage II according to known method and use suitable pressure, for example be lower than under the pressure of 0.12mbar and carry out lyophilization.

Therefore, the present invention also provides pharmaceutical composition obtainable, that preferably obtain by one of said method.

For example, to mammal, preferably the human individual is used before, use suitable diluent as described herein or solvent dilution for example to dissolve freeze-dried composition again, so that obtain the Caspofungin final concentration with the calculating of Caspofungin alkali, for example about 5mg/ml or 7mg/ml.Can from bottle, extract again dissolved solution and change it over to transfusion bag, so that further use by intravenous infusion.According to this class mode, can further dilute dissolved again solution so that the solution that is suitable for patient's infusion is provided with suitable solvent as described herein or diluent.Preferred solvent or diluent are distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution.Can pass through 7ml-10ml with diluent as herein described, the solvent soln again of preferred 7ml or 10ml is diluted to the about 300ml of the about 100ml-of cumulative volume, the diluent of the pharmaceutical composition of the present invention of about 250ml of preferably about 110ml-or the aforesaid solvent soln again of about 260ml form.Should dilute again solvent soln so that the pharmaceutical composition of the Caspofungin that calculates with alkali that comprises pharmaceutically acceptable and treatment effective dose is provided according to this class mode.Term used herein " treatment effectively " be interpreted as meaning the treatment, prevention, physiology and/or the pharmacology that provide required and/antimicrobial, for example antibiotic or antifungal and/or protozoacide effect.The dosage that prevents and/or treats disease described herein is easy to by skilled clinicist, for example as described belowly determines.

Can with compositions of the present invention to mammal, preferably human individual and/or patient are used so that prevent/or the infectious disease that causes by fungus or protozoacide of treatment.

Therefore, the invention provides compositions of the present invention as preventing and/or treating mammal, the purposes of the medicine of preferred people's fungal infection, described fungal infection particularly those by the species of mycocandida, such as white candida mycoderma (C.albicans), candida tropicalis (C.tropicalis), Crewe Si Shi candida mycoderma (C.krusei), Candida glabrata (C.glabrata) and candida pseudotropicalis (C.pseudotropicalis) and by the species of aspergillus, such as Aspergillus fumigatus (A.fumigatus), the fungal infection that yellow aspergillosis (A.flavus) and black aspergillosis (A.niger) cause.Compositions of the present invention is also inferred the mycocandida bacterial strain of amphotericin B and fluconazol-resistance effective.In addition, compositions of the present invention can be used to prevent and/or treat because of the immunosuppressed patient of susceptible especially, for example the pneumonia that causes of those Jie Shi lung sac worms that suffer from the patient of AIDS.Jie Shi lung sac worm is classified as Pneumocystis carinii and protozoacide in advance, but is regarded as fungus at present.

Preferred compositions of the present invention comprises the Caspofungin as the treatment effective dose of medicine activity component.If use by intravenous, so most preferred active component dosage range was at about 1.67 μ g/kg/ minutes-Yue 33 μ g/kg/ minute, and infusion rates is about 200ml/ hour.With regard to this class was used, compositions of the present invention should have the 0.025mg/ml-0.5mg/ml active component based on 50kg patient, i.e. Caspofungin alkali is described in EP 0 904 098 B1.

Pharmaceutical composition of the present invention, particularly be substantially free of or do not contain any extra pH regulator agent and any extra buffer agent fully those provide several advantages than known caspofungin formulations.

In fluid composition of the present invention, particularly be substantially free of or do not contain fully that to be lower than in those of any extra pH regulator agent that visible amounts of particles reduces be unexpected feature of the present invention.Usually can be for example from US 6,900,184 or WO 02/41919 A1 in expect, need granule to form the existence of inhibitor such as EDTA sodium and be lower than visible granule in the injection solution so that effectively reduce, because the ion complexation in expection EDTA and the solution, the calcium ion that for example discharges from vial, calcium ion may form precipitation with for example hydroxide or silicate.Surprisingly, although do not exist any this class granule to form inhibitor, compositions of the present invention still demonstrates the more outstanding described visible particulate minimizing that is lower than.This result can use the present composition that is substantially free of any extra pH regulator agent to observe especially.

Therefore, compositions of the present invention preferably has and is less than 500, preferably is less than 300 and is lower than visible granule/bottle, described granule has the size greater than 10 μ m, particulate quantity is according to USP27,＜788〉" using the particulate matter in the injection of photoresistance grain count test " in measures.Therefore, compositions of the present invention causes the potential risk degree reduction of thromboembolism to advantageously provide the safety that increases to for example accept the patient of said composition by the intravenous mode by parenteral because of being lower than visible granule.

As another advantage, compositions of the present invention provides stable compositions, it shows a spot of total impurities, wherein main degradation products-this paper of Caspofungin also is called CAF-42-and decompose produces because of ethylenediamine, also obviously reduces (referring to embodiment 12 and table 5) especially in the present composition that is substantially free of any extra buffer agent or any pH regulator agent.The high stability of the present composition is also confirmed according to the active component high-load of keeping in its storage process.The present composition, particularly those this favourable stability that do not contain the compositions of any extra pH regulator agent needn't obtain by any extra buffer agent of interpolation of general 2 step of needs pH regulator.Therefore, preparing the liquid form of this class pharmaceutical composition-the be suitable for freeze dried time as described herein has according to estimates reduced 10% at least.Contain on a small quantity, the present composition that promptly is lower than the extra pH regulator agent of the Caspofungin salt that comprises in the 0.3 molar equivalent compositions also is high stability preparation, and its preparation only needs 1 step pH regulator.Therefore, compositions of the present invention is directly by the method production more easier than art methods.

As another advantage, pharmaceutical composition of the present invention, particularly those do not contain any extra pH regulator agent those show than the conventional caspofungin formulations that comprises extra acetate buffer forming less impurity, such as the purity (referring to embodiment 13) that for example CAF-dimer 1 aspect is higher.

The inventor also finds, although there is not any extra buffer agent, acetate buffer for example, but pharmaceutical composition of the present invention particularly shows good stable with water for injection or the dissolved again lyophilized powder of normal saline with regard under maintaining identical approximately value pH in 2 days storage process under 25 ℃.Also observe solvent soln more of the present invention, particularly be substantially free of or do not contain any extra pH regulator agent and any extra buffer agent fully those also showing unexpected good stability aspect a small amount of total impurities and/or main degradation products CAF-42 and/or the impurity CAF-dimer 1.

The inventor has also found the new salt of the chemical compound of formula I, the acid-addition salts that is suitable for pharmaceutical composition that forms with propanoic acid promptly as described herein.

Therefore, the present invention provides the new salt for the Caspofungin of the chemical compound of formula I in one aspect of the method,

It is the form of the acid-addition salts that forms with propanoic acid.Described new salt is also referred to as the propanoic acid Caspofungin.

One preferred aspect in, propanoic acid Caspofungin according to the present invention comprises Caspofungin and the propanoic acid of formula I, about 1: 3 of its mol ratio about 1: 1-, more preferably from about 1: about 1: 2.5 of 1.5-, for example 1: 1.8-1: 2.2, most preferably from about 1: 2.The latter can be defined as the dipropionic acid Caspofungin and can be equivalent to the chemical compound of formula II.

Therefore, one preferred aspect, the invention provides the propanoic acid Caspofungin of formula II:

The chemical compound of formula II is also referred to as the dipropionic acid Caspofungin.

The present invention also provides the Caspofungin of formula I, is the acid-addition salts form and/or the aforesaid propanoic acid Caspofungin of itself and propanoic acid, preferred crystallization or amorphous form.

Term used herein " propanoic acid Caspofungin " is interpreted as meaning according to the new salt of Caspofungin of the present invention and is understood to include " with chemical compound of the formula I of the acid-addition salts form of propanoic acid ", particularly the mol ratio of the Caspofungin of its Chinese style I and propanoic acid can be about 1: about 1: 3 of 1-, " chemical compound of formula II " and " dipropionic acid Caspofungin ".Term used herein " Caspofungin propanoic acid adduct " is interpreted as meaning the acid-addition salts of Caspofungin and propanoic acid.

Dipropionic acid Caspofungin according to propanoic acid Caspofungin, particularly crystal form of the present invention can be by as shown in following table 10 ¹H-NMR data (CD ₃OD, 300MHz) and/or ¹³C-NMR data (CD ₃OD 75MHz) characterizes.As preparation dipropionic acid Caspofungin as described in the embodiment 17.

Table 10: the dipropionic acid Caspofungin ¹The H-NMR data and ¹³The C-NMR data

In table 10: the PRA=propanoic acid; [PPM]=according to the chemical shift unit of umber/1,000,000; The m=multiplet, d=is bimodal, bimodal during dd=is bimodal, t=triplet, q=quartet.Numeral is based on the numbering among the structural formula IV of signal allocation:

Propanoic acid Caspofungin, particularly crystal form of the present invention can be by as shown in table 10 its ¹Derive from the H-NMR spectrum propanoic acid methyl about 1.11ppm place triplet and in the quartet at about 2.19ppm place of the methylene that derives from propanoic acid and characterize.

Its that propanoic acid Caspofungin, particularly crystal form are all right as shown in table 10 ¹³Derive from respectively in the C-NMR spectrum propanoic acid methyl, methylene and carboxyl about 10.1,30.6 and 182.2ppm signal and characterize.

In one aspect of the method, the dipropionic acid Caspofungin of propanoic acid Caspofungin, particularly crystal form can be by scheming to characterize according to the X-ray powder diffraction (XRPD) of Fig. 5 basically.Prepare the dipropionic acid Caspofungin as described in example 17 above, wherein also described the XRPD assay method.

In one aspect of the method, propanoic acid Caspofungin, particularly dipropionic acid Caspofungin crystal form can also characterize by X-ray powder diffraction (XRPD) figure with the intensity honeybee of about 2.92,5.04,5.88,9.02 and 10.23 2-θ degree value representation.

Perhaps, the propanoic acid Caspofungin, particularly the dipropionic acid Caspofungin of crystal form can be by having with 2.9 ± 0.2,5.0 ± 0.2,5.9 ± 0.2,9.0 ± 0.2 and 10.2 ± 0.2, for example the X-ray powder diffraction (XRPD) of the intensity honeybee of 2.9 ± 0.1,5.0 ± 0.1,5.9 ± 0.1,9.0 ± 0.1 and 10.2 ± 0.1 2-θ degree value representation is schemed and is characterized.

The crystallization of propanoic acid Caspofungin, the particularly crystalline feature of dipropionic acid Caspofungin can be further that crystal is a prism, and it can form aggregation, and are easy to flow with soluble in water.Therefore, for example the invention provides preparation comprise the propanoic acid Caspofungin as the pharmaceutical composition process of active component in the propanoic acid Caspofungin crystallization of easy operating.The crystallization of propanoic acid Caspofungin has the advantage more stable than amorphous form.

In a preferred embodiment, the mol ratio of determining that the propanoic acid Caspofungin is crystalline to be characterised in that the Caspofungin of formula I and propanoic acid is about 1: about 1: 3 of 1-, preferred about 1: about 1: 2.5 of 1.5-, for example 1: 1.8-1: 2.2, more preferably from about 1: 2.The latter can be defined as the dipropionic acid Caspofungin and can be equivalent to the chemical compound of formula II.The mol ratio of determining of the Caspofungin of described formula I and propanoic acid-except above-mentioned be easy to mobile and soluble in water-make the crystallization of propanoic acid Caspofungin, the particularly crystallization of dipropionic acid Caspofungin be particularly advantageous for preparing pharmaceutical composition as described herein.

Propanoic acid Caspofungin of the present invention crystallization, the particularly crystallization of dipropionic acid Caspofungin show high degree of crystallinity.The present invention thus one preferred aspect in also relate to the crystal form of propanoic acid Caspofungin, dipropionic acid Caspofungin crystal form particularly, it comprises and is lower than 5%, particularly is lower than 1% unbodied propanoic acid Caspofungin, particularly unbodied dipropionic acid Caspofungin.The present invention relates to the propanoic acid Caspofungin in one aspect of the method, the crystal form of dipropionic acid Caspofungin particularly, and it is substantially free of or does not contain any unbodied propanoic acid Caspofungin, particularly unbodied dipropionic acid Caspofungin fully.The crystallization of propanoic acid Caspofungin, the particularly crystallization of dipropionic acid Caspofungin that are substantially free of or do not contain amorphous propanoic acid Caspofungin and/or amorphous dipropionic acid Caspofungin fully show good stable.

Amorphous propanoic acid Caspofungin, particularly amorphous dipropionic acid Caspofungin soluble in water and for example the preparation comprise the propanoic acid Caspofungin as the pharmaceutical composition process of active component in easy operating.In a preferred embodiment, amorphous propanoic acid Caspofungin of the present invention is characterised in that the mol ratio of the Caspofungin of formula I and propanoic acid is about 1: about 1: 3 of 1-, preferred about 1: about 1: 2.5 of 1.5-, for example 1: 1.8-1: 2.2, more preferably from about 1: 2.The latter is defined as the dipropionic acid Caspofungin and can be equivalent to the chemical compound of formula II.

In another preferred embodiment, amorphous propanoic acid Caspofungin, particularly dipropionic acid Caspofungin show definite mol ratio of Caspofungin and the propanoic acid of formula I in above-mentioned scope.Can obtain described amorphous propanoic acid Caspofungin through the following steps: with crystallization propanoic acid Caspofungin with described definite mol ratio, particularly crystallization dipropionic acid Caspofungin changes into its amorphous form, and this step is by with crystallization propanoic acid Caspofungin or crystallization dipropionic acid Caspofungin is water-soluble and the solution that obtains according to the known method lyophilizing subsequently carries out.Therefore, the amorphous propanoic acid Caspofungin, particularly dipropionic acid Caspofungin with definite mol ratio is particularly suitable for preparing pharmaceutical composition as described herein.

Can prepare amorphous propanoic acid Caspofungin, particularly dipropionic acid Caspofungin of the present invention, wherein not detect the crystallization propanoic acid Caspofungin, particularly crystallization dipropionic acid Caspofungin of trace.The present invention relates to propanoic acid Caspofungin, the particularly amorphous form of dipropionic acid Caspofungin thus in a preferred embodiment, and it comprises and is lower than 5%, particularly is lower than 1% crystallization propanoic acid Caspofungin, particularly crystallization dipropionic acid Caspofungin.The present invention relates to the propanoic acid Caspofungin in aspect another is preferred, the amorphous form of dipropionic acid Caspofungin particularly, and it does not contain any crystallization propanoic acid Caspofungin, particularly crystallization dipropionic acid Caspofungin basically or fully.

Propanoic acid Caspofungin of the present invention, for example crystallization or amorphous form can further comprise residual solvent, and residual organic solvent for example is such as C ₁-C ₄-alcohol, for example methanol or ethanol, or acetic acid C ₁-C ₄-Arrcostab, for example ethyl acetate and/or water.In one aspect, the propanoic acid Caspofungin can comprise and reaches 10% approximately, for example reaches 10%, allly reach 5% according to appointment, for example reach 5% residual organic solvent, and/or reach 10% approximately, for example about 1%-is about 10%, the water of all 2%-according to appointment about 8%, and wherein % is weight percentage.Can for example measure water content according to known method according to Karl Fischer.Can pass through known method,, use the DB-Wax capillary column to measure residual organic solvent for example by head space gas chromatography GC.Do not wish to be subjected to theory constraint, the inventor thinks the residual organic solvent of the above-mentioned amount in the propanoic acid card is moored fragrant crystal form, and for example ethanol or ethyl acetate or water can have Stabilization.

Therefore, provide the propanoic acid Caspofungin among the present invention in one aspect, for example crystal form or amorphous form, it comprises and reaches 10% approximately, for example reaches 10%, allly reaches 5% according to appointment, for example reaches 5% residual organic solvent, preferred C ₁-C ₄-alcohol, for example methanol or ethanol, or acetic acid C ₁-C ₄-Arrcostab, ethyl acetate and/or reach 10% approximately for example, for example about 1%-is about 10%, and all 2%-according to appointment are about 8%, 2%-8% water for example, wherein % is weight percentage.

In another embodiment of the invention, the propanoic acid Caspofungin, for example crystal form or amorphous form can be substantially free of or not contain residual organic solvent fully.

By known drying means, for example from propanoic acid Caspofungin of the present invention crystallization, remove excessive residual organic solvent and/or water by vacuum drying or by for example applying nitrogen current according to informing method.Perhaps, can pass through at about 0 ℃-Yue 30 ℃, for example about 10 ℃-Yue 25 ℃, room temperature for example, such as the wet nitrogen that makes about 20%-about 55% under 25 ℃ ± 5 ℃ temperature, about 50% relative humidity of for example about 30%-is removed residual organic solvent by the solid crystallized product that obtains through methods described herein from the crystallization of propanoic acid Caspofungin, so that acquisition meets propanoic acid Caspofungin crystallization (the International Conference on Harmonization of TechnicalRequirements for Registration of Pharmaceuticals for Human Use of the residual solvent levels of ICH guideline, ICHHarmonized Tripartite Guideline, Impurities:Guideline for ResidualSolvents, Q3C (R3), Current Step 4 version, Parent Guideline dated 17 July1997).Perhaps, can pass through at about 0 ℃-Yue 30 ℃, for example about 10 ℃-Yue 25 ℃, room temperature for example, such as making described propanoic acid Caspofungin crystallization contact about 20%-about 80% under 25 ℃ ± 5 ℃ temperature, the relative humidity of preferred about 30%-about 50% is removed residual solvent from the crystallization of propanoic acid Caspofungin, so that acquisition meets the propanoic acid Caspofungin crystallization of the residual solvent levels of above-mentioned ICH guideline.As applying wet nitrogen current or contacting the propanoic acid Caspofungin crystallization that obtains after the above-mentioned humidity, optional can by water-soluble and as mentioned above lyophilizing it further changed into amorphous form obtain amorphous propanoic acid Caspofungin, particularly amorphous dipropionic acid Caspofungin, it does not contain residual solvent basically or fully and is particularly suitable for preparing pharmaceutical composition as described herein.

The present invention further provides and comprised propanoic acid Caspofungin of the present invention, for example the pharmaceutical composition of crystallization or amorphous form and optional extra one or more pharmaceutically acceptable excipient well known in the art.One preferred aspect in, pharmaceutical composition of the present invention comprises the propanoic acid Caspofungin of crystal form or amorphous form and one or more extra pharmaceutically acceptable excipient as herein described.

The amorphous form of propanoic acid Caspofungin of the present invention-when it is included in the pharmaceutical composition as described herein-in Fig. 6, the show remarkable peak that does not demonstrate among its XRPD figure, wherein prepared as described in example 21 above and comprised the propanoic acid Caspofungin, the pharmaceutical composition of the dipropionic acid Caspofungin of more specifically saying so; The XRPD-assay method as described in example 17 above.

One preferred aspect in, pharmaceutical composition of the present invention is a liquid form, more preferably the aqueous solution form.Pharmaceutical composition of the present invention for example can be used as and is used for the available immediately of parenteral administration, and for example aqueous solution exists.

In aspect another is preferred, pharmaceutical composition of the present invention is a solid form, preferred lyophilized powder form.

One preferred aspect in, pharmaceutical composition of the present invention comprises the propanoic acid Caspofungin as medicine activity component of the present invention, for example dipropionic acid Caspofungin and pharmaceutically acceptable excipient, be preferably suitable and/or effectively form the filler of lyophilized cake and extra buffer agent, being preferably as follows the literary composition definition effectively provides the propionate buffer agent of pharmaceutically acceptable pH value, about 5-about 8 for example is provided, for example about 5.5-about 7.5, all 5.5-according to appointment about 7.0, about 6.5 scopes of for example about 5.5-, for example about 6.0 pH value.Buffer agent, preferred propionate buffer agent has been contributed the buffer capacity of pharmaceutical composition.

In another preferred embodiment, pharmaceutical composition of the present invention comprises the propanoic acid Caspofungin of the present invention as medicine activity component, for example dipropionic acid Caspofungin and pharmaceutically acceptable excipient, be preferably filler suitable and/or that effectively form lyophilized cake and the extra pH regulator agent that pH value effectively is adjusted to pharmaceutically acceptable pH value as described herein, for example propanoic acid.Term pH regulator used herein agent is as above-mentioned definition.

In another preferred embodiment, pharmaceutical composition of the present invention comprises the propanoic acid Caspofungin of the present invention as medicine activity component, for example dipropionic acid Caspofungin and pharmaceutically acceptable excipient suitable and/or that effectively form lyophilized cake, wherein this pharmaceutical composition is substantially free of extra buffer agent or pH regulator agent." being substantially free of " used herein is interpreted as meaning buffer agent or the pH regulator agent of not adding additional quantity, for example propionate buffer agent or propanoic acid and form pharmaceutical composition of the present invention.

Preferred excipient in the pharmaceutical composition of the present invention is the filler that effectively forms lyophilized cake; The preferred filler of this class as mentioned above.

Compositions of the present invention can further comprise one or more extra pharmaceutically acceptable excipient, comprise known in this field for being suitable for expecting the compositions that is used for parenteral administration, such as the diluent or carrier of the preparation that is used for intramuscular, subcutaneous, intravenous, intraperitoneal or intramuscular administration.Suitable excipient and suitable solvent and/or diluent are as mentioned above.The preferred solvent and/or the diluent that are used for the pharmaceutical composition of the present invention of dissolved freeze-dried powder form again and/or further dilute thus obtained solvent soln again are: distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution.

Preferred compositions of the present invention is an aqueous solution, it comprises the propanoic acid Caspofungin, dipropionic acid Caspofungin particularly, concentration is equivalent to the about 500mg/ml of about 0.1mg/ml-, the about 200mg/ml of for example about 10mg/ml-, the about 60mg/ml of preferably about 20mg/ml-, the more preferably from about about 45mg/ml of 22mg/ml-, 25mg/ml most preferably from about, the Caspofungin that about 30.6mg/ml or about 42mg/ml calculate with alkali.

More preferably above-mentioned aqueous solution also comprises filler, it is with the concentration of the about 200mg/ml of about 10mg/ml-, the concentration of the preferred about 60mg/ml of about 20mg/ml-, the about 55mg/ml of for example about 25mg/ml-, the about 52mg/ml of 30mg/ml-more preferably from about, most preferably from about 32.5mg/ml, about 39.4mg/ml or about 50mg/ml existence.Preferred described filler is the mixture of mannitol and sucrose, and preferably its mol ratio is about 1: about 2: 1 of 2-, more preferably from about 1: 1.

One preferred aspect in, the present invention relates to the compositions of aqueous solution form thus, it comprises:

I) propanoic acid Caspofungin, dipropionic acid Caspofungin for example, its concentration is equivalent to the about 500mg/ml of about 0.1mg/ml-, the about 200mg/ml of for example about 10mg/ml-, the preferred about 60mg/ml of about 20mg/ml-, the about 45mg/ml of 22mg/ml-more preferably from about, 25mg/ml most preferably from about, the Caspofungin that calculates with Caspofungin alkali of about 30.6mg/ml or about 42mg/ml;

II) the about 200mg/ml of about 10mg/ml-, the preferred about 60mg/ml of about 20mg/ml-, the about 55mg/ml of for example about 25mg/ml-, the about 52mg/ml of 30mg/ml-more preferably from about, 32.5mg/ml most preferably from about, the excipient of about 39.4mg/ml or about 50mg/ml, it is a filler, the mixture of preferred filler, it can effectively form lyophilized cake; With

III) but the buffer agent of optional pharmacy receiving amount, preferred propionate buffer agent, or pH regulator agent, preferred propanoic acid, it can effectively provide about 5-about 7, preferably about 5.5-is about 6.5, more preferably from about 6.0 pH value;

And water.

Be preferred for composition II) filler be filler mixture, more preferably mannitol and sucrose mixture, preferably its mol ratio is about 1: about 2: 1 of 2-, more preferably from about 1: 1.

Therefore, in a preferred embodiment, the present composition of aqueous solution form comprises: composition I) and II) and composition III), buffer agent wherein, preferred propionate buffer agent exists with pharmaceutically acceptable consumption; And water., can use an amount of propanoic acid and sodium hydroxide or propanoic acid and sodium propionate or sodium propionate and strong inorganic acid, for example HCl for but the propionate buffer agent that effectively reaches required pH value of pharmacy receiving amount is provided.Preferably to make pH value be about 5-in the above-mentioned aqueous solution about 7 by an amount of propanoic acid and NaOH are joined, and preferably about 5.5-is about 6.5, and more preferably from about 6.0 preparations are present in composition III) in the propionate buffer agent.Can according to for example as European patent EP 0 904 098 B1 or for example as described in example 20 above the similar mode of method prepare and comprise extra buffer agent, the aqueous solution of preferred propionate buffer agent.Buffer agent, preferred propionate buffer agent be preferably with the about 200mmol/l of about 1mmol/l-, the about 100mmol/l of 12.5mmol/l-more preferably from about, the about 50mmol/l of 15mmol/l-most preferably from about, the scope existence of the about 25mmol/l of for example about 17mmol/l-.Anticipatory Buffering agent meeting is that I compositions of the present invention is added further buffer capacity.

In another preferred embodiment, the present composition of aqueous solution form comprises: mentioned component I) and II) and composition III), wherein pH regulator agent, preferred propanoic acid exists with the pharmaceutically acceptable amount that pH value effectively is provided, it is necessary pH value is adjusted to about 5-about 7, preferred about 5.5-is about 6.5, and more preferably from about 6.0; And water.Be used for composition III) preferred pH regulator agent be propanoic acid or hydrochloric acid, more preferably propanoic acid.Preferred extra pH regulator agent is to be higher or lower than the propanoic acid Caspofungin of the present invention of 0.3 molar equivalent, and particularly the consumption of propanoic acid Caspofungin exists.In aspect another is preferred, propanoic acid Caspofungin, particularly dipropionic acid Caspofungin and extra pH regulator agent mol ratio be greater than 2: 1, such as greater than 3: 1, is preferably greater than 4: 1,5: 1,8: 1 or 10: 1, particularly greater than 25: 1.PH regulator agent, preferred propanoic acid are preferably to reach 5mmol/l approximately, the about 4mmol/l of for example about 2mmol/l-, the preferably scope of about 3mmol/l existence.Can be according to for example described herein, for example embodiment 2 and 3 or as described in example 21 above the similar mode of method prepare and comprise extra pH regulator agent, the aqueous solution of preferred propanoic acid.

In another preferred embodiment, the present composition of aqueous solution form comprises mentioned component I) and II) and water, but be substantially free of and/or do not contain any extra buffer agent or any extra pH regulator agent fully.Can be by with for example described herein, for example embodiment 4 14 or for example as described in example 22 above the similar mode of method prepare the described compositions that does not contain any extra buffer agent or any extra pH regulator agent.

The particularly preferred embodiment of the present composition comprises: xi) propanoic acid Caspofungin, particularly dipropionic acid Caspofungin, and the about 28.4mg/ml of its concentration is equivalent to the Caspofungin that calculates with alkali of about 25mg/ml; Filler with about 32.5mg/ml for about 13mg/ml mannitol and about 19.5mg/ml sucrose mixture; And water; With the propionate buffer agent of optional about 17mmol/l or as the 1.8mmol/l propanoic acid of pH regulator agent; Or xii) propanoic acid Caspofungin, particularly dipropionic acid Caspofungin, the about 34.8mg/ml of its concentration is equivalent to the Caspofungin that calculates with alkali of about 30.6mg/ml; Filler with about 39.4mg/ml for about 15.8mg/ml mannitol and about 23.6mg/ml sucrose mixture; And water; With the propionate buffer agent of optional about 20mmol/l as the pH regulator agent or the propanoic acid of about 2.2mmol/l; Or xiii) propanoic acid Caspofungin, particularly dipropionic acid Caspofungin, the about 47.7mg/ml of its concentration is equivalent to the about 42mg/ml Caspofungin that calculates with alkali; With the about 20mg/ml mannitol of about 50mg/ml and the filler of about 30mg/ml sucrose mixture; And water; With the propionate buffer agent of optional about 25mmol/l as the pH regulator agent or the propanoic acid of about 3mmol/l.

It is about 7 that the optional buffer agent that exists, preferred propionate buffer agent or pH regulator agent make the pH value of aforesaid liquid compositions reach preferred about 5-effectively, and for example about 5.5-is about 6.5, and more preferably from about 6.0.

Preferably with the present composition of aforesaid aqueous solution form with the about 15ml of about 0.1ml-, the about 9ml of for example about 0.3ml-, the about 3.3ml of preferably about 0.1ml-, more preferably from about the volume of the about 3ml/ bottle of 0.3ml-is filled into bottle,

-compositions the xiii of the preferably about 0.476ml/ bottle of volume for example), so that obtain pharmaceutical composition, it comprises: the propanoic acid Caspofungin, and dipropionic acid Caspofungin for example, consumption is equivalent to the Caspofungin with the calculating of Caspofungin alkali of about 20mg; Or

-compositions the xiii of the preferably about 1.25ml/ bottle of volume for example), or the compositions xii of the preferably about 1.714ml/ bottle of volume), or the compositions xi of the preferably about 2.1ml/ bottle of volume), so that acquisition pharmaceutical composition, it comprises: the propanoic acid Caspofungin, dipropionic acid Caspofungin for example, consumption are equivalent to the Caspofungin that calculates with Caspofungin alkali of about 52.5mg; Or

-compositions the xiii of the preferably about 1.75ml/ bottle of volume for example), or the compositions xii of the preferably about 2.4ml/ bottle of volume) or the compositions xi of the preferably about 2.94ml/ bottle of volume), so that acquisition pharmaceutical composition, it comprises: the propanoic acid Caspofungin, dipropionic acid Caspofungin for example, consumption are equivalent to the Caspofungin that calculates with Caspofungin alkali of about 73.5mg; Or

-compositions the xiii of the preferably about 0.25ml/ bottle of volume for example), or the compositions xii of the preferably about 0.343ml/ bottle of volume), or the compositions xi of the preferably about 0.42ml/ bottle of volume), so that acquisition pharmaceutical composition, it comprises: the propanoic acid Caspofungin, dipropionic acid Caspofungin for example, consumption are equivalent to the Caspofungin that calculates with Caspofungin alkali of about 10.5mg; Or

-compositions the xiii of the preferably about 8.75ml/ bottle of volume for example), or the compositions xii of the preferably about 12ml/ bottle of volume), or the compositions xi of the preferably about 14.7ml/ bottle of volume), so that acquisition pharmaceutical composition, it comprises: the propanoic acid Caspofungin, dipropionic acid Caspofungin for example, consumption are equivalent to the Caspofungin that calculates with Caspofungin alkali of about 367.5mg.

Can also be with the present composition of aqueous solution form, for example for compositions xi), xii) or xiii) be filled into bottle to be different from above-mentioned those volume by ml, so that can obtain extra pharmaceutical composition, wherein be easy to calculate the propanoic acid Caspofungin that calculates with Caspofungin alkali, for example content of dipropionic acid Caspofungin.

By the present composition with an amount of aforesaid aqueous solution form, compositions xi for example), xii) or xiii) be filled into the dipropionic acid Caspofungin that pharmaceutical composition that bottle obtains preferably comprises the about 417.3mg of the about 11.93mg-of unit dose, be equivalent to the about 367.5mg of about 10.5mg-, the preferred about 77mg of about 50mg-, more preferably from about the Caspofungin of 52.5mg or about 73.5mg with the calculating of Caspofungin alkali.This pharmaceutical composition can be used for providing respectively about 10mg, about 350mg, and the Caspofungin with the calculating of Caspofungin alkali of the unit dose of preferably about 50mg or about 70mg is because their each excessive implants of self-contained 5%.Can pass through the parenteral mode like this, for example use these compositionss and/or can use by the parenteral mode using solvent described herein and/or diluent further to dilute the back as instant available solution.

One preferred aspect in, the present composition with the aqueous solution form, for example an amount of aforesaid compositions xi), xii) or xiii) be filled into bottle, vial for example, and subsequently according to the known method lyophilizing, be lyophilization, thereby obtain the pharmaceutical composition of the present invention of lyophilized powder form.

For example, can be as follows, for example according to carrying out lyophilizing with the similar as described in example 20 above mode of example; The part jam-pack contains suitable quantity of water solution, for example compositions xi), xii) or bottle xiii) and by using for example as Christ Epsilon 2-6 D ^TMThe freeze dryer lyophilizing that freeze dryer is purchased is to form cake on the bottle bottom.In brief, carrying out about 960 minutes preliminarily dried under about-40 ℃ the temperature and under the vacuum of about 0.04mbar.Under+15 ℃, carry out the drying second time in about 3 hours and under about 0.011mbar vacuum.Technological parameter can be suitable for for example different packed heights of bottle, and the process time that can adjust each lyophilization step is to guarantee to finish according to known method the drying of compositions.

Therefore, the present invention further provides-another preferred aspect-pharmaceutical composition of solid form, for example powder type, preferred lyophilized powder form, it can pass through, preferably by the aforesaid aqueous solution of lyophilizing, preferred composition xi), xii) or xiii) present composition of form obtain.Described lyophilized powder is suitable for preparing the liquid that is used for parenteral administration,, intravenous subcutaneous such as being used for, intraperitoneal or intramuscular administration, the injectable formulation that preferred intravenous is used.

The pharmaceutical composition of preferred lyophilized powder form comprises the about 417.3mg of about 11.93mg-, the preferred about 87.43mg of about 56.8mg-, the dipropionic acid Caspofungin of 59.61mg or about 83.46mg unit dose more preferably from about, be equivalent to the about 367.5mg of about 10.5mg-respectively, the preferred about 77mg of about 50mg-, more preferably from about the Caspofungin of 52.5mg or about 73.5mg with the calculating of Caspofungin alkali.This pharmaceutical composition can be used for using 10.5ml solvent described herein, for example aqueous solvent dissolves again, and extract 10ml again solvent soln the patient is used and/or further provides after the dilution and be about the about 350mg of 10mg-respectively, the Caspofungin with the calculating of Caspofungin alkali of preferred about 50mg or about 70mg unit dose is because they comprise 5% excessive implant separately.

In a preferred embodiment, lyophilized powder of the present invention comprises the about 62.45mg of about 56.78mg-, the dipropionic acid Caspofungin of preferred about 59.61mg unit dose, be equivalent to the about 55mg of about 50mg-respectively, the Caspofungin of preferred about 52.5mg with alkali calculating, and further comprise the about 28.7mg of about 23.8mg-, preferred about 28mg mannitol of about 25mg-and the about 43mg of about 35.6mg-, the preferred about 41mg sucrose of about 37mg-, and comprise the about 2.75mg of about 2.23mg-, the propanoic acid of the about 2.6mg of preferably about 2.3mg-.The ingredient of described extra propanoic acid-extra propionate buffer agent-when dissolving above-mentioned lyophilized powder again with about 10.5ml aqueous solvent described herein or diluent to be effectively providing about 5-about 8, the consumption existence of the pH value of preferably about 6.0-about 7.5.Above-mentioned lyophilized powder comprises the about 10.2mg of about 9mg-thus, in the propanoic acid that derives from the propionate buffer agent of the above-mentioned amount of total propanoic acid of the about 9.7mg of preferably about 9.4mg--additionally add to-also comprise the propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The lyophilized powder particularly preferred embodiment comprises 59.61mg dipropionic acid Caspofungin, be equivalent to the Caspofungin that 52.5mg calculates with alkali, and the mixture that further comprises 25mg mannitol and 37.5mg sucrose or 27mg mannitol and 40.5mg sucrose or 27.3mg mannitol and 40.95mg sucrose, and also comprise 2.31mg or 2.58mg or 2.5mg respectively be the propanoic acid of propionate buffer agent ingredient.This particularly preferred embodiment comprises total propanoic acid of 9.43mg or 9.62mg or 9.7mg thus respectively, and it comprises that 7.11mg derives from the propanoic acid of the propionate counter ion counterionsl gegenions of dipropionic acid Caspofungin.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 62.45mg of about 56.78mg-, the dipropionic acid Caspofungin of preferred about 59.61mg unit dose, be equivalent to the about 55mg of about 50mg-respectively, the Caspofungin of preferred about 52.5mg with alkali calculating, and further comprise the about 28.7mg of about 23.8mg-, preferred about 28mg mannitol of about 25mg-and the about 43mg of about 35.6mg-, the preferred about 41mg sucrose of about 37mg-, and also comprise the about 0.45mg of about 0.12mg-, the propanoic acid of the about 0.39mg of preferably about 0.19mg-.Described extra propanoic acid is aforesaid pH regulator agent and about 8 with the about 5-of effective acquisition during dissolved freeze-dried powder again with about 10.5ml aqueous solvent described herein or diluent, the consumption of the pH value of preferably about 6.0-about 7.5 exists.Above-mentioned lyophilized powder comprises the about 7.9mg of about 6.9mg-thus, the above-mentioned amount of total propanoic acid of the about 7.5mg of preferably about 7.3mg--additionally add to in the propanoic acid of pH regulator agent-also comprise the propanoic acid of the counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The particularly preferred embodiment of lyophilized powder comprises 59.61mg dipropionic acid Caspofungin, be equivalent to the Caspofungin that 52.5mg calculates with alkali, and further comprise 25mg mannitol and 37.5mg sucrose, or the mixture of 27mg mannitol and 40.5mg sucrose or 27.3mg mannitol and 40.95mg sucrose, and also to comprise about 0.29mg or about 0.31mg or about 0.32mg be the propanoic acid of pH regulator agent.This particularly preferred embodiment comprises total propanoic acid of about 7.40mg or about 7.43mg or about 7.44mg thus respectively, and it comprises that 7.11mg derives from the propanoic acid of the propionate counter ion counterionsl gegenions of dipropionic acid Caspofungin.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 62.45mg of about 56.78mg-, the dipropionic acid Caspofungin of preferred about 59.61mg unit dose, be equivalent to the about 55mg of about 50mg-respectively, the Caspofungin of preferred about 52.5mg with alkali calculating, and further comprise the about 28.7mg of about 23.8mg-, preferred about 28mg mannitol of about 25mg-and the about 43mg of about 35.6mg-, the preferred about 41mg sucrose of about 37mg-, but do not comprise any extra propanoic acid for pH regulator agent or propionate buffer agent ingredient.Above-mentioned lyophilized powder comprises the about 7.47mg of about 6.75mg-, preferably total propanoic acid of about 7.11mg-its integral body-derive from propionate counter ion counterionsl gegenions of the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The lyophilized powder particularly preferred embodiment comprises 59.61mg dipropionic acid Caspofungin, be equivalent to the Caspofungin that 52.5mg calculates with alkali, and further comprise the mixture of 25mg mannitol and 37.5mg sucrose or 27mg mannitol and 40.5mg sucrose or 27.3mg mannitol and 40.95mg sucrose.This particularly preferred embodiment also comprises total propanoic acid that 7.11mg derives from the propionate counter ion counterionsl gegenions of dipropionic acid Caspofungin.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 87.43mg of about 79.5mg-, the dipropionic acid Caspofungin of preferred about 83.46mg unit dose, be equivalent to the about 77mg of about 70mg-respectively, the Caspofungin that preferred about 73.50mg calculates with alkali, and further comprise the about 40.4mg of about 33.3mg-, preferred about 38.5mg mannitol of about 35mg-and the about 60.4mg of about 49.4mg-, the preferred about 57.5mg sucrose of about 52mg-, and comprise the about 3.85mg of about 3.05mg-, the propanoic acid of the preferred about 3.64mg of about 3.24mg-, wherein said propanoic acid is for the ingredient of extra propionate buffer agent and effectively provide about 5-about 8 when dissolving above-mentioned lyophilized powder again with about 10.5ml aqueous solvent described herein or diluent, the consumption existence of the pH value of preferably about 6.0-about 7.5.Above-mentioned lyophilized powder comprises the about 14.28mg of about 12.54mg-thus, total propanoic acid of the about 13.60mg of preferably about 13.20mg-, and it also comprises the propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin that is included in pharmaceutical composition.The particularly preferred embodiment of lyophilized powder comprises the dipropionic acid Caspofungin of 83.46mg, be equivalent to the Caspofungin that 73.5mg calculates with alkali, and further comprise 35mg mannitol and 52.5mg sucrose or 37.8mg mannitol and or the mixture of 56.71mg sucrose or 38.22mg mannitol and 57.33mg sucrose, and also comprise the propanoic acid that 3.24mg or 3.5mg or 3.62mg are extra propionate buffer agent ingredient respectively.Described particularly preferred embodiment comprises the propanoic acid of the total amount of 13.2mg or 13.47mg or 13.58mg thus respectively, comprises that 9.96mg derives from the propanoic acid of the propionate counter ion counterionsl gegenions of dipropionic acid Caspofungin.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 87.43mg of about 79.5mg-, the dipropionic acid Caspofungin of preferred about 83.46mg unit dose, be equivalent to the about 77mg of about 70mg-respectively, the Caspofungin that preferred about 73.50mg calculates with alkali, and further comprise the about 40.4mg of about 33.3mg-, preferred about 38.5mg mannitol of about 35mg-and the about 60.4mg of about 49.4mg-, the preferred about 57.5mg sucrose of about 52mg-, and also comprise the about 1.07mg of about 0.11mg-, the propanoic acid of the about 0.54mg of preferably about 0.34mg-.About 8 with the about 5-of effective acquisition when dissolving with about 10.5ml aqueous solvent as herein described or diluent for the described extra propanoic acid of pH regulator agent, the consumption of the pH value of preferably about 6.0-about 7.5 exists again.Above-mentioned lyophilized powder comprises the about 11.5mg of about 9.7mg-thus, the above-mentioned amount of total propanoic acid of the about 10.5mg of preferably about 10.3mg--additionally add to be the propanoic acid of pH regulator agent-also the comprise propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The particularly preferred embodiment of lyophilized powder comprises 83.46mg dipropionic acid Caspofungin, be equivalent to the Caspofungin that 73.5mg calculates with alkali, and the mixture that further comprises 35mg mannitol and 52.5mg sucrose or 37.8mg mannitol and 56.71mg sucrose or 38.22mg mannitol and 57.33mg sucrose, and also comprise about 0.40mg or about 0.44mg or about 0.45mg respectively be the propanoic acid of pH regulator agent.This particularly preferred embodiment comprises total propanoic acid of about 10.37mg or about 10.40mg or about 10.41mg thus respectively, and it comprises that 9.96mg derives from the propanoic acid of the propionate counter ion counterionsl gegenions of dipropionic acid Caspofungin.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 87.43mg of about 79.5mg-, the dipropionic acid Caspofungin of preferred about 83.46mg unit dose, be equivalent to the about 77mg of about 70mg-respectively, the Caspofungin that preferred about 73.50mg calculates with alkali, and further comprise the about 40.4mg of about 33.3mg-, preferred about 38.5mg mannitol of about 35mg-and the about 60.4mg of about 49.4mg-, the preferred about 57.5mg sucrose of about 52mg-, but do not contain any extra propanoic acid for pH regulator agent or propionate buffer agent ingredient.Above-mentioned lyophilized powder comprises the about 10.5mg of about 9.5mg-, the total propanoic acid of preferably about 10mg-its integral body-the derive from propionate counter ion counterionsl gegenions of the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The particularly preferred embodiment of lyophilized powder comprises the dipropionic acid Caspofungin of 83.46mg, be equivalent to the Caspofungin that 73.5mg calculates with alkali, and further comprise the mixture of 35mg mannitol and 52.5mg sucrose or 37.8mg mannitol and 56.71mg sucrose or 38.22mg mannitol and 57.33mg sucrose.Described particularly preferred embodiment also comprises the total propanoic acid of 9.96mg, and it derives from the propionate counter ion counterionsl gegenions of dipropionic acid Caspofungin.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 12.5mg of about 11.36mg-, the dipropionic acid Caspofungin of preferred about 11.9mg unit dose, be equivalent to the about 11mg of about 10mg-respectively, the Caspofungin that preferred about 10.5mg calculates with alkali, with the about 5.78mg of about 4.75mg-, the preferred about 5.5mg mg of about 5mg-mannitol and the about 8.6mg of about 7.1mg-, the preferred about 8.2mg sucrose of about 7.5mg-, and the optional about 0.56mg of about 0.44mg-that also comprises, the preferred about 0.53mg of about 0.46mg-is the propanoic acid of extra propionate buffer agent ingredient, when dissolving above-mentioned lyophilized powder again with about 10.5ml aqueous solvent as herein described or diluent, described propanoic acid is effectively to provide about 5-about 8, and the consumption of the pH value of preferably about 6.0-about 7.5 exists.If above-mentioned lyophilized powder comprises extra propionate buffer agent, it comprises the about 2.05mg of about 1.8mg-thus so, total propanoic acid of the preferred about 1.95mg of about 1.9mg-, it also comprises the propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin that is included in the pharmaceutical composition.With regard to the situation that above-mentioned lyophilized powder does not contain extra propionate buffer agent, it comprises the about 1.49mg of about 1.36mg-, preferably total propanoic acid of about 1.42mg-its integral body-derive from propionate counter ion counterionsl gegenions of the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The particularly preferred embodiment of above-mentioned lyophilized powder comprises 11.92mg dipropionic acid Caspofungin, be equivalent to the Caspofungin that 10.5mg calculates with alkali, and the mixture that further comprises 5mg mannitol and 7.5mg sucrose or 5.4mg mannitol and 8.11mg sucrose or 5.46mg mannitol and 8.19mg sucrose, and also optionally comprise the propanoic acid that 0.46mg or 0.5mg or 0.52mg are extra propionate buffer agent ingredient respectively.With regard to the situation that these particularly preferred embodiments comprise the propionate buffer agent, they comprise the total propanoic acid of 1.89mg or 1.92mg or 1.94mg respectively, comprise the propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin.With regard to the situation that these particularly preferred embodiments do not contain the propionate buffer agent, they comprise total propanoic acid that 1.42mg derives from dipropionic acid Caspofungin counter ion counterionsl gegenions.

In another preferred embodiment, lyophilized powder of the present invention comprises the about 438.3mg of about 397.4mg-, the dipropionic acid Caspofungin of preferred about 417.3mg unit dose, be equivalent to the about 386mg of about 350mg-respectively, the Caspofungin that preferred about 367.5mg calculates with alkali, with the about 200mg of about 166mg-, preferred about 192mg mannitol of about 175mg-and the about 300mg of about 250mg-, the preferred about 287mg sucrose of about 263mg-, and the optional about 19.1mg of about 15.27mg-that comprises, the preferred about 18.2mg's of about 16.2mg-is the propanoic acid of extra propionate buffer agent ingredient, when dissolving above-mentioned lyophilized powder again with about 10.5ml aqueous solvent as herein described or diluent, described propanoic acid is effectively to provide about 5-about 8, and the consumption of the pH value of preferably about 6.0-about 7.5 exists.If above-mentioned lyophilized powder comprises extra propionate buffer agent, it comprises the about 71.4mg of about 62.7mg-thus so, total propanoic acid of the preferred about 68mg of about 66mg-, it also comprises the propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin that is included in the pharmaceutical composition.With regard to the situation that above-mentioned lyophilized powder does not contain extra propionate buffer agent, it comprises the about 52.3mg of about 47.43mg-, preferably total propanoic acid of about 49.8mg-its integral body-derive from counter ion counterionsl gegenions of the propionate of the dipropionic acid Caspofungin that is included in the pharmaceutical composition.The particularly preferred embodiment of lyophilized powder comprises 417.30mg dipropionic acid Caspofungin, be equivalent to the Caspofungin that 367.5mg calculates with alkali, and the mixture that further comprises 175mg mannitol and 262.5mg sucrose or 189mg mannitol and 283.56mg sucrose or 191.1mg mannitol and 286.65mg sucrose, and also optionally additionally comprise the propanoic acid that 16.19mg or 17.52mg or 18.08mg are extra propionate buffer agent ingredient respectively.With regard to the situation that these particularly preferred embodiments comprise the propionate buffer agent, they comprise total propanoic acid of 65.99mg or 67.33mg or 67.88mg respectively, and it comprises the propanoic acid of the propionate counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin.With regard to the situation that these particularly preferred embodiments do not contain the propionate buffer agent, they comprise total propanoic acid of the counter ion counterionsl gegenions that derive from the dipropionic acid Caspofungin of 49.8mg.

The other embodiment preferred of above-mentioned lyophilized powder comprises the dipropionic acid Caspofungin of the unit dose of about 11.9mg or about 417.3mg, be equivalent to the Caspofungin that about 10.5mg or about 367.5mg calculate with alkali, these embodiments comprise propanoic acid, and can effectively to obtain about 5-as its consumption of pH regulator agent-rather than extra propionate buffer agent-when dissolving above-mentioned lyophilized powder again with about 10.5ml aqueous solvent as herein described or diluent about 8, the pH value of preferably about 6.0-about 7.5.Be easy to according to for example to above-mentioned other preferred embodiment, for example contain the described respective amount that the similar mode of the specified consumption of dipropionic acid Caspofungin that is equivalent to the Caspofungin that the about 55mg of about 50mg-calculates with alkali is calculated as the propanoic acid of pH regulator agent.

Can be by adding compatibility diluent and/or solvent as described herein before parenteral administration, for example use aqueous solution, for example be used for freeze dried bottle, for example dissolve the pharmaceutical composition of lyophilized powder form of the present invention as described herein in the vial again by an amount of described solvent or diluent are directly joined.

The present invention provides thus and can pass through, preferably by using aqueous solution, preferred water, for example use distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiological saline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution dissolve the pharmaceutical composition that aforesaid lyophilized powder of the present invention obtains again, forms the aqueous solution that freeze-dried composition is dissolved in the present invention who is suitable for parenteral administration more thus.

The present invention one preferred aspect in provide can be by use the 10.5ml aqueous solution, preferred above-mentioned preferred solution dissolves the pharmaceutical composition of lyophilized powder acquisition of the present invention again.The present invention one preferred aspect in provide can be by using the 10.5ml aqueous solution, preferred water, for example use distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline (normal saline) or normal saline (physiologicalsaline), 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution dissolve the pharmaceutical composition that the above-mentioned preferred embodiment of the present invention and particularly preferred embodiment obtain again.With regard to described preferred pharmaceutical composition, be easy to preferably calculate divided by 10.5 with the amount of the lyophilized powder of particularly preferred embodiment by the invention described above that will represent with mg in the concentration of the concentration of the dipropionic acid Caspofungin that calculates with Caspofungin alkali of mg/ml and mannitol wherein, sucrose and propanoic acid.

Can preferably further dilute again the pharmaceutical composition of the present invention of solvent soln form so that the solution that is suitable for patient's infusion is provided with appropriate solvent or diluent with preferred solvent as described herein and/or diluent.Can by with diluent as herein described with 7ml-10ml, the solvent soln again of preferred 7ml or 10ml is diluted to the about 300ml of about 100-, the cumulative volume of about 250ml of preferably about 110ml-or 260ml dilutes the pharmaceutical composition of the present invention of the above-mentioned form of solvent soln again.Should dilute solvent soln again according to this class mode, comprise propanoic acid Caspofungin, the particularly pharmaceutical composition of dipropionic acid Caspofungin pharmaceutically acceptable and the treatment effective dose so that provide.Term as herein described " treatment effectively " and the dosage that is used to prevent and/or treat are as above-mentioned definition.

Dissolving pharmaceutical composition behind the aforesaid lyophilized powder of the present invention again, preferably to have about 5-about 8, the pH value of preferably about 6.0-about 7.5.

One preferred aspect in, pharmaceutical composition of the present invention is suitable for parenteral administration as described herein.Do not wish to be subjected to theory constraint, the inventor thinks that pharmaceutical composition of the present invention has promoted the propanoic acid Caspofungin that wherein comprises, the stability of for example dipropionic acid Caspofungin.

One in addition preferred aspect in, the invention provides the pharmaceutical composition that comprises the propanoic acid Caspofungin that is used for parenteral administration, they show high-purity.For example in the pharmaceutical composition of dissolved freeze-dried powder more as described herein, for example in embodiment 20-28, observed described high-purity, as according to known method, measure by HPLC, they only show low total impurities content, for example be lower than 1.5%, preferably be no more than 1.3%, for example be no more than 1%, for example be no more than the total impurities of 0.7%-about 0.9%, and/or only show the granule that is lower than visible＞25 μ m on a small quantity, for example each bottle is less than 30, preferably be less than 25, for example be no more than 18 granules that are lower than visible＞25 μ m, and/or the granule that each bottle is lower than visible＞10 μ m for example is less than 650, preferably is less than 620, for example be no more than the granule that is lower than visible＞10 μ m greater than 615, as what measure according to known method.Mensuration by the HPLC total impurities and/or by USP 29,＜788 in being lower than described in visible particulate mensuration such as embodiment 20 and/or the embodiment 23-28 of method in " granule in the injection: photoresistance grain count test ".

In addition, pharmaceutical composition of the present invention comprises and is suitable for the pharmaceutical composition that oral, local, nose and suppository are used.Be used for Orally administered pharmaceutical composition and can be the liquid or solid compositions.Above-mentioned composition can also comprise the pharmaceutically acceptable excipient of using that is suitable for the above-mentioned type.This class excipient and mode how to use them to prepare described compositions are known.

One preferred aspect in, crystallization propanoic acid Caspofungin, for example crystallization dipropionic acid Caspofungin is used to prepare aforementioned pharmaceutical compositions.

In aspect another is preferred, as passing through to transform propanoic acid Caspofungin crystallization or the crystallization of dipropionic acid Caspofungin, comprise the amorphous propanoic acid Caspofungin that obtains with water dissolution and lyophilizing as described herein, for example amorphous dipropionic acid Caspofungin is used to prepare aforementioned pharmaceutical compositions.More preferably crystallization of propanoic acid Caspofungin or the crystallization of dipropionic acid Caspofungin that is used to transform with wet nitrogen treatment, or make its contact humidity so that before transforming as mentioned above, remove residual organic solvent.

The present invention also provides the method for preparing the propanoic acid Caspofungin.Therefore, in one embodiment, the present invention relates to prepare the method for propanoic acid Caspofungin, it comprises the following steps:

A) with the Caspofungin of salt form, preferred oxalic acid Caspofungin is dissolved in the mixture of organic solvent and water, is preferably C ₁-C ₄In the appropriate solvent of the mixture of-alcohol and water;

B) in the presence of propanoic acid is arranged by reversed-phase HPLC purification step A) in the mixture of acquisition; With

C) fraction that obtains step of freeze drying B).

Be used for steps A) the preferred C of organic solvent ₁-C ₄-alcohol, for example methanol or ethanol etc., more preferably methanol.Therefore, be used for steps A) organic solvent and the preferred solvent of the mixture of water be the mixture of methanol and water.

In said method, can be by being dissolved in suitable ORGANIC SOLVENT MIXTURES, for example C for the Caspofungin of alkali ₁-C ₄-alcohol, for example methanol or ethanol, particular methanol and water, by adding suitable acid, such as mineral acid or organic acid, preferred organic acid, more preferably propanoic acid prepares the Caspofungin of salt form in position, for example the oxalic acid Caspofungin.

Mixture that can be by using acetonitrile and water and propanoic acid are so that eluted product is carried out step B from the reversed-phase HPLC post), promptly in the presence of propanoic acid is arranged by reversed-phase HPLC purification step A) in the mixture of acquisition so that fraction is rich in acquisition.The mixture of acetonitrile and water can be 22 acetonitriles/78 water (v/v) mixture, and it comprises about 0.25% propanoic acid, for example about 0.05%-2.0%, and 0.1%-1.0% for example, such as the propanoic acid of 0.2%-0.5%, wherein % is weight percentage.Can and use for example C-8 or anti-phase adsorbent of C-18 and post according to known method, for example such as carrying out reversed-phase HPLC available from YMC Europe GmbH.

Can be according to carrying out step C with the similar mode of for example known method), i.e. step of freeze drying B) in the fraction that obtains.

Step C) product that obtains in, promptly lyophilized products is propanoic acid Caspofungin of the present invention, particularly its amorphous form, for example as preparation among the embodiment 17, wherein it is described as Caspofungin propanoic acid adduct.

The present invention relates to the method for preparing the propanoic acid Caspofungin in another embodiment, comprise-except that above-mentioned steps A)-C)-following extra step:

D) with step C) in the lyophilized products that obtains be dissolved in the mixture of organic solvent and water, preferably C ₁-C ₄The mixture of-alcohol and water,

E) add propanoic acid and add acetic acid C subsequently ₁-C ₄-Arrcostab, ethyl acetate so as to obtain suspension and

F) from step e) separate the propanoic acid Caspofungin in the suspension that obtains.

Be used for step D) organic solvent be preferably C ₁-C ₄-alcohol, for example methanol or ethanol etc., more preferably ethanol.Therefore, the preferred solvent of the mixture of organic solvent and water is the mixture of ethanol and water.

Be used for step e) acetic acid C ₁-C ₄-Arrcostab can be methyl acetate, ethyl acetate, n-propyl acetate or isopropyl acetate, n-butyl acetate or isobutyl acetate, ethyl acetate.Seed bed

For example, can followingly carry out step e), promptly add propanoic acid and add acetic acid C subsequently ₁-C ₄-Arrcostab, ethyl acetate, so that acquisition suspension: add propanoic acid and subsequently to step D) in adding first's ethyl acetate and in room temperature in the mixture that obtains, promptly be stirred to the beginning crystallization under about 25 ℃ ± 5 ℃, for example about 1 hour of lasting stirring is determined up to brilliant bed, and subsequently in time limit time expand, in about 5 hours of for example about 3-, add the second portion ethyl acetate in for example about 4 hours, and gained crystallization suspension was placed for example about 1 hour.Choose wantonly and can give this solution kind crystalline substance.

Can carry out step F according to known method), promptly for example by the filtering for crystallizing suspension so that for example reclaim at ambient temperature the vacuum, for example at room temperature, such as about 25 ℃ ± 5 ℃ down exsiccant crystalline solids from step e) separation propanoic acid Caspofungin in the suspension that obtains, so that obtain the propanoic acid Caspofungin, for example the dipropionic acid Caspofungin.Choose wantonly before dry and can wash, for example pass through to filter the solid that obtains with the mixture washing of ethanol, water and ethyl acetate.Can also carry out drying process by apply nitrogen current according to known method.Perhaps, can make wet nitrogen, 20%-55% for example is such as the crystalline solid of nitrogen by reclaiming after filtration of 30%-50% relative humidity, so that remove residual organic solvent as mentioned above.This processing can be controlled the residual moisture content of propanoic acid Caspofungin and reduce the formation of unwanted catabolite.

Preferred steps F) the propanoic acid Caspofungin that obtains in is the dipropionic acid Caspofungin, and more preferably the formula II of crystal form for example as among the embodiment 17 prepares.

In another embodiment, the invention provides the method for preparing the propanoic acid Caspofungin, comprise the following steps:

A ') with the Caspofungin of salt form, preferred oxalic acid Caspofungin is dissolved in suitable solvent, preferred water;

B ') with steps A ') in the pH value of the solution that obtains be adjusted to about 9.0 so that obtain suspension;

C ') suspension that obtains filtration step B '), and the optional products therefrom that washes with water;

D ') with step C ') in the product that obtains be dissolved in the organic solvent that contains propanoic acid, preferred C ₁-C ₄-alcohol is so that obtain solution;

E ') solution that obtains filtration step D ') and adding acetic acid C ₁-C ₄-Arrcostab, ethyl acetate is so that obtain suspension; With

F ') from step e ') separate the propanoic acid Caspofungin in the suspension that obtains.

Be used for step D ') organic solvent be preferably C ₁-C ₄-alcohol, for example methanol or ethanol etc., more preferably ethanol.

Be used for step e ') acetic acid C ₁-C ₄-Arrcostab can be methyl acetate, ethyl acetate, n-propyl acetate or isopropyl acetate, n-butyl acetate or isobutyl acetate, ethyl acetate.

For example, can followingly carry out step e '): to step D ') in add first's ethyl acetate in the mixture that obtains and in room temperature, promptly under about 25 ℃ ± 5 ℃, be stirred to the beginning crystallization, for example about 1 hour of lasting stirring, determine up to brilliant bed, and subsequently in time limit time expand, in about 5 hours of for example about 3-, add the second portion ethyl acetate in for example about 4 hours, and gained crystallization suspension was placed for example about 1 hour.Choose wantonly and can give this solution kind crystalline substance.

Can be according to known method, for example by filter and for example according to aforesaid step F) similarly mode carry out step F '), promptly from step e ') separation propanoic acid Caspofungin in the suspension that obtains.

Preferred steps F ') the propanoic acid Caspofungin that obtains in is the dipropionic acid Caspofungin, and the formula II of crystal form for example is as preparation among the embodiment 18 for example.

A ") is with chemical compound or its acid-addition salts of formula III:

Be dissolved in or be suspended in the mixture of organic solvent and water, more preferably C ₁-C ₄In the appropriate solvent of the mixture of-alcohol and water;

B ") is by at chemical compound or its acid-addition salts that the catalytic hydrogenation reduction formula III in the presence of the propanoic acid is arranged;

The reversed-phase HPLC purification step B of C ") by in the presence of propanoic acid ") in the product of acquisition; With

D ") step of freeze drying C ") the middle fraction that obtains.

The appropriate solvent that is used for steps A ") for reduction for inert.This kind solvent can be determined in routine test by those skilled in the art.Suitable solvent is: alcohols for example, and such as C ₁-C ₄-alcohols, for example methanol, ethanol or isopropyl alcohol; Amide-type, such as N, dinethylformamide or N-Methyl pyrrolidone, optional and water combination.Preferred suitable solvent is ORGANIC SOLVENT MIXTURES, more preferably C ₁-C ₄-alcohol, for example mixture of ethanol, methanol or isopropyl alcohol and water.A kind of preferred solvent is the mixture of isopropyl alcohol and water.

The preferred acid addition salts of the chemical compound of the formula III that uses in ") as steps A is an acetate, i.e. the chemical compound of formula III a:

For example, can followingly carry out reduction step B "): propanoic acid is joined steps A ") in the solution or suspension that obtain, and use alkaline reagent, for example use ammonia that pH value is adjusted to about 6.5.In order to reduce chemical compound or its acid-addition salts of formula III, can use nitrile Reducing agent arbitrarily.The preferred catalytic hydrogenation of using.Can reduce to chemical compound or its acid-addition salts of formula III by using catalyst described in International Application No. WO 2007/057141 A1 and condition.The chemical compound of the WO 2007/057141 A1 Chinese style VI that the chemical compound of formula III is equivalent to be incorporated herein by reference.

Can followingly carry out step C "); i.e. product by obtaining among the reversed-phase HPLC purification step B "): at step B ") in reduction fully after; can be from reactant mixture, for example by removing by filter catalyst and can choosing wantonly subsequently and use the remaining filtrate of activated carbon purification.Can choose wantonly then and further filter back evaporated filtrate-so that obtain viscous residue, it can be dissolved in the appropriate solvent for the mixture of organic solvent and water, wherein organic solvent is preferably C ₁-C ₄-alcohol, for example methanol or ethanol etc., more preferably methanol.Therefore, the mixture of particular methanol and water is used for step C ").Can according to step B for example as described herein) similarly mode carry out purification by reversed-phase HPLC having in the presence of the propanoic acid.

Can according to step C for example as described herein) similarly mode carry out step D "), i.e. the fraction that obtains among the step of freeze drying C ").

The product that obtains among the step D "), promptly lyophilized products is propanoic acid Caspofungin of the present invention, particularly its amorphous form, for example as preparation among the embodiment 19, wherein it is described as Caspofungin propanoic acid adduct.

The present invention relates to the method for preparing the propanoic acid Caspofungin in another embodiment, comprise-except that above-mentioned steps A ")-D ")-following extra step:

E ") is with step D ") in the lyophilized products that obtains be dissolved in the mixture of organic solvent and water, preferably C ₁-C ₄The mixture of-alcohol and water;

F ") adds propanoic acid and adds C subsequently ₁-C ₄-Arrcostab, ethyl acetate is so that obtain suspension; With

G ") is from step F ") separate the propanoic acid Caspofungin in the suspension that obtains.

The organic solvent that is used for step e ") is preferably C ₁-C ₄-alcohol, for example methanol or ethanol etc., more preferably ethanol.Therefore, the preferred organic solvent for the mixture of organic solvent and water of ") is the mixture of ethanol and water to be used for step e.

The acetic acid C that is used for step F ") ₁-C ₄-Arrcostab can be methyl acetate, ethyl acetate, n-propyl acetate or isopropyl acetate, n-butyl acetate or isobutyl acetate, ethyl acetate.

Can according to for example step D as herein described), E) and F) similarly mode carry out step e "), F ") and G ").

The propanoic acid Caspofungin that obtains among the preferred steps G ") is the dipropionic acid Caspofungin, and more preferably the formula II of crystal form for example as among the embodiment 19 prepares.

Can the Caspofungin crystallization that obtain by one of methods described herein is water-soluble; Subsequently can be according to the solution of known method lyophilizing acquisition, so that obtain the propanoic acid Caspofungin of amorphous form of the present invention.One preferred aspect in, crystallization of propanoic acid Caspofungin or the crystallization of dipropionic acid Caspofungin that is used to transform with wet nitrogen treatment or make it contact humidity as herein described so that before transforming as mentioned above, removing residual organic solvent.In aspect another is preferred, the Caspofungin of the formula I that the amorphous propanoic acid Caspofungin of acquisition shows and propanoic acid in definite mol ratio of scope as mentioned above, and be characterised in that the content of residual organic solvent as described herein reduces.

Therefore, the invention provides the propanoic acid Caspofungin of amorphous or crystal form, preferred dipropionic acid Caspofungin, it can pass through and preferably pass through any one acquisition in the said method.

Can be according to preparing the Caspofungin of salt form with the similar mode of method that for example discloses among WO 94/21677 and/or the WO96/24613 as mentioned above, pharmaceutically acceptable salt form for example, for example acetic acid or oxalic acid Caspofungin and/or be the Caspofungin of alkali, they are as the raw material in the methods described herein.Perhaps, as the chemical compound of one of the Caspofungin that further uses in the methods described herein or its salt and/or formula III, for example the chemical compound of formula III a can be produced described in International Application No. WO 2007/057141 A1 that is incorporated herein by reference.The chemical compound of the chemical compound of formula III and formula III a is equivalent to the chemical compound of the formula VI among WO 2007/057141 A1 and the chemical compound of formula VIa respectively.Generally speaking, can all can be as the raw material in method as herein described available from any other salt of the Caspofungin in any known source.

Propanoic acid Caspofungin of the present invention, for example crystal form or amorphous form dipropionic acid Caspofungin can be used as medicine.In addition, the propanoic acid Caspofungin, dipropionic acid Caspofungin for example, particularly preferably having the crystal form of the Caspofungin of the formula I of definite mol ratio of scope as mentioned above and propanoic acid or amorphous form can be used for preparation and prevent and/or treat mammal, medicine such as the fungal infection of human patients, pharmaceutical compositions for example of the present invention, described fungal infection is for example because of the species of mycocandida, such as white candida mycoderma, candida tropicalis, Crewe Si Shi candida mycoderma, Candida glabrata and candida pseudotropicalis and by the species of aspergillus, such as Aspergillus fumigatus, yellow aspergillosis and black aspergillosis cause.In addition, the propanoic acid Caspofungin, dipropionic acid Caspofungin for example, particularly preferably having the crystal form of the Caspofungin of the formula I of definite mol ratio of scope as mentioned above and propanoic acid or amorphous form can be further used for preparation and prevent and/or treat particularly mammal, such as human patients because of Jie Shi lung sac worm (formerly being classified as Pneumocystis carinii), the medicine of the infection that causes such as pneumocystosis (P.jirovecipneumonia), pharmaceutical compositions for example of the present invention; Described immunocompromised host, patient's susceptible pneumocystosis especially of for example suffering from AIDS.

Therefore, the present invention relates to the purposes of the propanoic acid Caspofungin of crystal form and/or amorphous form as medicine.In addition, the propanoic acid Caspofungin that the present invention relates to crystal form and/or amorphous form treats and/or prevents purposes in Yin Yinjieshi lung sac worm (formerly the being classified as Pneumocystis carinii) fungal infection that causes and/or the medicine of infection and/or the pharmaceutical composition in preparation.

The Caspofungin salt of crystal form of the present invention or amorphous form, it is the propanoic acid Caspofungin, for example the dipropionic acid Caspofungin is the new model of active component Caspofungin, and the valuable selection of preparation caspofungin formulations is provided for those skilled in the art thus.Advantageously, propanoic acid Caspofungin, particularly dipropionic acid Caspofungin can mass preparation, show good stable and purity, and when comprising its pharmaceutical composition with the industrially scalable preparation easy operating.

The crystallization of propanoic acid Caspofungin, for example the crystallization of dipropionic acid Caspofungin because of its stability, crystal structure and aggregation thereof form characteristic with and be easy to flow and ease of solubility in water is particularly advantageous for pharmaceutical compositions.Can the crystallization of mass preparation propanoic acid Caspofungin, and can remove residual organic solvent by short-cut method expediently, so that reach the pharmaceutically acceptable level of aforesaid ICH guideline Q3C (R3).In addition, be easy to the crystallization of propanoic acid Caspofungin is changed into the Caspofungin of the formula I with definite stoichiometric amount and the amorphous form of propanoic acid, and by straightforward procedure as described herein, the optional residual organic solvent content that also has reduction of amorphous form.

According to the method described above, unbodied propanoic acid Caspofungin, for example amorphous dipropionic acid Caspofungin shows at the ease of solubility of water and can obtain high-purity forms, does not promptly contain residual organic solvent basically or fully, makes it can be advantageously used in useful in preparing drug formulations.In addition, all right amorphous propanoic acid Caspofungin of mass preparation, for example amorphous dipropionic acid Caspofungin.

Be preferred for parenteral administration, the form of dissolved aqueous solution again that for example comprises propanoic acid Caspofungin of the present invention shows high-purity, because they only contain a small amount of total impurities and/or are lower than visible granule.In addition, pharmaceutical composition of the present invention provides the stability of the raising of the propanoic acid Caspofungin that wherein comprises.

By the present invention of the following example illustration, but the present invention is limited to these embodiment never in any form.All temperature all by degree centigrade and not the calibration.

In embodiment 1-5 and 14-16, table 1-4 and 7-9, shown composition for the compositions 1-8 of freeze dried liquid preparation.

With regard to embodiment 6-11, the bottle that contains 52.5mg Caspofungin alkali is used for wherein said analytical method.After with the dilution of 10.5ml ultra-pure water, described bottle comprises the Caspofungin alkali of 5.0mg/ml, the i.e. chemical compound of formula I.Each bottle comprises 5% excessive implant thus.

Embodiment 1 (contrast):

Preparation according to the compositions 1 of the acetate buffer that comprises oxalic acid Caspofungin and additional quantity of the embodiment 1 of EP 0 904 098 B1

Table 1:

By 5g mannitol and 7.5g sucrose are dissolved in the liquid preparation that about 200ml water prepares compositions 1.Measure pH value subsequently, and to add acetic acid to final concentration be 1.5mg/ml, and with 1NNaOH with pH regulator to pH 3.7.Add 11.7g oxalic acid Caspofungin subsequently, be equivalent to the Caspofungin that 46.6mg/ml oxalic acid Caspofungin or 42mg/ml calculate with alkali, using 1N NaOH is 6.0 with pH regulator to pH value.Water is adjusted to volume 250ml and passes through Millex ^TM-GV syringe-driving have a Durapore ^TM-film and diameter are that the defecator of 0.22 μ m filters this solution, and are packed into the 15ml vial with 1.25ml separately.Give the lyophilizing plug of bottle part jam-pack, and lyophilizing is to forming cake in the bottle bottom available from Helvoet Pharma.So that obtaining final concentration is the Caspofungin of 5.0mg/ml, after this carry out analytical test as herein described with 10.5ml ultra-pure water dilution freeze-dried composition.

Embodiment 2 and 3:

Comprise Caspofungin and extra pH regulator agent, be the preparation of the compositions 2 and the compositions 3 of acetic acid:

Table 2:

Component	Compositions	2	Compositions 3
Component	Compositions	2	Compositions 3	Mannitol	20mg/ml	20mg/ml
Sucrose	30mg/ml	30mg/ml		Mannitol	20mg/ml	20mg/ml
Sucrose	30mg/ml	30mg/ml	Acetic acid	In right amount	In right amount
The oxalic acid Caspofungin	46.6mg/ml	46.6mg/ml	Acetic acid	In right amount	In right amount
The oxalic acid Caspofungin	46.6mg/ml	46.6mg/ml	pH	6.0	6.5

Prepare the liquid preparation of

compositions

2 and 3 according to embodiment 1 by using 100ml batch size dissolving mannitol and sucrose.Add 46.6mg/ml oxalic acid Caspofungin subsequently, be equivalent to the Caspofungin alkali of 42mg/ml, measure pH value and be 6.59 and use 1N acetic acid to be adjusted to pH6.0 or pH 6.5 respectively.With regard to compositions 2, add 0.1315mg/ml acetic acid (calculating) based on the liquid preparation final volume, being equivalent to final molar concentration and being the extra acetic acid of 2.19mmol/l or extra acetic acid and the mol ratio of Caspofungin is 0.0569.After water was adjusted volume, the pH of acquisition was 6.05.With regard to compositions 3, add 0.0188mg/ml acetic acid (calculating) based on the liquid preparation final volume, being equivalent to final molar concentration and being the extra acetic acid of 0.31mmol/l or extra acetic acid and the mol ratio of Caspofungin is 0.00813.After water was adjusted volume, the pH of acquisition was 6.54.Adjust volume according to mode water similar to Example 1, promptly be adjusted to the 100ml final volume, filter this solution, be filled into bottle and lyophilized products.Dissolve and/or dilute freeze-dried

composition

2 and 3 again according to mode similar to Example 1.

Embodiment 4:

Comprise Caspofungin and do not contain the preparation of the compositions 4 of any extra pH regulator agent:

Table 3:

Prepare the liquid preparation of the compositions 4 of 200ml batch size according to

embodiment

2 and 3 by dissolving mannitol and sucrose.Add 42mg/ml Caspofungin alkali subsequently, i.e. 46.6mg/ml oxalic acid Caspofungin, not re-adjustment pH value.Adjust volume according to mode water similar to Example 1, promptly be adjusted to the 200ml final volume, obtain 5.96 pH value thus, filter this solution, be filled into bottle and lyophilizing bottle.Dissolve and/or dilute freeze-dried composition 4 again according to mode similar to Example 1.

Embodiment 5:

Comprise Caspofungin, the preparation of the compositions 5 of the acetate buffer of additional quantity and extra EDTA:

Table 4:

By dissolving mannitol and sucrose and adding acetic acid, regulate pH and add the liquid preparation that the oxalic acid Caspofungin prepares the compositions 5 of 50ml batch size as described in example 1 above by adding NaOH.The EDTA sodium dihydrate (based on the volume calculation of final adjustment) that adds 0.81mg/ml subsequently, and with lN NaOH with pH regulator to pH 6.0.Adjust volume according to mode water similar to Example 1, promptly be adjusted to the 50ml final volume, obtain 5.99 pH value thus, filter this solution, be filled into bottle and lyophilizing bottle.Dissolve and/or dilute freeze dried compositions 5 again according to mode similar to Example 1.

Embodiment 6:

The mensuration of total impurities:

After lyophilizing, promptly when " 0 week ", or under 2 ℃ of-8 ℃ of temperature, promptly on average analyzing freeze-dried composition 1-5 at once after storing for 2,4,8 or 12 weeks down at 5 ℃.By adding 10.5ml ultra-pure water dissolved composition and subsequently according to reversed-phase HPLC again, use UV detector analyzing total impurity level (mobile phase A: add the 1.0ml trifluoroacetic acid in 2000ml water; Mobile phase B: mix 1600ml acetonitrile and 400ml water and add the 1.0ml trifluoroacetic acid; Solvent: water/acetonitrile 70/30 (v/v); Immobile phase: Silica RP-18, Symmetry C18 for example, 3.5 μ m, 100 dusts-available from Waters; Gradient elution; Flow velocity: 1.5ml/min; Temperature: 20 ℃; UV-detects under 220nm).Quantitative limit is defined as＜0.1%.The total impurities scale of measuring according to this class mode shows the stability of different components.Fig. 1 shows the total impurities by the relative peak area of % of being expressed as of mensuration, determines by the difference of the summation (being expressed as 100%) of calculating all peak areas of measuring through HPLC and the peak area that Caspofungin is measured.Fig. 1 represents that all test formulation all demonstrate and is no more than 1.7% total impurities.Total impurities seems to be higher than 5 ℃ of storages (data not shown) down after 25 ℃ store down.

Astoundingly, the compositions 4 that does not contain extra pH regulator agent or acetate buffer seems to show similar and even higher stability, be that compositions 4 compares conventional composition after storage, comprise significantly less total impurities such as the compositions 1 that contains extra acetate buffer, as observed in Fig. 1.Even 25 ℃ down stored for 12 weeks after, compositions 4 still demonstrate be lower than conventional composition, such as the total impurities (data not shown) of compositions 1.

This result is unexpected, because instruction is with regard to regard to the conventional composition of compositions 1 in the documents of prior art, for example described in EP 0 904 098 B1, exists extra buffer agent necessary for obtaining stable composition.More particularly, mentioned among EP 0 904 098 B1 acetate buffer that has additional quantity be obtain to contain the more stable composition of less catabolite requisite-with contain another kind of buffer agent, promptly the preparation of tartrate buffer agent is compared.Therefore, compositions surprisingly of the present invention is not used in preparation such as compositions 4 to show under the situation of any buffer agent or pH regulator agent to be equal to good and even better stability.

Embodiment 7:

Compound I Determination on content (Caspofungin mensuration)

After lyophilizing, promptly when " 0 week ", or under 2 ℃ of-8 ℃ of temperature, promptly on average analyzing freeze-dried composition 1-5 at once after storing for 2,4,8 or 12 weeks down at 5 ℃.By adding 10.5ml ultra-pure water dissolved composition and subsequently according to reversed-phase HPLC again, use the UV detector, measure Caspofungin as described in example 6 above.Fig. 2 display card is moored fragrant net content, and the Caspofungin in % that promptly is expressed as relative peak area is measured, and determines by the difference of calculating all peak area sums (being expressed as 100%) of measuring through HPLC and the peak area % that infers total impurities mensuration.The Caspofungin content of measuring according to this class mode is represented the stability of different components.Therefore, Fig. 2 show compositions 2-4 in 2-8 ℃ of following storage process with conventional composition, compare such as compositions 1 and to have splendid stability.The compositions 4 that is substantially free of any extra pH regulator agent seems to demonstrate the highest Caspofungin content in maintaining test time limit process.Stability decreases is not observed in passing in time, does not promptly have Caspofungin content and obviously descends.Under 25 ℃, store and observed similar result, wherein compositions 4 shows the highest Caspofungin content in whole testing period process, but passing in time exist-Caspofungin of all test formulation-Yue 0.5%-about 1% is slightly reduced (data not shown).In addition, when storing down for 25 ℃, compositions table of the present invention reveals good stable, particularly is substantially free of the compositions of any extra pH regulator agent, such as compositions 4.As what discussed in embodiment 6, when prior art instruction when to have extra buffer agent be important for obtaining stable composition, this discovery is unexpected.

Embodiment 8:

The mensuration of residual water (water content KF)

After lyophilizing, or under 2 ℃ of-8 ℃ of temperature, promptly on average stored for 2,4,8 or 12 weeks down or analyze freeze-dried composition 1-5 at once after 1,2,4,8 or 12 weeks of storage down respectively at 25 ℃ at 5 ℃.By the colorimetric technology of K.Fischer, according to USP＜921〉method Ic and Ph.Eur.2.5.32 mensuration residual water.The residual water number of compositions 1-5 is at about 0.2%-about 2.3%.Storing back numerical value down at 25 ℃ trends towards higher.Generally speaking, the residual moisture content of inexpectancy specimen can play negative effect to the quality of compositions.

Embodiment 9:

The mensuration of nephelometric turbidity unit (NTU)

After lyophilizing, or under 2 ℃ of-8 ℃ of temperature, promptly on average stored for 2,4,8 or 12 weeks down or analyze freeze-dried composition 1-5 at once after 1,2,4,8 or 12 weeks of storage down respectively at 25 ℃ at 5 ℃.By adding 10.5ml ultra-pure water dissolved composition and subsequently according to Pharm.Eur. the 5th edition again, the methods analyst solution clarity of 2.2.1 chapter.The result provides according to wherein said nephelometric turbidity unit (NTU).NTU reflects visible particulate amount in the solvent soln again.All NTU value passing in time in the compositionss that 5 ℃ or 25 ℃ store down all are lower than 3.0, and the solvent soln again that this means compositions 1-5 is clarifying, and promptly these solution do not contain the visible granule of any vision.

Embodiment 10:

The pH value that dissolves lyophilizing solution is again measured

After lyophilizing, or under 2 ℃ of-8 ℃ of temperature, promptly on average stored for 2,4,8 or 12 weeks down or analyze freeze-dried composition 1-5 at once after 1,2,4,8 or 12 weeks of storage down respectively at 25 ℃ at 5 ℃.By adding 10.5ml ultra-pure water dissolved composition and use in concern pH scope calibrated standard laboratory pH-to score subsequently and analyse pH value again; Measure according to known potentiometry principle.The pH value of test formulation is all at 6.5-6.7 in 5 ℃ of following storage process, but the pH value of compositions 3 is 6.9-7.When storing down for 25 ℃, the pH value of test formulation the about 6.6-of 6.2-again except compositions 3, wherein pH value is at 6.9-about 7.2.The pH value that this means most of compositions of the present invention is all very nearly the same with those of conventional composition 1.

Embodiment 11:

Be lower than visible particulate mensuration

After lyophilizing, promptly when " 0 week ", or under 2 ℃ of-8 ℃ of temperature, promptly on average analyzing freeze-dried composition 1-5 at once after storing for 2,4,8 or 12 weeks down at 5 ℃.By add the 10.5ml ultra-pure water again dissolved composition and subsequent analysis be lower than visible granule, wherein according to USP 27,＜788〉" granule in the injection: photoresistance grain count test " measure amounts of particles.With regard to compositions 1-4, collect three bottles that are equivalent to the 31.5ml cumulative volume and be used for once measuring.With regard to compositions 5, according to USP 27,＜788〉" granule in the injection: photoresistance grain count test " and Pharm.Eur. the 5th edition, 10 bottles of method collection of 2.9.19 " photoresistance grain count test ".To be lower than visible granule in order measuring, whether to collect 3 or 10 bottles and be used for single mensuration and seem not crucial.Fig. 3 and 4 shows and to compare with compositions 1-5, each bottle has respectively＞10 μ m and＞25 μ m sizes be lower than visible particulate quantity.Fig. 3 and 4 clearly illustrates that the compositions 4 and all other compositionss that is substantially free of any extra pH regulator agent, comprise that conventional composition 1 compares, in storage process, show each bottle unexpectedly to have＞10 μ m and＞25 μ m sizes be lower than visible particulate quantity obviously lower-except 4 week the value measured of back, most probable reason is to measure due to the exceptional value of illusion.In addition,, compare with conventional composition 1 when when storing down for 12 weeks for 25 ℃, compositions 4 demonstrates obviously that each less bottle has＞10 μ m or＞25 μ m be lower than visible granule (data not shown).Even more surprisingly, compositions 4 is compared with the known combination thing that comprises known granule formation inhibitor EDTA and is also demonstrated the obviously less visible granule that is lower than.

Comprise additional quantity the pH regulator agent the

present composition compositions

2 and 3 result shows each other and the variability between storage process also, as what from Fig. 3 and 4, find out.Fig. 4 show compositions 2 have when comparing with 3 with conventional composition 1＞25 μ m size/bottles to be lower than visible granule less.Have＞the visible particulate quantity that is lower than of the size of 10 μ m/ bottles seems basically with observed those are very nearly the same to compositions 1.When storing down for 12 weeks for 25 ℃, compare with conventional composition 1,

compositions

2 and 3 demonstrates each less bottle to be had＞10 μ m or＞25 μ m be lower than visible granule (data not shown).

Embodiment 12:

The mensuration of catabolite CAF-42

After lyophilizing, promptly when " 0 week ", or under 2 ℃ of-8 ℃ of temperature, promptly on average analyzing freeze-dried composition 1-4 at once after storing for 12 weeks down at 5 ℃.By adding the 10.5ml ultra-pure water main Caspofungin catabolite that when from the Caspofungin molecule, coming off ethylenediamine, forms of dissolved composition and the CAF-42-that exists according to as described in example 6 above reversed-phase HPLC analysis subsequently again.By HPLC, by 1.98 o'clock peak integration of RRT (relative retention time), the chromatographic parameter of using is as described in example 6 above measured CAF-42.Quantitative limit is defined as＜0.1%.CAF-42 is expressed as relative peak area by %, determines with the ratio of the peak area summation at all peaks by the peak area that calculates when the RRT 1.98, wherein peak area＞=0.1%.Show amount in the following table 5 as the catabolite CAF-42 that measures in the storage process.

Table 5:

Table 5 shows that compositions 4 demonstrates especially significantly and is lower than conventional Caspofungin compositions, such as the main degradation products of the CAF-42-Caspofungin of compositions 1 formation-both all stored for 12 weeks down down and at 25 ℃ at 2-8 ℃.Storage 12 periderm U.S. Register authorities are considered as being suitable for testing submission and sell the mandatory condition of the medicine stability of the drug products of ratifying to obtain these class authorities under 25 ℃.Therefore, do not contain any extra pH regulator agent, such as the compositions 4 of for example acetic acid with conventional composition such as compositions 1, for example described in EP 0 904 098 B1-in storage process, also keep preferably stability-to form and show stability preferably aspect less at catabolite CAF-42.As what discussed among the embodiment 6, this discovery is unexpected with regard to EP 0 904 098 B1, and instruction exists that extra acetate buffer is more stable by acquisition, to generate the caspofungin formulations of less unwanted catabolite simultaneously requisite in the document.

Embodiment 13:

The mensuration of impurity CAF-dimer 1

After lyophilizing, promptly when " 0 week ", or under 2 ℃ of-8 ℃ of temperature, promptly on average analyzing freeze-dried composition 1-4 at once after storing for 12 weeks down at 5 ℃.By adding 10.5ml ultra-pure water dissolved composition and the impurity CAF-dimer 1-that exists according to as described in example 6 above the reversed-phase HPLC analysis subsequently amount that can in storage process, in the Caspofungin compositions, form again.Measure CAF-dimer 1 by the chromatographic parameter that RRT (relative retention time) 2.41 uses as described in example 6 above.Quantitative limit is defined as＜0.1%.CAF-dimer 1 is expressed as relative peak area by %, determines with the ratio of the peak area summation at all peaks by the peak area that calculates when the RRT 2.41, wherein peak area＞=0.1%.Following table 6 is presented at the amount of the impurity CAF-dimer of measuring in the storage process 1.

Table 6:

Table 6 shows that compositions 4 demonstrates significantly and is lower than conventional Caspofungin compositions, such as the impurity CAF-dimer 2 of compositions 1 form-both all at 2-8 ℃ down and when storing for 12 weeks down for 25 ℃.Therefore, do not contain any extra pH regulator agent, such as the compositions 4 of for example acetic acid with the conventional caspofungin formulations that comprises extra acetate buffer, in storage process, also kept higher degree-when comparing-such as compositions 1-and formed and show higher purity aspect less at impurity CAF-dimer 1.

Embodiment 14:

Comprise Caspofungin and do not contain the preparation of the compositions 6 of any extra pH regulator agent:

Table 7:

By prepare the liquid preparation of compositions 6 with the batch size of 200ml dissolving mannitol and sucrose according to embodiment 4.Add 42mg/ml Caspofungin alkali subsequently, i.e. 46.6mg/ml oxalic acid Caspofungin, and re-adjustment pH value not.Water is adjusted volume, and promptly reaching final volume is 200ml, and obtaining pH value thus is 5.96, filters this solution similar to Example 1ly, is filled into bottle and lyophilizing bottle.Opposite with embodiment 1, the 1.75ml filled with solution is gone into bottle.Dissolve and/or dilute the final concentration that freeze-dried composition 6 obtains the 7.0mg/ml of Caspofungin according to embodiment 1 similar mode again by adding the 10.5ml ultra-pure water.

Embodiment 15:

Comprise Caspofungin and contain a kind of extra pH regulator agent the preparation of the compositions 7 that is acetic acid:

Table 8:

Component	Compositions 7
Component	Compositions 7	Mannitol	20mg/ml
Sucrose	30mg/ml	Mannitol	20mg/ml
Sucrose	30mg/ml	Acetic acid	In right amount
The oxalic acid Caspofungin	46.6mg/ml	Acetic acid	In right amount
The oxalic acid Caspofungin	46.6mg/ml	pH	5.0

Has the liquid preparation that 40ml criticizes the compositions 7 of size according to embodiment 1 by dissolving mannitol and sucrose preparation.Add 46.6mg/ml oxalic acid Caspofungin subsequently, be equivalent to 42mg/ml Caspofungin alkali, pH value is determined as 5.68, and uses 1.25N acetic acid to be adjusted to pH 5.0.With regard to compositions 7, add 0.82mg/ml acetic acid (final volume based on liquid preparation calculates), being equivalent to the final molar concentration of the extra acetic acid of 13.75mmol/l or the mol ratio of extra acetic acid and Caspofungin is 0.179.After water was adjusted volume, promptly reaching final volume was 40ml, obtained 5.00 pH value.Filter this solution similar to Example 1ly, be filled into bottle and lyophilized products.Ground similar to Example 1 dissolves and/or dilutes freeze-dried composition 7 again.

Obtain following analysis result by those methods described in

embodiment

8,9,10,11 and 12 respectively, wherein directly measuring residual water after the lyophilizing and after dissolving lyophilized products again, directly measuring NTU, pH, be lower than visible granule and CAF-42:

Residual water (KF): 0.6%

NTU：0.1

pH：5.6

Be lower than visible granule＞10 μ m:143/ bottles

Be lower than visible granule＞25 μ m:12/ bottles

CAF-42 is 0.15% after measured; Do not detect extra catabolite 〉=0.1%.

Embodiment 16:

Comprise Caspofungin and do not contain any extra pH regulator agent, the i.e. preparation of the compositions 8 of acetic acid/sodium hydroxide:

Table 9:

Component	Compositions	8
Component	Compositions	8	Mannitol	20mg/ml
Sucrose	30mg/ml		Mannitol	20mg/ml
Sucrose	30mg/ml	Sodium hydroxide/acetic acid	In right amount
The oxalic acid Caspofungin	46.6mg/ml	Sodium hydroxide/acetic acid	In right amount
The oxalic acid Caspofungin	46.6mg/ml	pH	7.0

Has the liquid preparation that 40ml criticizes the compositions 8 of size according to embodiment 1 by dissolving mannitol and sucrose preparation.Add 46.6mg/ml oxalic acid Caspofungin subsequently, be equivalent to 42mg/ml Caspofungin alkali.PH value is determined as 5.68, and uses sodium hydroxide/acetic acid to be adjusted to pH7.0.After water was adjusted volume, promptly reaching final volume was 40ml, obtained 6.84 pH value.Filter this solution similar to Example 1ly, be filled into bottle and lyophilized products.Ground similar to Example 1 dissolves and/or dilutes freeze-dried composition 8 again.

Obtain following analysis result by those methods described in

embodiment

Residual water (KF): 0.67%

NTU：0.2

pH：6.7

Be lower than visible granule＞10 μ m:338/ bottles

Be lower than visible granule＞25 μ m:19/ bottles

CAF-42 is 0.26% after measured; Do not detect extra catabolite 〉=0.1%.

Embodiment 17:

Prepare the dipropionic acid Caspofungin by preparation HPLC

Oxalic acid Caspofungin (3.5g) is dissolved in methanol (50ml) and water (250ml) and, uses anti-phase C-8 post and carry out purification as C-8 adsorbent available from YMC Europe GmbH by preparation HPLC.Use comprises 22 acetonitriles/78 water (v/v) the mixture eluted product of about 0.25% propanoic acid, and wherein % is weight percentage.Collection is rich in fraction and lyophilizing to obtaining Caspofungin propanoic acid adduct (3.7g), is amorphous white solid.

Under 25 ℃, lyophilized products (3.7g) is dissolved in ethanol (33.3ml) and water (3.7ml).By removing by filter undissolved material.(224 μ l) joins in the filtrate with propanoic acid.In 30 minutes, add ethyl acetate (44.4ml) subsequently, and this mixture is stirred to crystallization takes place under 25 ℃, and about 1 hour of restir subsequently.Added part ethyl acetate (29.6ml) at 4 hours in the process again and the crystallization suspension was placed 1 hour.Filter out crystalline solid and wash with ethanol/water/ethyl acetate (18ml/2.2ml/40ml) mixture.At ambient temperature with vacuum in dry wet cake and obtain the dipropionic acid Caspofungin crystallization of 2.5g.

Measure Caspofungin: 82.6% (HPLC calculates with free alkali)

Water content: 5.5% (according to the method for Karl Fischer, coulometer thermostat/110 ℃)

Propanoic acid: 10.5% (HPLC)

The XRPD that obtains product schemes as shown in Figure 5. ¹The H-NMR data and ¹³The C-NMR data are as shown in table 10.

Method:

According to known method, by using following condition Caspofungin is carried out HPLC mensuration: post: YMC-Pack ODS-AQ, S-3 μ m, 12nm, 150 * 4.6mm, flow velocity: 1.6ml, column temperature: 25 ℃, wavelength: 210nm,

Eluent A:40mM sulfamic acid

The sulfamic acid of eluent B:40mM in water/acetonitrile/methanol=250/550/30 (w/w/w)

Gradient:

Time [min]	0	13	35
Time [min]	0	13	35	％B	40	46	96

The HPLC of propanoic acid measures: post: Aquasil C 18,5 μ m,

(angstrom's unit), 250 * 4.6mm, flow velocity: 1.0ml/min, column temperature: 40 ℃, wavelength: 220nm

Eluent A:10mM sulfamic acid

Eluent B: acetonitrile

Gradient:

Time [min]	0	10	15	18	21
Time [min]	0	10	15	18	21	％B	0	0	70	70	0

Ethanol: 2.46% gas chromatography, post DB-WAX, 30m x 0,53mm ID, 1.0 μ m layers, flow velocity: 2.5ml He/min, 250 ℃ of detector: FID, injector: 200 ℃, space sampler on the liquid.

Temperature program(me):

Time [min]	0	6	21	23
Time [min]	0	6	21	23	Temperature [℃]	60	60	160	220

Under following condition, measure X-ray powder diffraction (XRPD) figure: equipment: X-ray powder diffraction instrument D-8 (AXS-BRUKER), θ-θ-goniometer, sample changer, target: copper, K α 1+K α 2 wavelength: 0.15406nm, parallel beam optics (accept Suo Le-slit: 0.07mm), energy-disperse enumerator, standard sample bin.Data collection: 40kV, 40mA, continuous sweep 2-40 degree θ/2 θ, step-length: 0.01, gate time 2 seconds; Environmental condition (20 ℃ ± 5 ℃ and 30%-60% humidity).

Embodiment 18:

The dipropionic acid Caspofungin is by the preparation of Caspofungin alkali

With oxalic acid Caspofungin (5.0g) water-soluble (400ml).Be adjusted to 9.0 by slow interpolation 1N NaOH with the pH value of this solution is careful.The gained suspension was stirred 30 minutes, filter then.Water thorough washing filter cake.The product that will wet is dissolved in the ethanol (36.0ml) that contains propanoic acid (616 μ l).(0.5g) handles this solution and filtration with active carbon.In 30 minutes, in filtrate, add ethyl acetate (60ml), plant crystalline substance subsequently and descend stirring 1 hour at 25 ℃.Added part ethyl acetate (40ml) at 4 hours in the process again and the crystallization suspension was placed 1 hour.Filter out solid and at ambient temperature with vacuum in dry, obtain the crystallization of 3.4g dipropionic acid Caspofungin.

Embodiment 19:

Prepare the dipropionic acid Caspofungin by preparation HPLC

Chemical compound according to the embodiment 7 of the International Application No. WO 2007/057141A1 that is incorporated herein by reference and embodiment 9 preparations formula III a as described herein.The chemical compound of formula III a is equivalent to the chemical compound of WO2007/057141A1 Chinese style VIa.The chemical compound of 1g formula III a is dissolved in the mixture of 2-propanol (24ml) and water (4ml).Add propanoic acid (4,4ml) and 25% ammonia (2.2g), obtain having the solution of about 6.5 pH value.Adding 5%Rh/Al ₂O ₃(100mg), with this mixture 30 ℃ down and in the hydrogen environment with atmospheric pressure under vigorous stirring to the raw material that keeps below 0.5%.Filter out catalyst and filtrate is stirred with active carbon (100mg).Filter suspension and evaporated filtrate.Residue is dissolved in methanol (12.5ml) and water (62.5ml) and by preparation HPLC, uses the anti-phase C-8 column purification available from YMC Europe GmbH.With 22 acetonitriles that comprise about 0.25% propanoic acid/78 water (v/v) mixture eluted product, wherein % is weight percentage.Collection is rich in fraction and lyophilizing to obtaining Caspofungin propanoic acid adduct (0.8g), is amorphous white solid.

Make lyophilized products crystallization, separation and drying as described in example 17 above and obtain the crystallization of 0.55g dipropionic acid Caspofungin.

Embodiment 20:

The preparation of drug combination that comprises the dipropionic acid Caspofungin

Prepare fluid composition through the following steps: mannitol and sucrose is the water-soluble and solution that obtains having 40mg/ml and 60mg/ml concentration respectively, the mixture that 5ml is obtained joins in the glass beaker, and adding the 154.2mg/ml propanoic acid of 120 μ l and obtaining pH is 3.21 and by adding 10 μ l 1N NaOH with pH regulator to 3.64.Add the 533.3mg dipropionic acid Caspofungin crystallization (being determined as 78.6%) of preparation as described in example 17 above and obtain final concentration, be equivalent to the Caspofungin that 42mg/ml calculates with alkali.Behind dissolving dipropionic acid Caspofungin, obtaining pH is 5.08, is adjusted to 6.0 by adding 60 μ l 1N NaOH.Change this solution over to the 10ml volumetric flask and priming petock to final volume is 10ml; The density that final solution has at ambient temperature is 1.02396g/ml, by volumetric flask being carried out the gravimetric analysis mensuration of weighing.476 these solution of μ l are changed over to available from ISOGmbH, Bad Konigshofen, Germany has an Eppendorf Multipette ^TMThe 6R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use D as Christ Epsilon 2-6 ^TMThe freeze dryer that freeze dryer is purchased carries out lyophilization.In brief, followingly carry out lyophilization: vial is stored 60 minutes down at 5 ℃.Make temperature in 50 minutes, reduce to-45 ℃ from+5 ℃.Temperature is remained on-45 ℃ following 150 minutes and begin preliminarily dried by applying the 0.04mbar vacuum.Make temperature in 5 minutes, rise to-40 ℃.Carried out preliminarily dried by maintaining the temperature at-40 ℃ and vacuum in 960 minutes at 0.04mbar.Dry in order to carry out the second time, make vacuum drop to 0.011mbar.Make temperature with the speed straight line of 1K/min rise to+15 ℃.It is dry to carry out the second time under+15 ℃, under the 0.011mbar vacuum and in 3 hours.

Each lyophilizing bottle comprises 22.7mg dipropionic acid Caspofungin, is equivalent to 20mg Caspofungin alkali, 9.5mg mannitol, 14.3mg sucrose and 0.88mg propanoic acid.Dissolve again by adding the 4.0ml ultra-pure water, obtain having 5.0mg/ml Caspofungin final concentration and show high-purity, the solvent soln again of the total impurities of promptly about 1.30% amount (as measuring) by HPLC as described below.Ultra-pure water is available from the ultra-pure water purification system, for example has the water of the Millipore GradientA10 of UV-lamp and ultrafiltration.Ultra-pure water has the characteristic very nearly the same with the water for injection of USP and Ph.Eur..The pH of solvent soln is 6.4 again.Be lower than visible granule＞10 μ m:390/bottle; Be lower than visible granule＞25 μ m:18/bottle (according to USP 27,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; Dissolve 3 bottles separately again with 4ml water, change the solution that obtains over to Falcon ^TMPipe and injection do not contain particulate water to about 30ml).

The HPLC method of total impurities is measured:

According to rp-hplc method, use UV detector (mobile phase A: the 0.61g sulfamic acid is dissolved in 767.5g water and 182.8g acetonitrile; Mobile phase B: the 0.15g sulfamic acid is dissolved in 250g water and 589.5g acetonitrile); Solvent: sulfamic acid/water/acetonitrile 0.61g/930ml/70ml; Post, 150 * 4.6mmID; Immobile phase: Silica RP-18, Symmetry C18 for example, 3.5 μ m,

(angstrom's unit)-available from Waters Corporation, Massachusetts, USA; Gradient elution; Flow velocity: 1.5ml/min; Temperature: 25 ℃; UV-detects under 210nm.Quantitative limit is defined as＜0.1%.Use Caspofungin reference solution evaluation all peaks in the test solution that relates to the Caspofungin related substances.

Embodiment 21:

Prepare fluid composition through the following steps: mannitol and sucrose is the water-soluble and solution that obtains having 40mg/ml and 60mg/ml concentration respectively, the mixture that 5ml is obtained joins in the glass beaker and adds the 533.5mg dipropionic acid Caspofungin crystallization (being determined as 78.6%) of preparation as described in example 17 above and obtain final concentration, is equivalent to the Caspofungin that 42mg/ml calculates with alkali.The dipropionic acid Caspofungin dissolved in about 3 minutes, obtained 6.99 pH value.By adding 25 μ l 1.25N propanoic acid solution pH value is adjusted to 6.0.Give the solution priming petock that obtains to 10ml.Change 476 these solution of μ l over to GmbH available from ISO, Bad Konigshofen, Germany has an Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Each cryovial comprises 22.7mg dipropionic acid Caspofungin, is equivalent to 20mg Caspofungin alkali, 9.5mg mannitol, 14.3mg sucrose and 0.1102mg propanoic acid.Dissolve by adding the 4.0ml ultra-pure water, generation has 5.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC as described in example 20 above) of promptly about 0.65% amount again.The pH of solvent soln is 6.2 again.Be lower than visible granule＞10 μ m:226/bottle; Be lower than visible granule＞25 μ m:5/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above).

The XRPD figure of lyophilized products as shown in Figure 6; Measure XRPD figure as described in example 17 above.

Embodiment 22:

Prepare fluid composition through the following steps: mannitol and sucrose is the water-soluble and solution that obtains having 40mg/ml and 60mg/ml concentration respectively, the mixture that 5ml is obtained joins in the glass beaker and adds the 533.5mg dipropionic acid Caspofungin crystallization (being determined as 78.6%) of preparation as described in example 17 above and obtain final concentration, is equivalent to the Caspofungin that 42mg/ml calculates with alkali.The dipropionic acid Caspofungin dissolved in about 3 minutes, obtained 6.99 pH value.Add entry to final volume 10ml for the solution that obtains.476 these solution of μ l are changed over to have Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Each bottle comprises 22.7mg dipropionic acid Caspofungin, is equivalent to 20mg Caspofungin alkali, 9.5mg mannitol, 14.3mg sucrose.Dissolve by adding the 4.0ml ultra-pure water, generation has 5.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 0.95% amount again.The pH of solvent soln is 6.3 again.Be lower than visible granule＞10 μ m:315/bottle; Be lower than visible granule＞25 μ m:8/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above).

Embodiment 23:

With preparing and add entry to final volume as described in example 20 above is that the 1.25ml solution of 10ml changes over to and has Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Adjust process time to guarantee to finish preliminary and drying steps for the second time, promptly prolong procedure of processing to product temperature and reach storage temperature.Each lyophilizing bottle comprises 59.6mg dipropionic acid Caspofungin, is equivalent to 52.5mg Caspofungin alkali, 25mg mannitol and 37.5mg sucrose and 2.31mg propanoic acid.Dissolve by adding the 10.5ml ultra-pure water, generation has 5.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 1.1% amount again.The pH of solvent soln is 6.4 again.Be lower than visible granule＞10 μ m:512/bottle; Be lower than visible granule＞25 μ m:16/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above); Use 10.5ml water to dissolve 3 bottles separately again, change the solution that obtains over to Falcon ^TMPipe).

Embodiment 24:

With preparing and add entry to final volume as described in example 20 above is that the 1.75ml solution of 10ml changes over to and has Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Adjust process time to guarantee to finish preliminary and drying steps for the second time, promptly prolong procedure of processing to product temperature and reach storage temperature.Each lyophilizing bottle comprises 83.5mg dipropionic acid Caspofungin, is equivalent to 73.5mg Caspofungin alkali, 35mg mannitol and 52.5mg sucrose and 3.24mg propanoic acid.Dissolve by adding the 10.5ml ultra-pure water, generation has 7.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 1.0% amount again.The pH of solvent soln is 6.5 again.Be lower than visible granule＞10 μ m:485/bottle; Be lower than visible granule＞25 μ m:12/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " measure and determine to be lower than visible granule; As described in example 20 above; Use 10.5ml water to dissolve 3 bottles separately again, change the solution that obtains over to Falcon ^TMPipe).

Embodiment 25:

With preparing and add entry to final volume as described in example 21 above is that the 1.25ml solution of 10ml changes over to and has Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Adjust process time to guarantee to finish preliminary and drying steps for the second time, promptly prolong procedure of processing to product temperature and reach storage temperature.Each lyophilizing bottle comprises 59.6mg dipropionic acid Caspofungin, is equivalent to 52.5mg Caspofungin alkali, 25mg mannitol and 37.5mg sucrose and 0.29mg propanoic acid.Dissolve by adding the 10.5ml ultra-pure water, generation has 5.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 1.1% amount again.The pH of solvent soln is 6.4 again.Be lower than visible granule＞10 μ m:512/bottle; Be lower than visible granule＞25 μ m:16/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above; Use 10.5ml water to dissolve 3 bottles separately again, change the solution that obtains over to Falcon ^TMPipe).

Embodiment 26:

With preparing and add entry to final volume as described in example 21 above is that the 1.75ml solution of 10ml changes over to and has Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and the method for using are as described in example 20 above carried out lyophilization.Adjust process time to guarantee to finish preliminary and drying steps for the second time, promptly prolong procedure of processing to product temperature and reach storage temperature.Each lyophilizing bottle comprises 83.5mg dipropionic acid Caspofungin, is equivalent to 73.5mg Caspofungin alkali, 35mg mannitol and 52.5mg sucrose and 0.40mg propanoic acid.Dissolve by adding the 10.5ml ultra-pure water, generation has 7.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 1.2% amount again.The pH of solvent soln is 6.4 again.Be lower than visible granule＞10 μ m:615/bottle; Be lower than visible granule＞25 μ m:21/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above; Use 10.5ml water to dissolve 3 bottles separately again, change the solution that obtains over to Falcon ^TMPipe).

Embodiment 27:

With preparing and add entry to final volume as described in example 22 above is that the 1.25ml solution of 10ml changes over to and has Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Adjust process time to guarantee to finish preliminary and drying steps for the second time, promptly prolong procedure of processing to product temperature and reach storage temperature.Each lyophilizing bottle comprises 59.6mg dipropionic acid Caspofungin, is equivalent to 52.5mg Caspofungin alkali, 25mg mannitol and 37.5mg sucrose.Dissolve by adding the 10.5ml ultra-pure water, generation has 5.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 1.3% amount again.The pH of solvent soln is 6.5 again.Be lower than visible granule＞10 μ m:395/bottle; Be lower than visible granule＞25 μ m:13/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above; Use 10.5ml water to dissolve 3 bottles separately again, change the solution that obtains over to Falcon ^TMPipe).

Embodiment 28:

With preparing and add entry to final volume as described in example 22 above is that the 1.75ml solution of 10ml changes over to and has Eppendorf Multipette ^TMThe 10R vial.Bottle part jam-pack and lyophilizing are extremely formed cake in the bottle bottom, wherein use 2-6D as Christ Epsilon ^TMFreeze dryer that freeze dryer is purchased and use method are as described in example 20 above carried out lyophilization.Adjust process time to guarantee to finish preliminary and drying steps for the second time, promptly prolong procedure of processing to product temperature and reach storage temperature.Each lyophilizing bottle comprises 83.5mg dipropionic acid Caspofungin, is equivalent to 73.5mg Caspofungin alkali, 35mg mannitol and 52.5mg sucrose.Dissolve by adding the 10.5ml ultra-pure water, generation has 7.0mg/ml Caspofungin final concentration and shows high-purity, the solvent soln again of the total impurities (HPLC method as described in example 20 above) of promptly about 0.9% amount again.The pH of solvent soln is 6.4 again.Be lower than visible granule＞10 μ m:587/bottle; Be lower than visible granule＞25 μ m:23/bottle (according to USP 29,＜788〉in " granule in the injection: photoresistance grain count test " determine to be lower than visible granule; As described in example 20 above; Use 10.5ml water to dissolve 3 bottles separately again, change the solution that obtains over to Falcon ^TMPipe).

Claims

1.) pharmaceutical composition, it comprises

A) pharmaceutically acceptable salt of Caspofungin;

B) extra pH regulator agent, its consumption is lower than the described Caspofungin salt of 0.3 molar equivalent; With

2.) the pharmaceutical composition of claim 1, the pharmaceutically acceptable salt of wherein said Caspofungin is and the organic acid acid-addition salts that described organic acid is selected from acetic acid, citric acid, tartaric acid, propanoic acid, succinic acid, oxalic acid, malic acid, maleic acid, lactic acid, glutamic acid or pounces on acid.

3.) claim 1 or 2 pharmaceutical composition, the pharmaceutically acceptable salt of wherein said Caspofungin is the oxalic acid Caspofungin.

4.) any described a pharmaceutical composition among the claim 1-3, wherein the mol ratio of Caspofungin salt and extra pH regulator agent is greater than 4: 1, particularly greater than 10: 1.

5.) any pharmaceutical composition among the claim 1-4, wherein extra pH regulator agent is an acetic acid.

6.) the pharmaceutical composition of any aforesaid right requirement, wherein said filler is made up of one or more filleies.

7.) the compositions of claim 7, wherein said filler are mannitol, sucrose or its combination.

8.) the pharmaceutical composition of any aforesaid right requirement, it comprises:

A) the about 500mg/ml of about 0.1mg/ml-that calculates with Caspofungin alkali, the Caspofungin of the about 60mg/ml of preferably about 20mg/ml-,

B) but the pH regulator agent of pharmacy receiving amount, preferred acetic acid, it can effectively provide about 5-about 7, the pH value of preferably about 5.5-about 6.5,

C) the about 200mg/ml of about 10mg/ml-, the about 60mg/ml's of preferably about 40mg/ml-is the excipient of filler, preferably fills the mixture of saccharide, it can effectively form lyophilized cake and water.

9.) the pharmaceutical composition of claim 8, it comprises:

A) with about 42mg/ml Caspofungin of Caspofungin alkali calculating, be equivalent to the oxalic acid Caspofungin of 46.6mg,

B) but the pH regulator agent of pharmacy receiving amount, preferred acetic acid, it can effectively provide about 6.0 pH value,

C) filler of about 50mg/ml, it is the mixture of about 20mg/ml mannitol with about 30mg/ml sucrose, and water.

10.) the pharmaceutical composition of any aforesaid right requirement, wherein said compositions is substantially free of any extra pH regulator agent.

11.) any pharmaceutical composition that requires of aforesaid right, it is about 7 to have about 5-, and preferably about 5.5-is about 6.5, more preferably from about 6.0 pH value.

12.) can require described pharmaceutical composition to obtain and be suitable for being dissolved into again the lyophilized powder that is used for the fluid composition that parenteral, preferred intravenous use by any aforesaid right of lyophilizing.

13.) can dissolve the pharmaceutical composition that the described lyophilized powder of claim 12 obtains again by using following liquid: aqueous solution, preferred distilled water and/or sterile water for injection, the optional bacteriostatic water that comprises methyl parahydroxybenzoate and/or propyl p-hydroxybenzoate and/or 0.9% benzylalcohol, or normal saline, 0.9% sodium chloride solution for example, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution and/or woods lattice lactic acid solution.

14.) pharmaceutical composition of claim 13, it is about 8 to have about 5-, the pH value of preferably about 6.0-about 7.5.

15.) any pharmaceutical composition that requires of aforesaid right, it is a stable formulation.

16.) according to the pharmaceutical preparation of item arbitrarily among the claim 13-15, it demonstrates the quantity that is lower than visible particle and reduces.

17.) pharmaceutical composition of claim 16, have and be less than 500, preferably be less than 300 and be lower than visible granule/bottle, these granules have the size greater than 10 μ m, these particulate quantity are according to USP 27,＜788〉" granule of injection " determine by photoresistance grain count test.

18.) arbitrarily aforesaid right require described compositions to be used to prevent and/or treat mammal in preparation, the purposes in the medicine that preferred philtrum is used by candida mycoderma species (Candida sp.) and/or aspergillus species (Aspergillus sp.) and/or Jie Shi lung sac worm (Pneumocystis jiroveci) fungal infection that causes or the medicine of disease, preferred intravenous.

19.) preparation comprises the method for pharmaceutical composition of the pharmaceutically acceptable salt of Caspofungin, this method comprises the following steps:

It is 1) compositions of filler or filler is water-soluble,

3) add extra pH regulator agent with the consumption that is lower than the described Caspofungin salt of 0.3 molar equivalent,

4) filtration step 3) the middle solution that obtains,

5) solution that obtains in the freezing step 4) and

6) the refrigerated solution of lyophilizing.

20.) method of claim 19, it does not comprise step 3).

21.) compositions that can obtain by claim 19 or 20 method.