Containing epothilone composition

 

Described containing epothilone pharmaceutical composition in the form of a concentrate for infusion. The compositions contain in addition to epothilone pharmaceutically acceptable organic solvent. As the organic solvent used alcohol or N-alkylpyridine. In a preferred embodiment, the pharmaceutical composition epothilones does not contain a surface-active substance is hydrophilic-lipophilic balance (products HLB) which is 10 or more. Song epothilones are intended for parenteral, e.g. intravenous, administration. New pharmaceutical compositions are characterized by improved solubility epothilone, long-term storage at low temperatures and absence of allergic reactions in patients taking the drug. 4 C. and 6 C.p. f-crystals, 4 PL.

The present invention relates to containing epothilone pharmaceutical compositions, in particular to pharmaceutical compositions intended for parenteral, e.g. intravenous, administration.

Epothilone represent a class of stabilizing microtubules cytotoxic agents (see Gerth, K., and others, J. Antibiot. 49, 560-563 (1966), or Hoefle and others , DE Ilon, where R denotes a methyl group.

They are 16-membered macrolides containing seven chiral centers, and can be characterized by the presence of a variety of functionally active groups. For example, they may include other ring systems, such as epoxy and/or thiazole ring. They may include two free, capable of forming derivatives of hydroxyl group, and the macrolide may contain an ester link. Epothilone and their synthesis are described, for example, in applications WO 93/10121 and DE 4138042 A2, the contents of which are incorporated into this description by reference. Typical derivatives epothilone and their synthesis are described in applications WO 97/19086 and WO 98/25929, the contents of which are incorporated into this description by reference. At the mention epothilones preferably refers epothilone or epothilone In or their salts and derivatives or their respective mixtures. Epothilone And or can be used separately, or they can be used as mixtures epothilones a and b, but preferably they are used either in the form of only epothilone And or only epothilone, more preferably in the form of only epothilone Century

It is well known that citibankonline inhibition of cell proliferation and subsequent induction of apoptosis and cell death. Most cytotoxic agents appear to act by affecting the synthesis of DNA and/or RNA. However, the activity of certain cytotoxic agents, such as representatives of the family taxane, such as paclitaxel and epothilone is related to their interaction with the dynamics of microrobot. Microtubules are an important and promising target for new anti-cancer compositions.

However, we know only a small number of publications relating to compositions that can be included epothilone. In the claimed invention, it was found that 16-membered macrolide system are particularly susceptible to decomposition. Moreover, the poor solubility of these compounds makes it difficult to fabricate the pharmaceutical compositions for parenteral administration. Poorly soluble compounds, as a rule, can be dissolved by heating the solvent in the process of dissolution. However, these compounds due to their high reactivity can decompose at elevated temperatures. In addition, these highly reactive compounds may decompose when stored in aqueous solution for extended LINE">described concentrated solutions that can be diluted in water before intravenous injection. However, such solutions typically used surfactant, such as Cremophor(polyethoxysiloxane castor oil). It is well known that surfactants such as Cremophormay cause allergic reactions in patients.

Thus, there is a need to create suitable-for-sale pharmaceutical compositions that include epothilone, such as pharmaceutical compositions which can be stored, for example, in the refrigerator, for example, at 2-8oC.

When creating inventions developed new approaches to improve the solubility epothilone, for example epothilone or epothilone In, and/or give them a more rapid solubility, which do not involve the use of surface-active substances such as surfactants, products HLB value (hydrophilic-lipophilic balance) which is 10 or more, for example Cremophorand who do not have the OTE is a pharmaceutical composition, including epothilone, for example epothilone or epothilone In that later in the description designated as the composition of the present invention.

Preferred pharmaceutical composition in the form of a concentrate for infusion, which includes epothilone and pharmaceutically acceptable organic solvent, for example a composition in which no surfactant, the products HLB value of which is 10 or more, for example Cremophor. In concentrate for infusion does not require the use of surfactants to enhance the solubility epothilone, for example epothilone or epothilone In, and/or to give them a more rapid solubility. As described above, surface-active substances, such as polyhydroxyalkane natural or hydrogenated castor oil, products HLB value which is more than 10, for example Cremophorcan cause allergic reactions and they may leaching plasticizers of the standard containers, test tubes, etc. from polyvinyl chloride (PVC). Thus, in cases where they are applied, may require special devices for infusion, nab the Irka, etc.

The above-mentioned pharmaceutically acceptable organic solvent may be selected from any such organic solvents, the use of which is known in this field. Such a solvent may be used individually or in combination with other solvents. Preferably the solvent is a liquid at room temperature. Preferably the solvent is selected from the group including (I) the alcohol with a long hydrocarbon chain of at least 2, for example With2-C5in particular2or3or4or (II) N-alkylpyridine, for example With1-C4pyrrolidone, in particular N-organic. Typical examples of alcohols include, in particular, miscible with water, alcohols, such as absolute ethanol or glycerol. Other alcohols include glycols such as any of the glycol, which can be obtained from an oxide, such as ethylene oxide, for example propylene glycol. Other examples include polyols, such as polyalkyleneglycol, in particular poly(C2-C3)allenglish. A typical example is a polyethylene glycol, for example with a molecular weight of preferably 200-600 Yes, more preferably 200-400 Yes, most preferably 300 Yes. In the Noi or more of the following characteristics: (I) the content of ethylene oxide to a maximum of 20 hours/million usually less than 1 h/mn, for example 0.1 to 0.5 hours/million, (II) the pH value in the range of 4 to 7, and (III) the absence of reducing agents and aldehydes (which is determined by evaluating the intensity of staining of the investigated liquid in comparison with a control solution containing salts of iron chloride (solution a yellow color) or salts chlorides of cobalt (solutions red) according to the experimental methods described in the European Pharmacopoeia, 3rd ed., 1997, Council of Europe, Strasbourg, Chapter 2.2.2. Degree of coloration of liquids, pages 15-17 (publication included in the present description by reference). For specialists in the art it is obvious that the glycols with different molecular weights can be applied only when they are physiologically acceptable. The above solvents can, obviously, contain residual amounts of water, obtained by cooking or absorbed from the atmosphere, for example to saturating concentrations, for example up to 2%, in particular up to 0.5%, usually less than 0.1%, for example from 0.01 to 0.05%. If necessary, pharmaceutically acceptable solvent miscible with water (added water), for example, it can include up to 45% water, for example up to 30%, for example 20%, in particular 5%. Typical examples include a mixture of e is La.

Epothilone, for example epothilone or epothilone, may be present in the concentrate for infusion at a concentration of 0.1-100 mg/ml, for example, 1-100 mg/ml, more preferably 0.5 to 50 mg/ml, most preferably 0.5 to 10 mg/ml, even more preferably 1 mg/ml

Aptilon, for example epothilone or epothilone, can be used individually or as mixtures epothilones, for example a mixture epothilone and epothilone Century in greater antitumor activity epothilone In it can be used in the composition in a lower concentration than epothilone A. When used individually epothilone And is preferably used in a concentration of 0.1-100 mg/ml, for example, 10-100 mg/ml, preferably 0.1 to 50 mg/ml, for example 20-50 mg/ml, especially preferably 1 mg/ml When used individually epothilone In is preferably used in a concentration of 0.1-50 mg/ml, for example 10-50 mg/ml, in particular 1-50 mg/ml, particularly preferably 1 mg/ml

The pharmaceutical composition of the present invention in the form of a concentrate for infusion may be obtained by using this process, as, for example, dissolution epothilone in a pharmaceutically acceptable solvent according to the invention, optionally with other excipients. Preferably defaults to less than 5%, for example, less than 2%, in particular from 0.1 to 1.5%.

Concentrate for infusion according to the present invention is usually stored in appropriate containers, such as vials, dual chamber vials or ampoules. Typically, bubbles or ampoules made of glass, such as borosilicate glass or soda-lime glass. The vials or ampoules can be of any amount, which is usually used in this field, preferably they are of a size sufficient for completion of 1-5 ml, more preferably 2 ml of concentrate for infusion. The vessel preferably can be provided with a stopper, for example a sterile rubber stopper with a hole, which can ensure tight closing of the container and which allows to transfer the liquid from the vessel or into it.

Concentrate for infusion according to the present invention can maintain stability for a long period of time, for example up to 12-36, in particular in a period of 24 months at a temperature of at least 2-8oWith that confirmed using standard tests to assess the stability, in particular, by the method described in the examples.

In addition, the concentrate for infusion have low evaporation rate, and they can bopasno equipment, and they can be compatible with the rubber plugs in the storage tanks, i.e. do not cause decomposition of the tubes.

Concentrate for infusion before the introduction epothilone the patient parenterally, for example intravenously, can be diluted pharmaceutically acceptable solvent, for example an aqueous medium, which is used for intravenous infusion solution for infusion. Obviously, parenteral administration includes an introduction by infusion or injection.

Thus, another object of the invention is a solution for infusion, containing a mixture of concentrate for infusion, as defined above, and a diluent selected from pharmaceutically acceptable solvent, and preferably is an aqueous environment.

Pharmaceutically acceptable solvent, which is used as a diluent, can be any of those solvents or combinations of solvents that are used in concentrate for infusion. However, preferably it is a water, for example water for injections. Solution for infusion preferably has the same or almost the same osmotic pressure as that of the shared water body. Thus, rasb the La infusion of the same or almost the same osmotic pressure, as the total water in the body.

The agent or agents to maintain isotonicity can be selected from any known in this area substances, for example, are mannitol, dextrose, glucose or sodium chloride. Preferably the agent to maintain isotonicity is a glucose or sodium chloride. The agent or agents to maintain isotonicity can be used in amounts which give the solution for infusion is the same or almost the same osmotic pressure as that of the shared water body. The exact necessary amount can be determined using conventional experiments and may depend on the composition of the solution for infusion and the nature of the agent or agents to maintain isotonicity. Specific agent or agents to maintain isotonicity can be chosen based on the properties epothilone, for example epothilone or epothilone C. Thus, in particular, when epothilone In applied individually or in combination with epothilones And then some(e) agent(s) to maintain isotonicity may(may) cause the turbidity of solution for infusion. Turbidity may be associated with the dissolution epothilone, for example epothilone Century

In the claimed invention was unexpectedly ustanavlivaetsya an extended period of time, for example, within 24 hours, or not at all happening.

The concentration of the agent or agents to maintain isotonicity in the aquatic environment should depend on the specific nature(s) used(s) agent(s), preferably the concentration is 5% or less. When using glucose, its concentration is preferably from 1 to 5% wt. /about. , more preferably 5% wt./about. When the agent is to maintain isotonicity is a sodium chloride, it is preferably used in quantities of up to 1% wt./about, in particular 0.9% wt./about.

Solutions for infusion according to the invention may include other excipients commonly used in compositions intended for intravenous administration. Such excipients include antioxidants. Antioxidants can be used to protect epothilone, for example epothilone, oxidative decomposition. Antioxidants can be selected from antioxidants, known in this area and is suitable for intravenous compositions. The amount of antioxidant can be determined using conventional experiments. Alternatively, antioxidants or in addition to anti-oxidant activity can be achieved by preventing contact and purge with an inert gas such as nitrogen.

The amount of diluent used in a mixture with concentrate for infusion to obtain solution for infusion may be selected depending on the desired concentration epothilone, for example epothilone, solution for infusion. Preferably the solution for infusion is prepared by mixing the contents of the vial or ampoule (as described above concentrate for infusion) with a diluent, for example from 5% wt./about. glucose solution in water for injection in a suitable vessel, for example in a container or vessel for infusion, leading to volume with diluent to 50-1000 ml, for example, 200-1000 ml or preferably 50-100 ml of thus Obtained solution for infusion should preferably be used immediately or within a short period of time after preparation, for example for 6 hours In an alternative embodiment, the concentrate for infusion and a predetermined quantity of diluent may be in separate chambers of a two-chamber vial and mixed only immediately before intravenous patient.

In another embodiment, the pharmaceutical composition of the present invention may take the form of a lyophilized composition comprising e is filaseta, consisting only of epothilone, for example epothilone or epothilone In, can be very small, which makes it impossible to obtain by conventional freeze-dried composition having acceptable bulk, for example different acceptable uniformity of content, or can even be so low that it is difficult to detect visually. Therefore, you may need the use of excipients in freeze-dried compositions according to the invention, which may contribute to the increase of the content of solids and increase the main mass of liofilizovannyh composition. Acceptable excipients can be any of the excipients, which when used alone or in combination should increase the bulk of the freeze-dried composition without adversely interact with epothilones, such as destabilization epothilone or reduce any otherwise its effectiveness. Furthermore, the possibility of the use of excipients in pharmaceutical compositions, such as compositions for parenteral administration, such as intravenous pharmaceutical compositions. Thus, when choosing excipient or excipients should the Examples of suitable excipients include phosphates of sodium or potassium, citric acid, tartaric acid, gelatin, lactose or other carbohydrates, such as dextrose, mannitol and dextran, and any of cyclodextrins suitable for use intravenously, for example beta-cyclodextrin. Typical beta-cyclodextrins also include derivatives of beta-cyclodextrin, for example alkyl - or allinstevie derivatives, or hydroxyalkyl derivatives, which receive, for example, by the condensation reaction of beta-cyclodextrin with an oxide, such as propylene oxide. In a more preferred embodiment, a derivative of beta-cyclodextrin can be a hydroxypropyl-beta-cyclodextrin. Preferably hydroxypropyl-beta-cyclodextrin can be any of the following in Roger A. and Rajewski and others in the Journal of Pharmaceutical Sciences, volume 85, 11, November 1996 , pages 1142-1169 (publication included in the present description by reference).

Through purposeful selection of excipients in the claimed invention was installed, which can be obtained lyophilized composition with acceptable primary mass, including epothilone, for example epothilone or epothilone In which features improved solubility characteristics epothilone, for example epothilone or epothilone In, ineffectively epothilone.

The share of excipients or mixtures thereof may be from 50 to 99.9% based on the total solids content in the freeze-dried composition, more preferably from 90 to 99%, for example 95%, calculated on the total content of solids in the composition.

The share epothilone can be 100% based on the total solids content in the freeze-dried composition, although it is preferable to his share may be from 0.1 to 10%, more preferably from 0.1 to 1.5%, for example of 1.2%, calculated on the total content of solids in the composition.

If the content epothilone and cyclodextrin or mannitol is not 100% based on the total solids content in the freeze-dried composition, the balance of solids can be achieved through any of the excipients commonly used in lyophilizate, which can be recovered for pharmaceutical purposes, such as any of the other above-listed excipients.

Freeze-dried compositions according to the invention can be obtained from solutions (below marked as "original solution") containing epothilone, for example epothilone or epothilone In, and described above acceptable excipients. Acceptable solvents which may include pharmaceutically acceptable miscible with water and organic solvents, for example, alcohols, in particular ethanol or polyethylene glycol.

Original solutions may contain from 0.01 to 0.5% (wt./about.) epothilone, for example epothilone or epothilone Century

The starting solutions can be obtained by dissolving epothilone, for example epothilone or epothilone In, and excipients in an acceptable solvent followed by filtration of the solution through the filter, for example a sterile filter with a pore size of 0.22 μm. Thus obtained initial solution can be filled bubbles suitable amount, preferably having a capacity of 30 ml filling volume of 4.2 ml

Another object of the present invention is a method for freeze-dried composition, providing for (I) mixing epothilone, for example epothilone or epothilone In with pharmaceutically acceptable excipient, for example mannitol or cyclodextrin, in particular hydroxypropyl-beta-cyclodextrin in a suitable solvent to obtain the original solution and (II) dehydration of the starting solution.

The lyophilization can be performed by known methods. In a preferred embodiment, the above-mentioned filled bubbles can be frozen in lyophilization the camera for approximately 3 h at temperatures which may be evacuated of air to a pressure of about 0.1-0.2 mtorr. Then the temperature in the chamber can be increased in order to cause sublimation of the frozen liquids. Preferably the temperature was raised to about 0oC, and this temperature can be maintained within 8-15 h for the implementation of lyophilization.

Freeze-dried composition can be used for the preparation of parenteral compositions, and therefore, the process of freeze-drying is preferably carried out under sterile conditions, for example, using aseptic processes of preparing or using irradiation. Preparation aseptically solutions containing pharmaceutically active compound, filling in aseptic conditions bubbles and methods of freeze-drying under aseptic conditions well known to specialists in this field.

The moisture content in the thus obtained freeze-dried composition can be 3% or less, calculated on the total weight of the dried composition. However, after lyophilization may not necessarily be the stage of hydration, which in lyophilization chamber at atmospheric pressure or below, reduced pressure may be introduced sterile water vapor. Obviously, if the specified Osmaniye pressure can be controlled, and this pressure can optionally be adjusted using methods well known in the field. Stage humidification can last 4-8 hours depending on, spend it at atmospheric or under reduced pressure.

Lyophilized composition obtained by hydration, hereinafter designated as hydrated lyophilizate. These hydrated lyophilizate may contain from 0.1 to 5 wt.% water.

Lyophilized compositions of the present invention can be placed in a container in a single dose. A container containing a single dose, may be of any reasonable size. The concept of "reasonable size" means the size that corresponds to the volume of the solution up to which you want to restore the freeze-dried composition. To obtain these dosage forms can be any acceptable capacity. The term "acceptable" means any vessel that can be used in the processes of filling in aseptic conditions, can maintain a sterile environment and does not react with freeze-dried composition. Preferred containers may be made of glass, for example of glass type I, and can be supplied with a plug, for example, sterile The preferred tube, which can also provide access to the contents of the vessel for the introduction of the freeze-dried composition of the solvent, for example water for injection.

Freeze-dried composition according to the invention can maintain stability within 24-36 months at a temperature of from 2 to 30oC. In lyophilised compositions that were stored during these time periods show no signs of decomposition, and they retain without change the solubility characteristics.

When you want to get epothilone in a form suitable for parenteral, e.g. intravenous, injection, freeze-dried composition can be recovered, preferably just before the introduction.

Recovery may include dissolving the freeze-dried composition in water or any other pharmaceutically acceptable solvent as described above, for example in physiological solution, in aqueous solution pharmaceutically acceptable alcohol, for example ethanol, propylene glycol, polyethylene glycol, such as polyethylene glycol 300, and so on, or any other sterile, suitable for injection under aseptic conditions the solvent. Form in containers designed to ADNOC the concentration epothilone, for example epothilone or epothilone In required for parenteral administration. This restored lyophilized composition may preferably be used immediately or within a short period of time after preparation, for example for 6 hours

The pharmaceutical composition of the present invention in a form suitable for parenteral administration, such as intravenous administration, in particular the solution for infusion, obtained by dilution of a concentrate for infusion or recovery of freeze-dried compositions (such compositions hereinafter designated as the diluted compositions of the present invention), can be filled to capacity, selected from any conventional containers, the material which does not react with the above pharmaceutical compositions. Can be used a glass bottle, made of glass above types, although it is preferable to use plastic containers such as plastic bottles for infusion.

Plastic containers can be a first of all containers from thermoplastic polymers. Plastic can optionally include additives, such as plasticizers, fillers, antioxidants, anti the present invention, must be resistant to the high temperatures required for heat sterilization. The preferred plastic bottles for infusion are cylinders made of known in the field of plastics, such as PVC.

Can be applied capacity, the dimensions of which vary widely. When choosing the size of the tank should take into account the solubility epothilone in a particular solvent and the simplicity of its preparation and, if necessary, the ability of the vessel to storage. It is preferable to use a container that can hold approximately 200-1000 ml, for example 250-1000 ml, diluted compositions of the present invention.

The diluted composition of the present invention should preferably be sterile. This goal can be easily achieved, for example, by irradiation or filtration indicated the diluted composition through sterile filtration membranes. Getting in aseptic conditions any composition in liquid form, filling in aseptic conditions bubbles and/or Association under aseptic conditions liquids for parenteral application with acceptable diluent is well known to specialists in this field.

The diluted compositions is s disease, for example, if the indications and conditions described in the applications WO 93/10121 and DE 4138042 A2, the contents of which are incorporated into this description by reference. More specifically, they can be used for the treatment of tumour-related diseases, such as melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head and neck cancer, bladder cancer, kidney cancer, brain, stomach or preferably colorectal Department, prostate, breast, lung (especially lung cancer) or epithelium, especially epidermal, such as cervical cancer. In addition, the diluted composition of the present invention may be suitable for the treatment of conditions for which illustrates the use of Paclitaxeland used in a similar way. In respect of certain tumors epothilone have more valuable properties compared with Paclitaxel. In respect of certain tumors, such as some types of lung tumors, particularly tumors of the lung A, epothilone In is more valuable properties compared with Paclitaxel. In celeities effective against a proliferative disease, to ensure which shows the use epothilone, for example epothilone and/or epothilone In primarily epothilone Century Such proliferative diseases include any above proliferative disease, especially associated with tumour disease sensitive therapeutically effective amount epothilone that preferably is manifested in the reduction of cell proliferation, for example in reducing the rate of tumor growth or even (what is even more preferable) in regression of the tumor, or (which is most preferred) in complete disappearance of the tumor. The exact number and duration of treatment may vary depending on the nature epothilone, for example whether epothilone And epothilone In, or their mixtures, of the specific type of malignant proliferating cells specific to the tumor, the severity of the condition, the injected doses, as well as from the General health of the patient and his response to treatment.

In addition, the pharmaceutical composition of the present invention suitable for parenteral administration form, for example in the form of solution for infusion, obtained by dilution of a concentrate for infusion or restoring dried the Anna area, for example, by irradiation, or may be one of the components of the joint therapy, including at least one non-epothilone chemotherapeutic agent. The combination of active substances can be administered simultaneously or sequentially, with the first may be any of the active substances. The dose of active ingredients when combined treatment may depend on the efficiency and location of each active ingredient, as well as from synergistic interactions between agents, which are used for joint therapy.

Other chemotherapeutic agents may include first of all any chemotherapeutic agent that is used or may be used for the treatment of tumour-related diseases, including chemotherapeutic agents, which are derived agents of the following classes: (A) alkylating agents, preferably sewn chemotherapeutic agents, preferably balkanarama agents, (B) anti-cancer antibiotics, preferably doxorubicin (Adriamycin, Rubex), (B) antimetabolites, plant alkaloids, (D) hormonal Agay is bitory proteins, such as tyrosine kinase and/or serine/trionychinae,
(C) the antisense oligonucleotides or oligonucleotide derivatives or
(And) a variety of agents or other agents with other or unknown mechanism of action, preferably from the class taxane primarily Taxotereor most preferably paclitaxel (Taxol).

Thus, the diluted composition of the present invention can be used as the sole anti-cancer composition or as part of a joint therapy for the treatment of various tumors.

The applicability of all the diluted compositions of the present invention can be installed using standard clinical tests, for example using known data about doses epothilone required to obtain equivalent concentrations epothilone in the blood, in particular using doses in the range of from about 0.1 to 6 mg/m2epothilone for weekly use and from about 0.3 to 18 mg/m2epothilone to apply once in three weeks when administered to a mammal weighing 75 kg, for example, an adult with PL is e when using single doses studied on the model of ovarian cancer human SKOV3, and also on the model of glioma U373.

Increased bioavailability epothilone with the introduction in the form of a diluted composition of the present invention can be installed using standard tests on animals and in clinical trials, for example by the method described above. Obviously, the exact number epothilone and pharmaceutical compositions intended for insertion, can depend on numerous factors, such as subject to treatment status, specific epothilone, desired duration of treatment and on the speed of introduction epothilone. For example, the required number epothilone and the rate of administration can be determined on the basis of known methods in vivo and in vitro, in particular with the methods described above, to determine how long remains in plasma concentration epothilone on required for therapeutic action.

The diluted compositions of the present invention, can generally be administered intravenously at a dose of from about 0.1 to 100 mg/m2for example from 0.2 to 100 mg/m2, epothilone and from about 0.1 to 50 mg/m2for example from 0.2 to 50 mg/m2, epothilone Century For weekly application of a preferred dose is from 0.1 to 6 mg/Mr>2and most preferably from 0.1 to 1 mg/m2; for handling once in three weeks, the dose is from 0.3 to 18 mg/m2preferably from 0.3 to 15, more preferably from 0.3 to 12, even more preferably from 0.3 to 7.5 mg/m2and most preferably from 1.0 to 3.0 mg/m2. The dose is preferably administered to a human intravenously over 2-180 min, preferably within 2-120 min, more preferably for 5 to 30 minutes, most preferably within 10-30 minutes, for example within 30 minutes

The preferred concentration and doses are to achieve the level of effective dose is about 0.5 to 15 mg/day, more preferably 1-10 mg/day, most preferably 2-8 mg/day. Intravenous dose and concentration in blood can be accurately determined on the basis of the known methods in vivo and in vitro.

Another object of the invention is a method of introducing epothilone to a patient in need of treatment epothilones providing for the introduction of parenteral diluted compositions of the present invention to a patient in need of such treatment. More specifically, this method of introduction epothilone provides for (a) dilution of the pharmaceutical compositions according to the invention, ora, suitable for parenteral, e.g. intravenous, injection, and (b) the introduction of such a solution for the patient.

Another object of the invention is the use of epothilone in the preparation of medicines, suitable for parenteral administration.

Below the invention is illustrated in the examples which do not limit its scope. All percentages are wt.%, if not stated otherwise. Any components and pharmaceutical compositions are also described in the book Fiedler, H. P. "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", published by Editio Cantor, D-7960 Aulendorf, 4th ed., revised and enlarged, 1996 (incorporated in the present description by reference).

Examples
Example 1
Epothilone (15 mg epothilone or 50 mg epothilone A) is dissolved in 98-100% propylene glycol (1.0 ml). The solution is sterile-filtered through a filter with a pore size of 0.22 μm and fill ampoules of 1 ml of Filled ampoules are used for storage and transportation. The contents of the filled vials stable for at least 12 months at 2-8 ° oC. Before intravenous contents of the ampoules add to 250-1000 ml of 5% glucose solution in water for injection. Thus obtained solution for intravenous webtorials using as solvent system of absolute and aqueous ethanol and the various systems of solvents polyethyleneglycol (see table 1).

All solutions for infusion, obtained according to examples 2-7, is stable for 8 h at room temperature.

Example 8
Solubility data in different solvents are summarized in table 2. Unless otherwise stated, all solubility data obtained at a temperature (t) of the 22oC.

Solubility epothilone In water at a neutral pH value of approximately 160 mg/l, and significantly higher solubility obtained using mixtures of PEG/water, propylene glycol/water or t/water. For comparison, according to the previously published data solubility in water epothilone And is 940 mg/l, and the mixture epothilones and 700 mg/L.

Example 9
Determine stability at different temperatures water concentrate for infusion in comparison with the non-aqueous polyethyleneglycol concentrates, containing different concentrations epothilone C. As a rule, a known amount epothilone dissolved In 1.0 ml of each of the systems studied solvents and every solution is sterilized by filtration and filled bubbles in a volume of 1 ml of white glass with stoppers of grey rubber grey removable caps. Table 3 presents data on the number of roslogistics the decomposition in each of concentrate for infusion as a function of time and temperature. Each sample analyzed by GHWR, the sample is prepared by diluting the concentrate with an aqueous medium. The stability of all concentrate for infusion after 3 months of storage at 2-8oWith appeared to be comparable. At higher temperatures, for example at 25oWith non-aqueous solvent system comprising PEG, showed significantly higher stability in comparison with the aqueous solvent system comprising PEG.

Example 10
An aqueous solution prepared by dissolving epothilone In (5.0 mg) and mannitol (1500 mg) in water for injection, receiving up to 30 ml. The solution is passed through a sterile membrane filter with a pore size of 0.22 μm before filling solution under aseptic conditions in a glass vial and then it sealed under sterile conditions with sterile tube to bubble, preparing them for the drying process. The filled vial is then placed in lyophilization chamber and is cooled to a temperature of about -40oC. the Capacitor lyophilizate cooled to about -60oTo and from the chamber pump out the air to a pressure of about 0.1 mtorr. The temperature in the chamber is maintained at about 20oWith starting the drying process. After about 20 h of drying pressure among patients with by introducing into the chamber under aseptic conditions with sterile air or nitrogen. After that, the stopper on the vial sealed under aseptic conditions, which provides a sterile airtight closure. Sealed bubble consists of a container containing a single dose of epothilone In which to restore just before the introduction using 25 ml of water for injection. The dose is injected.

Dried product has the required characteristics corresponding to the freeze-dried compositions according to the invention.

Examples 11-14
To obtain a lyophilized product, the components of which are shown in table 4, using the method described in example 10.

Lyophilized products obtained according to examples 11-14, possess the required characteristics corresponding to the freeze-dried compositions according to the invention.


Claims

1. Pharmaceutical composition in the form of a concentrate for infusion, which contains epothilone and pharmaceutically acceptable organic solvent.

2. Pharmaceutical composition, which contains epothilone and pharmaceutically acceptable organic solvent and does not contain a surface-active substance is hydrophilic-lipophilic balance of the 3. Pharmaceutical composition, which contains epothilone and pharmaceutically acceptable organic solvent selected from (I) alcohol or (II) N-alkylpyridine.

4. The pharmaceutical composition according to any one of the preceding paragraphs, in which the pharmaceutically acceptable organic solvent is a glycol.

5. The pharmaceutical composition according to any one of the preceding paragraphs, which additionally contains water.

6. The pharmaceutical composition according to any one of the preceding paragraphs, in which water is present in an amount up to 45% wt./about.

7. The pharmaceutical composition according to p. 6, in which water is present in amounts up to 0.5% wt./about.

8. The pharmaceutical composition according to any one of the preceding paragraphs, in which the concentration epothilone is from 1 to 5 mg/ml

9. The solution for infusion, including composition according to any one of the preceding paragraphs and a pharmaceutically acceptable solvent.

10. Composition under item 1, which contains no surfactant, the value of the hydrophilic-lipophilic balance (products HLB) which is 10 or more.

Priority items:
05.02.1998 on PP.1-10.

24.06.1998 on PP.1-10 (clarification of their signs).

 

Same patents:

The invention relates to pharmaceuticals, to pharmaceutical compositions which possess improved antitumor effect or reduced(and) side(s) effect(s) consisting of the active substance having antitumor action, or a pharmaceutically acceptable salt thereof and a derivative of hydroxamic acids according to the formula or therapeutically applicable its acid salt additive

The invention relates to a new compound - peptide of General formula Thr-Gly-Glu-Asn-His-Arg, possessing the biological activity of inducing differentiation and inhibiting cell proliferation in tumors and activity of the tread and the normalizing action on the vital processes of mammalian cells obtained by the method of solid-phase peptide synthesis by sequential growth of the peptide chain and having the following properties: mol

The invention relates to new derivatives epothilone

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where Q is selected from the group consisting of

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where R8is hydrogen, alkyl;

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where R11- alkyl, heterocycle; R12is hydrogen, W represents O or NR15where R15is hydrogen, Y and X represent O, Z1and Z2represent-CH2B1and IN2HE, R1-R7is hydrogen, alkyl; and their pharmaceutically acceptable salt, geometric, optical and stereoisomers, provided that compounds in which W and X both represent O; R1, R2and R7represent H; R3, R4, R6represent methyl; R8represents H or methyl; Z1and Z2represent CH2; G represents 1-methyl-3-(substituted-4-thiazolyl)ethynyl; Q is as defined above, is excluded, as well as to a method of treating cancer, diseases associated with hyperproliferating cells and method of achieving the patient antiangiogenesis effect
The invention relates to medicine and can be used in the treatment of multiple myeloma, mostly complicated radicular syndrome

The invention relates to veterinary

The invention relates to medicine, in particular to surgery, and can be used for sclerotherapy of large metastases in the liver

The invention relates to new derivatives of aminothiazole formula I and their pharmaceutically acceptable salts, where R1and R2independently of one another denote hydrogen, fluorine or lower alkyl; R3denotes heteroaryl selected from oxazolyl, which is substituted by one or more substituents selected from lower alkyl, halogen, carbamoyl, allyloxycarbonyl, alkylcarboxylic; or benzoxazole; R4denotes hydrogen;-alkyl which can be optionally substituted with halogen, alkoxy, hydroxy, allyloxycarbonyl, alkylcarboxylic, amino, carbamoyl; CO-cycloalkyl; CO-aryl, where aryl represents phenyl which may be optionally substituted with halogen, lower alkyl, alkoxy, amino, cyano or naphthyl, and so on; or COO-alkyl; COO-cycloalkyl; soo-phenyl; COO-alkyl-phenyl; SO2-alkyl; SO2-phenyl, C(NCN)NH-phenyl, where phenyl may be optionally substituted with halogen; R5denotes hydrogen; m is an integer from 0 to 2; n is 0

The invention relates to new imidazole derivative of formula I and II

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or

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where 1, m, r, s, and t = 0 or 1; n = 1 or 2; provided that when 1 and m = 0, n = 2 Y - SO2or CH2; Z - CR12, NR32SO; NR13, NR36CO., OCONR15, SO2NR14; R1selected from the group consisting of hydrogen, alkyl, or aralkyl, the symbola single or double bond, R7, R8selected from the group consisting of hydrogen, aryl, - CN, halogen, and U-R44group, where U = O and R44and R11selected from the group consisting of hydrogen, alkyl, aralkyl, aryl; R32selected from the group consisting of hydrogen, lower alkyl, unsubstituted or substituted phenyl, and tanila; R9, R10, R12, R13, R14, R15, R36, R57and R58represent hydrogen or lower alkyl; one of R, S and T is CH2or CH(CH2)pQ, where Q denotes NR57R58; where p = 0,1 or 2; provided that when Y is - SO2, R11cannot be hydrogen; its enantiomers, diastereoisomers, pharmaceutically priemel the
The invention relates to medicine, namely to Oncology, and can be used for the treatment of malignant tumors of the nasopharynx
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose, and in particular to method of obtaining a composition by mixing cromolyn sodium and/or other drug inflamatornog steps of 0,5-4,0, dexamethasone-21-phosphate sodium salt and/or other glucocorticoid-steroid drug 0,05-0,1, ephedrine hydrochloride, and/or other adrenalinerush means 1,0-5,0, sterile buffer solution to 100.0 with the addition of neomycin sulfate or boric acid and/or other antibacterial and antiseptic
The invention relates to medicine, namely to create funds for the treatment of infectious diseases, accompanied by the discharge from the nose

The invention relates to the field of medicine and relates to an infusion solution for improving cerebral circulation
The invention relates to the field of medicine
The invention relates to medicine, namely to facilities for the treatment of skin diseases: eczema, dermatitis of various etiologies, neurodermatitis, prurigo

The invention relates to the field of medicine and for the preparation of Bresolin drops nasal 0.06% and 0.1% for the treatment of diseases of the nose and throat

The invention relates to the field of medicine and is about creating funds on the basis of Bromhexine hydrochloride

The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to a composition for injection on the basis of mannitol
The invention relates to medicine

The invention relates to new pharmaceutical compositions in the form of a self emulsifiable compositions containing the primary amine, which provide a high concentration and a high oral bioavailability of the compounds of piranha, which are inhibitors of retroviral protease
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