FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.
EFFECT: improved and valuable properties of composition.
10 cl, 4 tbl, 14 ex
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 4138042) formula I. Typical representatives of this class include epothilone And where R denotes a hydrogen atom, and epothilone, 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 And what do 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 cytotoxic agents used to treat tumors. Antitumor activity of many of these compounds caused 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. Bad Rast is orime connection 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 during storage in aqueous solutions over a long period of time. For such an agent affecting microtubules as Taxol®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 Cremophor®may 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 2-8°C.
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 p is supercial-active substances, for example surface-active substances, products HLB value (hydrophilic-lipophilic balance) which is 10 or more, for example Cremophor®and which do not adversely impact on the effectiveness of these connections.
Thus, one of the objects of the invention is a pharmaceutical composition comprising 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 Cremophor®can cause allergic reactions, and they may leaching plasticizers of the standard containers, test tubes, etc. from polyvine the chloride (PVC). Thus, in cases where they are applied, may require special devices for infusion, for example tubes nitroglycerin and do not contain plasticizers capacity, such as glassware, test tubes, 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 polietilenglikol is, for example with a molecular weight of preferably 200-600 Yes, more preferably 200-400 Yes, most preferably 300 Yes. The glycols can be used in a distilled form, and can be characterized, for example, by the presence of one or more of the following characteristics: (I) the content of ethylene oxide - up to 20 ppm million, usually less than 1 part./million, for example 0.1 to 0.5 part./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 d is 0.05 percent. 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 ethanol/water, for example 70% wt./about. ethanol, or a mixture of glycol/water, for example 90% wt./about. poly (ethylene glycol).
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, particularly 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 con is entrata for infusion can be obtained using such a process as, for example, dissolution epothilone in a pharmaceutically acceptable solvent according to the invention, optionally with other excipients. Preferably it does not present any of the excipients. If they are present, their concentration is preferably 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 retirieve-kalileo-silicate 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 2-8°that is confirmed using the standard TES the s on stability evaluation, in particular, according to the method described in the examples.
In addition, the concentrate for infusion have low evaporation rate, and they can be obtained using conventional equipment, for example, if necessary, without the use of intrinsically safe 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 represents water, such as water on the I injection. Solution for infusion preferably has the same or almost the same osmotic pressure as that of the shared water body. Thus, the diluent preferably contains an agent or agents to maintain isotonicity, which give the solution for infusion is the same or almost the same osmotic pressure as that of 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) DL who maintain isotonicity may(may) cause the turbidity of solution for infusion. Turbidity may be associated with the dissolution epothilone, for example epothilone Century
With the invention it has been unexpectedly found that if the agent to maintain isotonicity use glucose, the turbidity does not occur over an extended period of time, for example within 24 hours, or does not occur.
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 of oxygen (air) solution for infusion. As a rule, for this purpose, the vessel containing the solution for infusion, blow 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 PA is Ianto.
In another embodiment, the pharmaceutical composition of the present invention may take the form of a lyophilized composition comprising epothilone, for example epothilone or epothilone Century due To the bad solubility epothilone and epothilone weight of the lyophilisate, 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 p is enteralnogo introduction, particularly in intravenous pharmaceutical compositions. Thus, when choosing excipient or excipients should consider not only the nature of the freeze-dried compositions, but also feature the final pharmaceutical form. 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, No. 11, November 1996, str-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 is th main mass, including epothilone, for example epothilone or epothilone In which features improved solubility characteristics epothilone, for example epothilone or epothilone In, or in which epothilone dissolves faster, but which have no negative impact on the efficiency 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 could have the t can be obtained from solutions (indicated below as "initial solutions"), containing epothilone, for example epothilone or epothilone In, and described above acceptable excipients. Acceptable solvents such initial solutions are either only water or a solvent, which is water and which include pharmaceutically acceptable miscible with water and organic solvents such as 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 ishodnoj the 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 hours at a temperature below the eutectic point, preferably at about -40°C.
Then from lyophilization chamber 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 approximately 0°C, 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. Od is ako after lyophilization may not necessarily be the stage of hydration, where lyophilization chamber at atmospheric pressure or below, reduced pressure may be introduced sterile water vapor. Obviously, if the hydration is carried out at reduced pressure, then the pressure may change with the introduction of water vapor, and the pressure change 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 in order to 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 a sterile rubber stopper, which can be connected with the walls of the container to provide a tight seal.
The preferred tube that can also provide access to the contents of the container with the purpose of introducing in 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 30°C. 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, for example intravenous, lyophilized 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 is of glicole 300, and the like, or any other sterile, suitable for injection under aseptic conditions the solvent. In form of capacity, designed for a single dose, can be filled with an appropriate amount of solvent, allowing to obtain the desired 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 may represent the first of all containers from thermoplastic polymers. Plastic can optionally include additives, such as plasticizers, fillers, antioxidants, antistatic agents and other additives known in this field.
Plastics suitable for the diluted compositions of 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 is of alcosta for parenteral application with acceptable diluent is well known to specialists in this field.
The diluted composition of the present invention may be used for the treatment and prevention of malignant proliferative diseases, such as 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 Paclitaxel®and 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 General, the diluted composition of the present invention can be applied to measure the e which is therapeutically effective against a proliferative disease, for the treatment of which is shown applying 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 recovery of freeze-dried composition can IP olsavica in combination with other methods of treatment of tumors well-known experts in this field, 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®),
(G) vegetable alkaloids,
(D) hormonal agents and antagonists
(E) biological response modifiers, preferably lymphokines or interferons,
(W) inhibitors Proteus is s, 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 Taxotere®or 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 having a body surface area of 1.73 m2and using standard animal models. For example, anti-tumor effects when using single doses studied on the model of rakamonie 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/m2epothilone and from about 0.1 to 50 mg/m2for example from 0.2 to 50 mg/m2epothilone Century For weekly application of a preferred dose is from 0.1 to 6 mg/m2mainly from 0.1 to 5, more preferably from 0.1 to 3, more preferably from 0.1 to 1.7 mg/m2/sup> and most preferably from 0.1 to 1 mg/m2; for use 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, for example in the form of a concentrate for infusion or lyophilized composition, an aqueous medium to obtain a solution, p is Igumnovo for parenteral, for example, 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 NR: "Lexikon der Hilfsstoffe für 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).
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 ° °C. Before intravenous contents of the ampoules add to 250-1000 ml of 5%glucose solution in water for injection. Thus obtained solution for intravenous injection is stable for 8 h at room temperature.
Described in example 1, the experiment is repeated using ka is este systems absolute solvents and aqueous ethanol and the various systems of solvents polyethyleneglycol.
|Example||The solvent system|
|3||polyethylene glycol 300|
|4||the polyethylene glycol 400|
|Example||The solvent system|
|6||polyethylene glycol 300: 90-100%|
|7||the polyethylene glycol 400: 90-100%|
All solutions for infusion, obtained according to examples 2-7, is stable for 8 h at room temperature.
Solubility data in different solvents are summarized in table 2. Unless otherwise stated, all solubility data obtained at a temperature (T) 22°C.
|Solubility epothilone In different solvent system|
|Solvent/solvent system||Solubility (g/l) ±10%|
|H2On (pH 6.0)||0,16 (19,4°)|
|phosphate buffer pH 7.4||0,16 (19,4°)||H2Oh, 0,9% glucose||0,16|
|H2Oh, 5% glucose||0,16|
|H2Oh, 15% glycerol||0,19|
|H2About 5% of poloxamer 188||0,23|
|PEG 300/N2About (./about.)100/0||12|
|PEG 400/H2O (./about.)100/0||30|
|propylene glycol/N2About (./about.)100/0||26|
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 EtOH/water. For comparison, according to previously published data, the solubility in water epothilone And is 940 mg/l, and the mixture epothilones and 700 mg/L.
Determine stability at different temperatures of water to the of lantratov for infusion in comparison with the non-aqueous polyethyleneglycol concentrates, includes various 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 decomposed product during the period of time up to 7 months. The stability of analyzing the formation of decomposition products 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 2-8°were comparable. At higher temperatures, for example at 25°C, non-aqueous solvent system comprising PEG, showed significantly higher stability in comparison with the aqueous solvent system comprising PEG.
|The relative content of decomposition products in water compared with the non-aqueous containing PEG concert for infusion|
|The solvent system||Dose||Time||2-8°||25°|
|PEG 400||1 mg/ml||3 months||<0,1||0,2|
|PEG 400/water 90:10 (wt./wt.)||1 mg/ml||3 months||<0,1||0,4|
|PEG 300||1 mg/ml||3 months||<0,1||-|
|PEG 300/water, 90:10 (wt./wt.)||15 mg/ml||7 months||<0,1||1,0|
|ethanol/water, 59:41 (wt./wt.)||5 mg/ml||the initial|
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 -40°C. the Capacitor lyophilizate cooled to about -60°and from the chamber pump out the air to a pressure of about 0.1 mtorr. The temperature in the chamber support the claim at the level of about 20° With starting the drying process. After about 20 h of drying pressure in the chamber increases to about 0.2 mtorr and the drying process is considered completed. The pressure in the chamber is raised to atmospheric 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.
To obtain a lyophilized product, the components of which are presented in the table below (table 4), using the method described in example 10.
|Example||Epothilone In mg||Hydroxypropyl-beta-cyclodextrin mg||Water for injection/ml|
Lyophilized products obtained according to examples 11-14, possess the required characteristics corresponding to the freeze-dried compositions according to the invention.
1. Lyophilized composition comprising (I) epothilone in an effective amount and (II) mannitol or cyclodextrin.
2. Freeze-dried composition comprising epothilone in an effective amount and hydroxypropyl-beta-cyclodextrin.
3. Freeze-dried composition according to claim 1 or 2, in which the content epothilone is from 0.1 to 1.5% based on the total weight of solids.
4. Freeze-dried composition according to claim 1 or 2, in which the content epothilone is from 0.1 to 1.5% based on the total weight of solids and the content of the cyclodextrin is from 90 to 99% based on the total weight of solids.
5. Restored lyophilized composition comprising the pharmaceutical composition according to claim 1 or 2 in a pharmaceutically acceptable solvent.
6. Restored lyophilized composition comprising the pharmaceutical composition according to claim 3 in a pharmaceutically acceptable solvent.
7. Restored lyophilized composition comprising the pharmaceutical composition according to claim 4 in a pharmaceutically acceptable Rast is oritel.
8. The use of freeze-dried composition according to claim 1 or 2 for the preparation of antitumor drug suitable for parenteral administration.
9. The use of freeze-dried composition according to claim 3 for the preparation of antitumor drug suitable for parenteral administration.
10. The use of freeze-dried composition according to claim 4 for the preparation of antitumor drug suitable for parenteral administration.
FIELD: medicine, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to using 4-chloro-2-methylphenoxyacetic acid of the formula (I)
and its pharmacologically acceptable sodium, potassium and lithium salts (mixture of these salts, or mixture of salts and 4-chloro-2-methylphenoxyacetic acid) as a medicinal agent possessing immunomodulating, anti-inflammatory and antitumor properties, and antiviral activity also. 4-Chloro-2-methylphenoxyacetic acid and its mixtures with pharmacologically acceptable alkaline metal salts possess high effectiveness and enhanced bioavailability.
EFFECT: valuable medicinal properties of medicinal agent.
9 cl, 13 ex
FIELD: chemistry of peptides, medicine.
SUBSTANCE: invention relates to preparing new peptides possessing immunomodulating, anti-proliferative, anti-tumor and antiviral activity. Invention proposes new peptides comprising up to 30 amino acid residues of the general structural formula: X1-Trp-Gly-Gln-X2 wherein X1 is taken among the following group: -His-Gly-Val-Ser-Gly-, -His-Gly-Gly-Gly-, -His-Val-Gly-Gly-, -His-Gly-Gly-Gly-Gly-, and -Gln-Gly-Gly-Gly-Gly, or absent; X2 is taken among the following group: -His-Gly-Thr-His-Gly, -Gly-Gly-Thr-His-Gly, -Pro-His-Val-Gly-Gly, -Pro-His-Gly-Gly-Gly, -Pro-His-Gly-Gly-Gly-Trp-Gly, -Gly-Gly-Gly-Thr-His-Ser, or absent.
EFFECT: valuable medicinal properties of peptides.
8 cl, 5 tbl, 5 dwg, 6 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):
wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.
EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.
17 cl, 7 tbl, 7 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to new derivatives of acridine of the formula (1):
wherein R, R1, R2 and R3 mean hydrogen atom; Z means oxygen or sulfur atom; X means nitrogen atom or C-R5 wherein R5 means hydrogen atom; n = 2; m = 0; R4 means (C1-C3)-alkyl residue that can be substituted with aryl, (C4-C10)-heteroaryl and other substitutes, (C6-C10)-aryl and others, and to their pharmaceutically acceptable salts. Compounds of the formula (1) possess an anti-tumor activity and can be used as an active component of the medicinal agent.
EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.
9 cl, 1 tbl, 20 ex
SUBSTANCE: method involves combining vaccine prepared from 107 cells of autologic tumor lysate with 60 mg of betaleukine and introducing it strictly in intracutaneous paravertebral mode in three points arranged 3 cm far from each other. The introduction takes place every 3 weeks so that the first two vaccinations are combined with 470 mg of betaleukine introduced into anterior abdominal wall. Vaccination treatment is continued on receiving positive retarded type hypersensitivity response to injection after every vaccination with tumor lysate without betaleukine.
EFFECT: enhanced effectiveness in inducing and supporting antitumor immune response.
FIELD: organic chemistry, biochemistry, pharmacy.
SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)
or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).
EFFECT: improved preparing methods.
10 cl, 2 sch, 25 tbl, 7 ex
FIELD: medicine, oncology.
SUBSTANCE: invention relates to method for malignant tumor treatment (including cancer, sarcoma, melanocytoma) in human by ectasceine ET743 intravenous infusion in dose of 500-1650 mug/m2 of surface are; to similar treatment by combination of ET743 with antiemetic agent; as well as to relative composite preparation. Method of present invention provides clinical amelioration in subject suffering from progressive or metastasing cancer and improves treatment effectiveness of diseases being progressed after known chemotherapy.
EFFECT: new effective method for cancer treatment; drug with good acceptability.
31 cl, 3 ex, 1 tbl
FIELD: medicine, oncology, gastroenterology, immunobiotechnology.
SUBSTANCE: invention describes an antibody or its derivative, or its fragment showing the structure able to bind the target structure. Antibody is located inside and on surface of human gastroenteric tract epithelial tumor cells and in subpopulation of normal gastroenteric tract epithelial cells. Indicated binding structures comprise sequences determining the complementarity of the region (CDR) in light chain comprising in main amino acids at number 23-33 (CDR 1), 49-55 (CDR 2), 88-98 (CDR 3) of amino acid sequence represented in SEQ ID NO:2, and CDR sequence in heavy chains comprising in main amino acids at number 158-162 (CDR 1), 177-193 (CDR 2), 226-238 (CDR 3) of amino acid sequence represented in SEQ ID NO:2, or other binding structures with similar unique binding properties. Also, invention describes the target-structure located inside or on surface of tumor cells: vaccine composition designated for treatment of malignant disease in human and comprising abovementioned antibody. Also, invention describes methods for treatment and diagnosis of malignant disease. Using this invention provides preparing antibodies that relieve identification of new phenotype-specific tumor-associated antigens, to predict and treat metastatic human diseases. Invention can be used in medicinal practice.
EFFECT: valuable medicinal properties of antibodies.
37 cl, 21 dwg, 4 tbl, 8 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to compounds of the formula (I): or their pharmaceutically acceptable salts or solvates wherein Ar represents a substituted or unsubstituted (preferably aromatic one) carbocyclic or heterocyclic group wherein abovementioned carbocyclic or heterocyclic group comprises 5 or 6 atoms in cyclic structure wherein a heteroatom is taken among the group consisting of nitrogen (N) and sulfur (S) atom and any substitutes at Ar group are taken independently of one another of the group consisting of Cl, Br, F atoms and OR10 wherein R10 represents saturated or unsaturated lower hydrocarbon (C1-C6)-radical of normal or branched structure; R represents OR10 wherein R10 corresponds to above given value; R1 represents lower hydrocarbon (C1-C6)-radical of normal or branched structure under condition that if R1 represents -CH3 and R means -OCH3 or -OH then Ar group can't represent 4-methoxyphenyl or 3,4-dimethoxyphenyl. Also, invention proposes a component of medicinal agent used in treatment or prophylaxis of neoplasms. Also, invention proposes a pharmaceutical composition possessing with an anti-proliferative activity and comprising the effective amount of one or some compounds of the formula (I) in combination with one or some pharmaceutically acceptable additives. Invention provides the development of chalcone coumarins possessing with the enhanced anti-proliferative effect with respect to sensitive tumor cells, cells with resistance to conventional chemotherapeutic agents, among them, to anti-tumor medicinal agents of the last generation represented by paclitaxel and docetaxel.
EFFECT: valuable medicinal properties of compounds and compositions.
1 tbl, 21 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to substituted derivatives of N-benzylindol-3-yl-glyoxylic acid of the formula (1): wherein groups R, R1, R2, R3, R4 and Z have the following values: R means -NO2, -NH2, (C1-C6)-acylamino-, aroylamino-, nicotinoyl or isonicotinoyl, arylsulfonylamino-, succinimido- wherein this residue R can be substituted with (C1-C6)-group by choosing by carbon atom at positions 2, 3 and 4 of phenyl ring; R1 means hydrogen atom (H), (C1-C6)-alkyl that can be replaced with at least one phenyl group; R2 means pyridyl; R3 and R4 mean H; Z means oxygen (O), sulfur (S) atom. Compounds of the formula (1) possess an antitumor effect that allows their using in pharmaceutical compositions.
EFFECT: valuable medicinal properties of compounds and compositions.
6 cl, 2 dwg, 3 tbl, 9 ex
FIELD: chemico-pharmaceutical industry.
SUBSTANCE: the present innovation deals with new stabilized pharmaceutical composition in its lyophilized form including the compound of formula I
as an active ingredient and lactose disaccharide as a stabilizing agent. The present pharmaceutical compositions are of high stability at storage. As for active ingredient it is not destroyed in the course of time.
EFFECT: higher efficiency.
10 cl, 15 ex, 6 tbl
SUBSTANCE: preparation comprises echinocandine substance of formula I or its pharmaceutically permissible salt, pharmaceutically permissible micelle-forming surface-active agent and non-toxic aqueous solvent and stabilizing agent.
EFFECT: improved stability and bioaccessibility properties.
48 cl, 4 tbl
FIELD: medicine, hematology, pharmacy.
SUBSTANCE: invention relates to the composition of factor VIII composed without addition of albumin and comprising the following excipients of composition in addition to factor VIII: from 4% to 10% of filling agent taken among group consisting of mannitol, glycine and alanine; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance about between 6 and 8. Alternatively, the composition can comprise from 2% to 6% of hydroxyethylstarch; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance between 6 and 8. In additional variant of realization of invention the composition can comprise: from 300 mM to 500 mM of NaCl, from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose and arginine; from 1 mM to 5 mM of calcium salt, and buffer agent. The composition provides stability in the absence of albumin or other proteins.
EFFECT: valuable properties of compositions.
35 cl, 11 tbl, 7 ex
SUBSTANCE: according to the present invention pharmacological composition is in form of quick soluble granules, containing particles of at least two different carrier materials with surface being at least partially coated with at least one layer, comprising 50-120 wt.pts, preferably, 60-100 wt.pts of at least one active ingredient based on 100 wt.pts of carrier material. Active ingredient is preferably insoluble or low soluble substance such as amino acids or antioxidants. The first carrier material comprises about 50-80 wt.% of total carrier material and has bulk density of 58-100 g/ml, preferably of 63-90 g/100 ml. The second carrier material has bulk density of 30-55 g/100 ml, preferably of 33-50 g/100 ml. Granulated composition has high solubility, high content of active ingredient and little amount of excipients. Further composition is quickly suspended in little amount of water, doesn't form agglomerates for a long time, ant has acceptable taste.
EFFECT: pharmacological composition in form of quick soluble granules with improved quality.
22 cl, 4 tbl, 5 ex