Application of carboxymethylcellulose for control of pressability and hardening time of compositions, containing one or more ceramic materials

FIELD: chemistry.

SUBSTANCE: invention relates to a set, containing calcium sulphate hemihydrates, pressed particles of calcium sulphate dehydrate, additionally containing one or more therapeutically, preventively and/or diagnostically active substances, and sodium-carboxymethylcellulose (Na-CMC) and a water medium, including water. The ratio R of sodium-carboxymethylcellulose and calcium sulphate in the set constitutes from 0.1 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulphate to 8 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulphate. When mixed, the said components of the set form a bioresorbable ceramic composition. The invention also relates to the application of the set for the treatment of a disease or condition, associated with prostate. Also claimed is a composition ready for application in the form of a paste for introduction to a patient during the time period from 5 minutes to 1 hour before hardening, obtained by mixing the components of the set. Also claimed are: a hardened composition and a method of obtaining the hardened composition or the composition ready for application.

EFFECT: control of the time of the set and composition hardening.

13 cl, 12 tbl, 9 ex

 

The technical field to which the invention relates

The present invention relates to the use of carboxymethyl cellulose, in particular sodium carboxymethylcellulose or other salts of alkaline or alkaline earth metals and carboxymethyl cellulose, for controlling the time of curing of compositions containing one or more bioassays ceramic materials, in particular hydratherapy calcium sulfate, in order to facilitate the availability of ready-to-use compositions to be placed in the body by injection. In particular, the present invention provides compositions having a specific range of ratios by weight of the amount of carboxymethyl cellulose (presented in the form of sodium carboxymethylcellulose) and the number Gidrodinamika bioreserves ceramic material (presented in the form of hemihydrate calcium sulphate) in ready-to-use compositions. Moreover, the present invention provides compositions having properties suitable for operation of compositions before, during and after administration to a mammal, such as man. So, before the introduction of ready-to-use compositions can be easily prepared by mixing a composition containing one or more bioassays ceramic materials, with liquid containing sodium Carbo is sematically. Received ready-to-use composition should have a viscosity that is neither too high (which can lead to the fact that the resulting ready-to-use composition cannot be administered by injection) or too low (which may cause difficulty in obtaining a homogeneous dispersion Gidrodinamika bioreserves ceramic material), i.e., the use of sodium-carboxymethylcellulose gives sufficient viscosity, excellent dispersion and, moreover, leads to such time of solidification, which is balanced between the need for handling ready-to-use composition as a liquid composition prior to introduction and relatively rapid solidification after as ready-to-use composition was put in a destination and, if necessary, was properly distributed at the destination. After the introduction of the ready to use composition to harden to such an extent that the composition will remain at the injection site injection. Too long solidification time can lead to the fact that the song is uncontrolled distributed. Due to an internal pressure which is formed in the body, which introduced the ready-to-use composition according to the present invention, it is necessary to have a relatively short time for which verdiane composition to avoid displacement of the composition, for example, out of the hole/place of introduction.

The level of technology

Ceramic materials for many years been used for local application, for example, as a material for filling cavities in the bones in the clinic or in various forms of drug-delivery systems for controlled therapy and/or therapy with targeted delivery. Many of the used ceramic materials are bioreserves (or biorazlagaemykh), and have been described various ceramic materials on the basis of calcium phosphate or calcium sulfate. These ceramic materials are often referred to as gidriruemyi or gidratiruyuschimi ceramic materials due to their ability to react chemically with water for hardening by formation of hydrates. Some hydratherapie ceramic materials are stable in a biological environment, such as hydroxyapatite or calcium silicates.

Bioreserves ceramic materials have many favorable properties for use as implants or systems controlled release pharmaceutical compositions in comparison with, for example, polymers (such as polylactic acid or poly(lacto-co-glycolic acid)) because of their biocompatibility and bioreserves. In General bioreserves eroticheskie materials are non-toxic and is based on the molecules which in nature are found in living mammalian tissues. Calcium sulfate is particularly attractive because it is biodegradable and biocompatible material, i.e. it disappears over time.

In most cases, the composition is prepared by mixing Gidrodinamika ceramic material, such as calcium sulfate, and water, for example, drug or bone matrix to obtain a paste, which is implanted as such or in solid form. To minimize surgical intervention is desirable injecting the paste into the body or the body through a catheter of small size. However, the mixing of calcium sulfate and water leads to rapid onset of solidification, which reduces the time during which the surgeon must use the paste before it hardens and creates practical difficulties with the introduction of the paste through the catheter to the small size. To minimize surgical intervention is desirable to obtain a composition that has a prolonged solidification time and improved vydavlivaete of the catheter of small size, thus the composition can be implanted in the body without surgery or only with minimal surgery.

The present invention is to provide a composition, injectable che the ez small catheter into the patient's body, and to this composition had a prolonged curing time.

The authors of this invention have found that this is achieved by applying compositions containing aqueous solutions of carboxymethyl cellulose, namely, sodium salt (Na-CMC), hemihydrate calcium sulphate (CaSO4∙1/2H2O) and possibly particles of the dihydrate of calcium sulfate (CaSO4∙2H2O).

Na-CMC is often used as thickeners, binders, stabilizers, and suspending means in various forms of compositions. However, the authors of this invention have found that it is possible to control the three important parameters of the composition by small changes in the concentration of Na-CMC; namely, the mixing of the powder of the hemihydrate of calcium sulfate with water; vydavlivaete the resulting paste through a thin needle, a catheter and/or biopsy cannula and the slow time of solidification of this paste.

An important feature of this arrangement is that Na-CMC presents in aqueous form prior to its mixing with CaSO4∙1/2H2O. As Na-CMC slowly soluble in water, aqueous form can be obtained by mixing Na-CMC with water, stirring the mixture for several hours. An aqueous solution of completely dissolved Na-CMC is then mixed with CaSO4∙1/2H2O immediately before applying the resulting paste.Perhaps an aqueous solution of Na-CMC can be sterilized by autoclaving or possibly also by sterile filtration, if the viscosity is too high. Na-CMC is completely dissolved in the medium when the received transparent, clear, thermodynamically stable solution.

In addition, Na-CMC can also be supplied in dry form, preferably in the form of a thin film or lyophilized powder. In any case, if you use the Na-CMC, carboxymethylcellulose or other, is important to ensure that the carboxymethylcellulose relatively quickly dissolves. Normal Na-CMC has a relatively low dissolution rate, which means that the properties of Na-CMC may not be used for 5-15 minutes, available from receipt of the ready to use composition before the injection and solidification of the composition. Accordingly, if using carboxymethyl cellulose in the dry form, it must be either in the form of fine powder or lyophilized powder or in the form of a thin film. Another possibility could be the introduction of surfactant in the composition, ensuring that the substance did not have any negative impact on ready-to-use composition.

By doing this, the authors of this invention have reached composition, which allowed them kontrolirovat solidification and also made possible the injection through a thin needle of the syringe. Moreover, it was found that this composition retains acceptable Miscibility. In addition, the composition does not require any addition of acid or acidic solution, such as aqueous acetic acid, to control the solidification time.

In the US 2006/205652 disclosed composition in the form of a paste, gel or liquid for delivery of synthetic analogues heparinase factor for recovery of the bones and cartilage. In some aspects of the invention the composition may contain a component of calcium sulfate and Na-CMC (gelling agent). However, the composition with calcium sulfate is disclosed in the examples in degidratirutego form, used as the dihydrate of calcium sulfate. Moreover, in the disclosed examples, the surfactant (Pluronic) used in solutions of Na-CMC.

EP1208850 reveals pasta with a slow release enhancing osteogenesis, which contains the amplifier osteogenesis, calcium component and the tool, increasing the viscosity. Not shown any examples of ready-to-use composition comprising hydratherapy ceramic material of calcium sulfate (e.g., hemihydrate calcium sulphate) and Na-CMC.

In WO 2007/104549 disclosed high-density composition containing, for example, the calcium sulfate in the form of the hemihydrate of calcium sulfate and gelling or contributing to the swelling of the medium is in, which may include Na-CMC, for the treatment of benign prostatic hyperplasia. However, not shown any examples of ready-to-use composition comprising hydratherapy ceramic material calcium sulphate with Na-CMC, there are only examples where the methylcellulose is used in conjunction with acetic acid.

In WO 2004/000334 described replacement bone marrow transplantation composition, which may contain calcium sulphate, solution mixing, such as sterile water, and plasticizing material. However, examples of a combination of Na-CMC and calcium sulphate.

JP56026756 describes and discusses a method of producing alpha hemihydrate of gypsum containing carboxymethylcellulose, under high pressure, resulting in dry hemihydrate alpha gypsum. Open the solidification time is about 1 hour or more, and, moreover, in order JP56026756 is the provision of a plaster structures with lightweight structures (porous bubble structure) with a very high stability in water of the order of 6 months or more. However, no disclosure presents a method or composition according to the present invention, since the present invention is not getting dry CaSO4∙1/2H2O containing carboxymethylcellulose.

So, as far as we know the car is am this invention, no one has described a composition comprising Na-CMC, the hemihydrate of calcium sulphate and possibly sulfate dihydrate, which by a certain increase of the concentration of Na-CMC in the composition gives good mixing of the powder of the hemihydrate of calcium sulfate with an aqueous medium (e.g. water), acceptable vydavlivaete the resulting paste through a thin needle and a sufficient reduction of the time of solidification of the paste, allowing the processing and the introduction of ready-to-use composition without unnecessary prolongation of solidification in order to avoid inappropriate distribution or elimination of the introduction.

Detailed description of the invention

The present invention describes a pharmaceutical composition containing a mixture of calcium sulfate and carboxymethyl cellulose, which leads to prolonged time of solidification, and at the same time are able to maintain acceptable Miscibility obtained paste as acceptable vydavlivaete through a syringe with a fine needle.

In particular, the composition comprises a hemihydrate of calcium sulfate and sodium carboxymethyl cellulose (Na-CMC). The authors of this invention have found that by making small changes in the number added to such compositions of Na-CMC is possible to control the processes of solidification of the hemihydrate of calcium sulfate (i.e., CaSO4∙1/2H2/sub> O → CaSO4∙2H2O). Moreover, the viscosity is increased by adding Na-CMC, and it improves vydavlivaete from a syringe with needle/cannula of small size.

It also seems possible that other salts of carboxymethyl cellulose can be used in the present invention, such as, for example, salts of alkali metals (Li, K, Na) or alkaline earth metals (Ca, Mg, Sr) carboxymethylcellulose, ensuring their solubility and suitability for injection to a mammal, such as man.

Moreover, the authors of the present invention, it is surprisingly found that the composition containing the fully hydrated hemihydrate of calcium sulfate (i.e., the dihydrate of calcium sulfate and Na-CMC is firmly squeezing through the hole of the syringe may have a cannula of this size, as, for example, 6G, 8G, 9G, 10G, 11G, 12G, 13G, 14G, 16G, 19G, 20G, 21G, 22G, 23G, 24G and 26G. This means that Na-CMC acts not only as a hardening retarder, a viscosity modifier, but also has a dispersing effect, in which Na-CMC is particularly useful as an additive in, for example, therapeutic use of the composition through the cannula, or thin tube. In the context of medical applications, this is particularly important, because this feature of Na-CMC allows the introduction of a precise amount of a composition without the risk of interruption of the procedure due to partially the CSOs solidification of the composition, leading to interrupted introduction.

The solidification time and vydavlivaete are two very important parameters for the surgeon when implanting the above composition in the body of the subject. By changing the number of Na-CMC in the form of an aqueous solution, is added to the composition for the surgeon it is possible to change the process of solidification in the appropriate time frame (e.g., 5-15 minutes) that allows you to have enough time for a proper introduction of the composition before it becomes solid. At the same time is the possible introduction of the composition through a thin needle (for example, 15G or thinner) due to vydavlivaete composition. Thus, vydavlivaete allows the surgeon to introduce the composition into the body or the body without surgical intervention or with minimal invasive surgery. Because the time to 100% of solidification can be difficult to measure, the authors of this invention have introduced a measure for vydavlivaete in order to determine the properties of the curing composition according to the invention. So, in this context, in some cases, the solidification time is the time when the composition can no longer be squeezed out of a specific syringe. In other cases, the mixture can not be cured, but can not be squeezed out. The test described here.

An additional advantage of using water R as the sites of Na-CMC (or other salts of carboxymethyl cellulose, see above) as a solvent for the hemihydrate of calcium sulfate is ensuring good dispersion, which affects the Miscibility of hemihydrate of calcium sulfate with water.

The authors of this invention have found that the amount of carboxymethyl cellulose is important for the above characteristics, especially, what is possible to achieve the right balance of time of solidification, vydavlivaete, dispersion and viscosity when the carboxymethyl cellulose or its salt, namely Na-CMC) is used in a narrow range of concentrations, expressed as the ratio by weight between carboxymethylcellulose (calculated as Na-CMC) and the hemihydrate of calcium sulfate in the final ready-to-use composition.

Also a mixture of sodium carboxymethylcellulose and methylcellulose are of interest according to the invention. Addition of methylcellulose were made for increasing the viscosity of the solvent without affecting the time vydavlivaete.

In this context, the term "ready-to-use composition" is used to denote a composition obtained by mixing a first component containing composition with gidratirutmi calcium sulfate, namely the hemihydrate of calcium sulphate, with the second component containing an aqueous solution of carboxymethyl cellulose (or a salt thereof, namely, Na-CMC). G is preset to the application of the composition is in liquid form, i.e. it is a transitional form, where hydratherapy calcium sulfate takes water from the aqueous environment into hemisulfate in a completely or partially hydrated calcium sulfate (i.e., fully hydrated calcium sulfate dihydrate is calcium sulphate), thus transforming the composition of the liquid composition in the solid composition. A transitional form is a paste, i.e., viscous suspension. However, the existence of ready-to-use composition in liquid form must be continued for a sufficient period of time, which will allow medical personnel to ensure proper mixing of the two components and allows the introduction of all ready-to-use composition for at least about 5 up to about 15 minutes.

On the other hand, the solidification time is ready-to-use composition should not be too long. It is important that the ready to use composition has reached its destination in the body (for example, by direct injection into the target organ) and in this place hardens. Another important aspect is that if the solidification time is too long, there is a risk that the composition begins to flow from the space/hole injection, which will lead to inaccurate dosing of the active ingredient. A certain spreading of the composition of the target location may be desirable for purposes of distribution of the composition in the target organ, but if the solidification time is too long, increasing the risk of unwanted purification of the target organ and the possible transfer of the composition into unwanted parts of the body, where it will harden.

The dihydrate of calcium sulfate acts as an accelerator of hydration (hardening) of hemihydrate calcium sulphate. Thus, compositions containing a mixture of hemihydrate sulfate and calcium sulfate dihydrate calcium, harden very quickly and effectively slow down if necessary. This is an important aspect of the present invention, since some of the compositions disclosed here, are pharmaceutically active ingredients, mixed with particles of the dihydrate of calcium sulfate.

In this context, a suitable curing time is from about 5 minutes to about 15 minutes, or longer, such as, for example, from about 5 minutes to about 20 minutes. In certain cases, depending on the target body, a longer curing time may be appropriate. However, it is not expected that the solidification time is more than 1 hour is appropriate. Thus, the solidification time can be from about 5 minutes to about 25 minutes, such as from about 5 minutes to about 30 minutes, such as from about 5 minutes to about 35 minutes, such as from about 5 minutes to about 40 mine is, such as from about 5 minutes to about 45 minutes, such as from about 5 minutes to about 50 minutes, or such as from about 5 minutes to about 1 hour after mixing the above components (i.e. hemisulfate calcium, Na-carboxymethyl cellulose, dissolved in water, and the dihydrate of calcium sulfate). A critical moment in time comes when ready to use composition can no longer be delivered through 15G syringe with needle or needle other suitable size, such as 17G (17G = 1.5 mm outer diameter and 1.3 mm inner diameter) or 18G (18G = 1.3 mm outer diameter and 1.0 mm inner diameter). Needles of different sizes may be set in the application of the compositions of the present invention, are such as, for example, 6G, 8G, 9G, 10G, 11G, 12G, 13G, 14G, 16G, 19G, 2OG, 21G, 22G, 23G, 24G and 26G. As discussed here previously, vydavlivaete may differ from the time of solidification, as ready-to-use paste can not be cured, but not to be extruded from a syringe. Thus, in the present context, the solidification time is determined by measuring the time when the ready-to-use composition may not be delivered through a selected hole of the syringe (as described here).

In this context, the term "hydrating" refers to the chemical process prewash the tion, for example, the hemihydrate of calcium sulphate dehydrate calcium sulphate. The process of hydration usually starts adding water environment to the hemihydrate of calcium sulfate and depends on the amount of added water and the amount of hemihydrate calcium sulphate, hydrating can be partial or complete. In this context, the term "partially hydrated" is understood as defining a ceramic material, where the amount of added water environment corresponds to at least about 20% of the stoichiometric amount required for hydration of one or more Gidrodinamika and bioreserves ceramic material, whereas the term "fully hydrated" is understood as defining a ceramic material, where the amount of added water environment corresponds to at most about 90%, such as, for example, at most about 95%, at most about 99% or at most about 100% of the stoichiometric amount, necessary for hydration of one or more Gidrodinamika and bioreserves ceramic material.

Vydavlivaete

In the present context the term "vydavlivaete" composition refers to a composition in the syringe is able to pass through the bore of the syringe, possibly with the cannula or needle of this size, as, for example, 6G, 8G, 9G, 10G,11G, 12G, 13G, 14G, 16G, 19G, 20G, 21G, 22G, 23G, 24G, 25G or 26G or flexible tube. In this context, vydavlivaete tested by mixing an aqueous solution of Na-CMC and CaSO4(hemihydrate possibly together with dehydrate, which can be further compectitive) in amounts as described herein, the premises of the resulting mixture in a plastic syringe and extrusion of the mixture/suspension arm. Mixture/suspension is squeezing when there is no obstruction or difficulties impeding the passage of the mixture through the opening when the average power in such a way that it allows the professional practitioner to squeeze the mixture with your hand.

Accordingly, there is described the mixing amount of an aqueous solution of Na-CMC with dry calcium sulfate-hemihydrate, possibly containing the dihydrate of calcium sulfate in the form of powder and in the form of particles) in the range from about 0.1 mg to 8 mg Na-CMC/g CaSO4such as, for example, 0.1 to 6 mg Na-CMC/g CaSO4, 0.1 to 4 mg Na-CMC/g CaSO4, 0.1 to 3 mg Na-CMC/g CaSO4, 0.1 to 2 mg Na-CMC/g CaSO4, 0,1-1 mg Na-CMC/g CaSO4or 0.1-0.5 mg Na-CMC/g CaSO4or Roptas described below, is then possible to vigorous stirring with a spatula and further processing the mixture with ultrasound in a water bath at a temperature of about 40°C for less than 1 minute. If the mixture meets the criteria, as already indicated above, the mixture was treated the ü as extruding, if could be extruded through 17G cannula.

Moreover, in the present context, the term "time of vydavlivaete" means the time during which the ready-to-use composition is squeezing through the hole, for example, syringe, possibly with a cannula, a needle or a flexible tube. In the compositions, as described above, the time vydavlivaete is from about 5 to about 15 minutes, or longer, such as from about 5 to about 20 minutes, such as from about 5 to about 25 minutes, such as from about 5 to about 30 minutes, such as from about 5 to about 35 minutes, such as from about 5 to about 40 minutes, such as from about 5 to about 45 minutes, as, for example, from about 5 to about 50 minutes, or from about 5 minutes to about 1 hour.

The degree of dispersion/mixing

In the present context the terms "degree of dispersion", "dispersion" or "mixing" means the ability of two or more components to be dispersible with the other to form a dispersion or suspension. In the present invention, the calcium sulfate is usually used in powder form prior to mixing with the aqueous solution of Na-CMC. The high degree of dispersion leads to a good mixing/contact between the two components with few or no lumps formed in finals is m solution, and, thus, indicates the absence or low level of agglomeration. This also means that after mixing the aqueous solution of Na-CMC and calcium sulphate will be very low deposition of any particles, and thus, the mixture remains homogeneous from the time of mixing the ingredients until the mixture hardens. When used in medicine, when the mixture is injected through the syringe, it is important that high dispersion will lead to a lack of solidification at the bottom of the syringe, which leads to clogging of the mixture. Moreover, one effect of high dispersion in this case is that the amount of water can be reduced, while together with it will lead to supple/extruding a homogeneous suspension.

Accordingly, there is described the mixing amount of an aqueous solution of Na-CMC with dry calcium sulfate-hemihydrate, possibly containing the dihydrate of calcium sulfate, both in powder form and in the form of particles) in the range from about 0.1 mg to 8 mg Na-CMC/g CaSO4such as, for example, 0.1 to 6 mg Na-CMC/g CaSO4, 0.1 to 4 mg Na-CMC/g CaSO4, 0.1 to 3 mg Na-CMC/g CaSO4, 0.1 to 2 mg Na-CMC/g CaSO4, 0,1-1 mg Na-CMC/g CaSO4or 0.1-0.5 mg Na-CMC/g CaSO4or Roptas described below, is then possible to vigorous stirring with a spatula and further processing the mixture by ultrasound on Wodan the second bath at a temperature of about 40°C for less than 1 minute. If the resulting mixture was not observed visible precipitation, the mixture was considered as having a suitable dispersion according to the invention.

Curing and hardening

In the context of this description, the terms ”curing time”, "time setting", "duration hardening” or "curing time" means the period of time from the moment the composition of the invention is originally obtained before they were fully gidratirovana or hardened. In this context, the solidification time is meant as a time, starting with mixing the ingredients of the composition, before mentioned mixture forms a practically non-rigid body.

Accordingly, by mixing an aqueous solution of Na-CMC with dry calcium sulfate-hemihydrate, possibly containing the dihydrate of calcium sulfate in the form of powder and in the form of particles) in the range from about 0.1 mg to 8 mg Na-CMC/g CaSO4such as, for example, 0.1 to 6 mg Na-CMC/g CaSO4, 0.1 to 4 mg Na-CMC/g CaSO4, 0.1 to 3 mg Na-CMC/g CaSO4, 0.1 to 2 mg Na-CMC/g CaSO4, 0,1-1 mg Na-CMC/g CaSO4or 0.1-0.5 mg Na-CMC/g CaSO4or Roptas described below, it is possible vigorous stirring with a spatula and further processing the mixture with ultrasound in a water bath at a temperature of about 40°C for less than 1 minute, the time during interval mixing vysheukazannoe the x ingredients before as the mixture forms a virtually undistorted body, is the solidification time.

Viscosity

The term "viscosity" refers to the designation of the dynamic or absolute viscosity (at 20°C and normal pressure), which is a measure of the resistance of the liquid, which is subjected to deformation or shear stress or tensile strength. Thus, the "viscosity" describes the internal resistance to fluid flow and can be considered a measure of hydrodynamic friction. Thus, the less viscous substance is, the higher the lightness of its movement (fluidity). In this context, sufficient adhesiveness approximately 10-10000 mPas, such as, for example, 20-9000 mPas, such as about 30-8000 mPas, such as about 40-7000 mPas, such as about 50-6000 mPas, such as about 70-5000 mPas, such as about 90-4000 mPas, for example, such as approximately 100-3000 mPas or about 10 mPas, or about 20 mPas, or about 30 mPas, or about 40 mPas, or about 50 mPas, or between the viscosity of pure deionized water and the viscosity of the concrete used party/type Na-CMC, such as, for example, from about 1 mPas to 20 mPas, such as about 2 mPas, such as about 3 mPas, such as about 4 mPas, such as about 5 mPas, such as about 6 mas, such as about 7 mPas, such as about 10 mPas, approximately 13 mPas, approximately 15 mPas, about 20 mPas.

Accordingly, by mixing an aqueous solution of Na-CMC with dry calcium sulfate-hemihydrate, possibly containing the dihydrate of calcium sulfate, both in powder form and in the form of particles) in the range from about 0.1 mg to 8 mg Na-CMC/g CaSO4such as, for example, 0.1 to 6 mg Na-CMC/g CaSO4, 0.1 to 4 mg Na-CMC/g CaSO4, 0.1 to 3 mg Na-CMC/g CaSO4, 0.1 to 2 mg Na-CMC/g CaSO4, 0,1-1 mg Na-CMC/g CaSO4or 0.1-0.5 mg Na-CMC/g CaSO4or Roptas described below, it is possible vigorous stirring with a spatula and further processing the mixture with ultrasound in a water bath at a temperature of about 40°C for less than 1 minute, the viscosity of the mixture is, for example, about 10-10000 mPas, such as 20-9000 mPas, as, for example, about 30-8000 mPas, as, for example, about 40-7000 mPas, as, for example, about 50-6000 mPas, as, for example, about 70-5000 mPas, as, for example, about 90-4000 mPas, as, for example, approximately 100-3000 mPas or about 10 mPas, or about 20 mPas, or about 30 mPas, or about 40 mPas, or about 50 mPas, or between the viscosity of pure deionized water and the viscosity of the concrete used party/type Na-CMC.

In this context, the term "bioassay" refers to a material that can be dissolved and/or destroyed in the body fluids or organs or any Lieb is otherwise removed from the human body. It seems that the implanted/injected composition dissolved since the introduction within about 2-3 days, or up to about 1 week, or up to about 2 weeks to about 3 weeks to about 1 month to about 3 months to about 6 months to about 1 year. The process/progress of destruction can be observed by standard methods, such as ultrasound, palpation, x-ray or magnetic resonance techniques.

In the present context the term "carboxymethyl cellulose" includes salts of carboxymethylcellulose, including salts of alkaline and alkaline earth metals, and such salts, which have been approved or may be approved for internal use in mammals, including humans. Sodium carboxymethylcellulose, also referred to here Na-CMC was found as suitable salt, but it is assumed that other salts of carboxymethyl cellulose can have similar effects. Moreover, carboxymethyl cellulose can be obtained in different viscosity grades (low, medium, high). As is clear from the examples, the optimal ratio, Roptslightly differs depending on the grades of viscosity. Sufficient adhesiveness Na-CMC (dynamic or absolute viscosity (at 20°C and normal pressure)) is p is IMEMO 10-10000 mPas, for example, such as 20-9000 mPas, such as about 30-8000 mPas, such as about 40-7000 mPas, such as about 50-6000 mPas, such as about 70-5000 mPas, such as about 90-4000 mPas, for example, such as approximately 100-3000 mPas or about 10 mPas, or about 20 mPas, or about 30 mPas, or about 40 mPas, or about 50 mPas or between the viscosity of pure deionized water and the viscosity of the concrete used by party Na-CMC, such as, for example, from about 1 mPas to 20 mPas, such as about 2 mPas, such as about 3 mPas, such as about 4 mPas, such as about 5 mPas, such as approximately 6 mPas, such as about 7 mPas, such as about 10 mPas, approximately 13 mPas, approximately 15 mPas, about 20 mPas.

The optimal ratio, Roptis from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 10 mg, such as from about 0.1 mg to about 7 mg, as, for example, from about 0.1 mg to about 5 mg, such as from about 0.1 mg to about 3 mg, where Roptdefined as the ratio between the amount of carboxymethylcellulose (calculated as Na-CMC) in aqueous solution and the total amount of calcium sulfate (hemihydrate possible with the dihydrate of calcium sulfate) present in ready-to-use composition.

In this context, a narrow window of concentrations for which the actual content of carboxymethyl cellulose in ready-to-use composition, which provides suitable properties with respect to vydavlivaete, dispersion, viscosity and solidification, is expressed as the ratio, R, between the amount of carboxymethylcellulose (calculated as Na-CMC) and the number of hemihydrate calcium sulphate contained in the ready to use composition.

In accordance with the foregoing, the present invention provides a new use of carboxymethyl cellulose, namely, Na-CMC, for controlling the time of curing of compositions containing hydratherapie ceramic materials, namely, the hemihydrate of calcium sulfate.

The present invention also provides methods and compositions that do not include surfactants (cationic, anionic or nonionic) or detergenty compounds such as ammonium salts, sulfonates, fatty acids and their salts, long-chain alkylamine salt derivatives of acrylic acid, poloxamer, such as pluronic and its derivatives, etc. According to the present invention is unwanted/unneeded property bubble in ready-to-use compositions, foaming, as you know, is stabilized by adding detergenty compounds, as mentioned above.

Moreover, the present invention provides ready-to-use composition comprising hydratherapy slabs, the second material, namely, the hemihydrate of calcium sulfate, carboxymethylcellulose, namely, Na-CMC, where the weight ratio, R, between carboxymethylcellulose (namely Na-CMC) and gidratirutmi ceramic material (namely the hemihydrate calcium sulphate) is from about 0.1 mg carboxymethylcellulose (calculated as Na-CMC)/g of dihydrate of calcium sulfate to about 5 mg of carboxymethylcellulose (calculated as Na-CMC)/g of dihydrate of calcium sulfate.

Ready-to-use composition is obtained by mixing the aqueous medium containing carboxymethylcellulose, with a composition comprising or consisting of hemihydrate calcium sulphate, where the paste thus obtained, which is in liquid form within 5-15 minutes and then hardens. Aqueous medium is usually water, and the share of carboxymethyl cellulose is selected so that the number of carboxymethyl cellulose in the final ready-to-use composition is within the limits stated herein (i.e. the ratio between carboxymethyl cellulose and the hemihydrate of calcium sulfate corresponds to from 0.1 mg Na-CMC/g hemihydrate of calcium sulfate to 5 mg Na-CMC/g hemihydrate calcium sulphate), and the amount of water should at least match the amount of water required to convert the hemihydrate of calcium sulphate dehydrate calcium sulphate.

Stechiometric and 1,000 g CaSO 4·1/2H2O (0,007 mol) requires 0,186 g of water (1,5·to 0.007 mol), to be fully transformed in CaSO4·2H2O, i.e., 1,186 g (to 0.007 mol). In order to obtain an acceptable consistency of the final paste, the amount of water per gram of the hemihydrate of calcium sulfate should not exceed 1.0 g, i.e., to 1.0 ml of a Suitable range of concentrations of Na-CMC in water is 0.05 to 1.0% wt./mass., more preferably 0.2 to 0.4 wt. -%/mass. The actual concentration of Na-CMC depends on the specific composition of powder mixture of calcium sulfate, and the molecular weight used Na-CMC.

According to the invention one or more biorelativity hydroceramic ceramic materials can be selected from several biorelativity and biocompatible hydroceramic ceramic material, the ceramic material may be UN-hydrated or palpitations or partially gidratirovannym. Suitable hydratherapie ceramic materials for use in compositions according to the invention can be selected from the group consisting of calcium sulfate, such as, for example, α-calcium sulfate, β-calcium sulfate; the hemihydrate of calcium sulphate; the dihydrate of calcium sulfate (i.e. palpitations form or partially hydrated form), or any combinations thereof.

In a preferred embodiment of the invention one or more biora sashimi and hydroceramic ceramic materials is the hemihydrate of calcium sulfate.

The hemihydrate of calcium sulfate is preferred in the form of a powder, for example with an average particle size of at most about 75 microns, for example at most about 50 microns, at most about 25 microns or at most about 10 microns. Alternatively, the powder may slagalica of two (or more) fractions according to the size of the granules; for example, one with beads <10 μm and one with an average particle size of at most about 75 microns, for example at most about 50 microns, at most about 25 microns or at most about 10 microns.

However, in the preferred embodiment, calcicola part of the composition may, in addition to the above, one or more fractions of granules of the hemihydrate of calcium sulfate to contain nepressovannaya and/or compressed particles of dihydrate of calcium sulfate. Thus, the composition can contain one part nepressovannaya and/or compressed particles of dihydrate of calcium sulfate and one part of the hemihydrate of calcium sulfate. Alternatively, the composition may include one piece of compressed particles of dihydrate of calcium sulfate and at least two parts of the hemihydrate of calcium sulfate, for example, three parts, four parts, or five parts of the hemihydrate of calcium sulfate.

The presence nepressovannaya and/or compressed particles of dihydrate of calcium sulfate in the composition with hemihydrate the calcium sulphate leads to initiation (acceleration) of the processes of solidification, because the crystals of the dihydrate of calcium sulfate acts as a Central nucleation in the conversion of the hemihydrate to the dihydrate. Thus, the presence of a dihydrate of calcium sulfate in the initial composition sets even shorter solidification time.

Compressed particles of dihydrate of calcium sulfate can be obtained when the hemihydrate of calcium sulfate is subjected to external applied pressure during the hydration process. External pressure applied in any suitable way, for example, by mechanical or hydraulic means. Principles of obtaining a very dense ceramic materials by hydration under pressure can be used for any Gidrodinamika ceramic material. This method does not require high temperature to produce a dense structure, as in the normal processes of sintering.

Alternative particle can be vysokoplotnoy particles of ceramic material, as described in international publication WO 2007/104549 in which the hemihydrate of calcium sulfate was subjected to the action of an external applied pressure, such as compression, in combination with hydration under pressure. In this way the seal is at the same time, when the hydration of ceramic material, with the aim of obtaining vysokoplotnoy the Noah patterns. Compressed particles dihydrate calcium sulphate obtained when the external applied pressure, such as compression, in combination with at least partially gidratirovannym ceramic material, resulting in pore size and porosity at least partly hydrated ceramic material is reduced, which leads to a highly compact structure of the particles. Thus, compaction/compression ratio is held at the same time as the hydration of hemihydrate calcium sulphate, with the aim of obtaining vysokoplotnoy patterns. Received vysokoplotnoy structure (exemplifies calcium sulphate) is characterized by typical pore size, as, for example, at most about 100 nm, such as at most about 75 nm, at most about 50 nm, or at most about 10 nm; and porosity, as, for example, at most about 10%, such as at most about 5%, at most about 3%, at most about 2% or at most about 1%. For example, hydration with an applied pressure of at least 100 MPa and preferably 200 MPa or more reduces the porosity below 10% and reduces pore size to a size below 100 nm.

Accordingly, various methods can be used for the application of external pressure, such as a unidirectional pressing and isostatic pressing (th is the mesh or cold). Cold isostatic pressing, Cold Isostatic Pressing, CIP) applied to preparirovaniem particles of calcium sulphate, containing the active substance was found as an effective way of obtaining vysokonapolnennyh and homogeneous particles. For optimal compaction of the particles of calcium sulfate can be covered, for example, a capsule (e.g., elastic cylinder) during pressing. Normal applied pressure must be at least 50 MPa, for example at least about 100 MPa, at least about 200 MPa, preferably 300 MPa or higher. However, the required pressure depends on the pressure device. Thus, the above-mentioned pressures are suitable for use in the CIP, as in the case of, for example, a constant unidirectional pressing usually applies a higher pressure, as, for example, about 200 MPa, preferably about 300 MPa or more, about 400 MPa or more, or about 500 MPa or more. The method described in detail in WO 2007/104549 included in this application by reference.

Compressed particles of dihydrate of calcium sulfate can have a particle size of from about 50-600 μm, such as from about 100-500, from about 100-400 or from about 125-300 μm. It is additionally assumed that the composition may contain one or more fractions according to size pressed ASTIC dihydrate calcium sulphate.

Both powder hemihydrate of calcium sulfate and dihydrate calcium sulphate, as well as compressed particles of dihydrate of calcium sulfate or an aqueous solution of Na-CMC, can contain one or more therapeutically, prophylactically and/or diagnostically active substance. The active substance may include, but are not limited to, androgens or their derivatives (e.g., testosterone), antiandrogens (cyproterone, flutamide, 2-hydroxyflutamide, bikalutamid, nilutamide) or derivatives thereof, estrogens or their derivatives, antiestrogens (for example tamoxifen, toremifene), or their derivatives, a gestagen or their derivatives, antigestagen or their derivatives, oligonucleotides, Progestogens or their derivatives, gonadotropin-releasing hormone or its analogues and derivatives, inhibitors of the synthesis of enzymes of the adrenal glands and the prostate (such as inhibitors of α-reductase), proteins membrane release and membrane transport (such as PSC 833, verapamil), and cytotoxic other means, modulators of the immune system and inhibitors of angiogenesis by themselves or in combinations.

Preferably, the active substance is selected from flutamide, 2-hydroxyflutamide and/or bikalutamida, including combinations thereof, and any other antiandrogen.

Download the drug in the composition, i.e. the amount of active substance of the composition, may be varied within wide limits. The active substance may be presented in aqueous solution, which is added to the calcium sulfate, or competitivenes or nekompensirovanna powder of calcium sulfate as the hemihydrate and dihydrate. The concentration of active substance in ready-to-use composition according to the present invention can be in the range of from about 0.01% wt./mass. to about 75% wt./mass., for example, from about 0.01% wt./mass. to about 50 wt%./mass., from about 0.01% wt./mass. up to about 40% wt./mass., from about 0.05% wt./mass. up to about 30% wt./mass., from about 0.05% wt./mass. up to about 20% wt./mass. or from about 0.1% wt./mass. up to about 10% wt./mass. So, some of the active substance can be present in an amount of up to 75% wt./mass. in the powder of the hemihydrate of calcium sulfate and/or particles of the dihydrate of calcium sulfate or an aqueous solution, whereas the active substance may also, depending on the nature and capacity of the active substance of interest to be represented in the composition in much smaller quantities.

By mixing the hemihydrate of calcium sulfate and/or compressed particles of dihydrate of calcium sulphate with Na-CMC results in paste, which preferably has a prolonged solidification time, right vydavlivaete and good Vara is rnost.

Na-CMC is an anionic water-soluble polymer obtained by reaction of cellulose with monochloracetate sodium. The polymer is characterized by its molecular weight, which affects the viscosity, when dissolved in water, and the degree of zamestnanosti that affects thixotropic and adsorption properties of the resulting solution. The degree of zamestnanosti, or DS, is the average measure of the amount of sodium carboxymethyl groups (-CH2-COONa) associated with hydroxyl groups anhydroglucose units, which form a cellulose chain. Na-CMC is soluble in cold and hot water at a pH above about 4. Na-CMC can be obtained from several commercial manufacturers, including non-limiting examples C9481 from Sigma-Aldrich and Blanose 7LF PH, Blanose 7M1F PH, Blanose 7MF PH, Blanose 7M8SF, Blanose 9M31F, Blanose 9M31CF, Blanose 9M31XF PH, Blanose 7M31C, Blanose 7HF and Blanose 7H4F, all from Hercules.

The authors of this invention have found that adding an aqueous solution of Na-CMC to the above described composition of calcium sulfate containing hemihydrate with or without compressed and/or nepressovannaya dihydrate particles, it becomes possible to change the time of curing, the thus obtained paste by small variation in the concentration of Na-CMC, while at the same time maintaining good Miscibility obtained paste, as well as acceptable vydavlivaete through a syringe with ka is Julia small size.

Moreover, the authors of the present invention unexpectedly discovered that addition of Na-CMC, as defined here, the paste for extrusion remains repeatable (reliably) extruding throughout the injection procedure for 5-15 minutes, which is especially important towards the end of the injection procedure. Other compositions that do not use Na-CMC, will be more susceptible to solidification occurring toward the end of the injection procedure that will lead to unreliable introduction, leading to further uncertainty in the exact dose of pharmaceutically active ingredient, because only part of the whole composition was introduced. The authors of this invention have found that by adding Na-CMC, this difficulty is overcome, and this provides a more secure introduction/injecting all of the prepared composition, and, thus, there is a reliable, proven composition which allows precise dosing pharmaceutically active ingredient(s).

Thus, the application of Na-CMC in the compositions of the present invention, the solidification time, the viscosity and the dispersion can be slightly adjusted to match the specific application of the composition. As previously noted, one important task of the invention is the reduction of the mixed water quantity in the finished primeneniyu composition, because it affects the final volume of the composition to be administered. For some applications it is desirable to have a small amount of composition, subject to the introduction, since this reduces the load on the body, which is introduced in the composition. However, without the use of dispersing tools (such as, for example, Na-CMC), the solidification time is too short for the task of the invention and the resulting composition contains parts with very heterogeneous structure.

Solutions on the basis of Na-CMC, thus, contribute to the joint effects of prolonged time of solidification, increased viscosity and improved dispersion of the powder in the solution. All these effects are achieved with Na-CMC as a sole additive to the composition. These effects are extremely useful for compositions based powders, which are a mixture of hemihydrate calcium sulphate and dehydraton. Dihydrate accelerate hydrating (solidification), i.e., the conversion of the hemihydrate to the dihydrate.

It is important that Na-CMC need of a complete dissolution in an aqueous solution to obtain this effect. One way to achieve complete dissolution of Na-CMC is a mixing of dry powder polymer with water (for example, soutfilename through the membrane with water, such as water, Milli-Q). This mixture is then stirred for several what their hours at room temperature and then placed in the refrigerator overnight for complete dissolution of the polymer material (as result of any lumps, formed during the stirring, dissolve during incubation). You can also buy the Na-CMC in dry form, preferably with a large surface area, so that the polymer swelled and dissolved instantly and completelyin situ. Examples of preferred dry forms are thin film and freeze-dried fine powders.

As discussed above, the number of Na-CMC added to the pharmaceutical composition according to the invention, given as mass of Na-CMC in mg relative to the hemihydrate of calcium sulfate (CaSO4·1/2H2O), a component of the composition in grams. The number of Na-CMC ready-to-use composition containing the hemihydrate of calcium sulfate ranges from about 0.1 to 8 mg Na-CMC/g hemihydrate CaSO4as, for example, 0.1 to 6 mg Na-CMC/g hemihydrate CaSO4, 0.1 to 4 mg Na-CMC/g hemihydrate CaSO4, 0.1 to 3 mg Na-CMC/g hemihydrate CaSO4, 0.1 to 2 mg Na-CMC/g hemihydrate CaSO4, 0,1-1 mg Na-CMC/g hemihydrate CaSO4or 0.1-0.5 mg Na-CMC/g hemihydrate CaSO4.

If the dihydrate of calcium sulfate is also present in the composition, the corresponding parameter can also be a relationship between the mass of Na-CMC in mg to the total weight of the calcium sulfate in grams, i.e., the component of the calcium sulfate includes the mass in grams of calcium sulfate as the hemihydrate and dihydrate. Therefore, the number of Na-CMC is given as mg Na-CMC/g CaSO4where CaSO4= d the Amma CaSO 4·1/2H2O (for example, in powder form) + g CaSO4·2H2O (for example, in the form of compressed particles). However, the preferred ratio is relative to the hemihydrate of calcium sulfate, because it is a component that takes water. In some of the tables presented here also calculated a different value, as appropriate ratios are as follows: number of Na-CMC ready-to-use composition containing the hemihydrate of calcium sulfate and other sulfate of calcium, namely the dihydrate of calcium sulfate ranges from about 0.1 to 8 mg Na-CMC/g CaSO4, such as 0.1-6 mg Na-CMC/g CaSO4, 0.1 to 4 mg Na-CMC/g CaSO4, 0.1 to 3 mg Na-CMC/g CaSO4, 0.1 to 2 mg Na-CMC/g CaSO4, 0,1-1 mg Na-CMC/g CaSO4or 0.1-0.5 mg Na-CMC/g CaSO4where CaSO4is the total mass of calcium sulfate (i.e., the sum of the masses of all of the sulfates of calcium in composition), where CaSO4indicates the total number of calcium sulfate, i.e., the amount of hemihydrate calcium sulphate and dihydrate calcium sulphate.

Further embodiments of the composition are as follows, where the mass ratio of Na-CMC and hemihydrate of calcium sulfate is in the range from 0.25 mg/g to 0.75 mg/g and the weight ratio of Na-CMC and the total amount of calcium sulfate is in the range from 0.2 mg/g 0.5 mg/g in the invention relevant vari the options can be pursued with equal quantities CaSO 4·2H2O CaSO4·1/2H2O.

Na-CMC (mg)/the dihydrate of calcium sulfate (g)An implementation option 11An implementation option 21An implementation option 31
5.5part 1 CaSO4·2H2O2,
2 parts CaSO4·1/2H2O, and 0,0055 parts Na-CMC (aq.)3
R=2,8
part 1 CaSO4·2H2O2,
3 parts CaSO4·1/2H2O, and 0,0055 parts Na-CMC (aq.)3
R=1,8
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0,0055 parts Na-CMC (aq.)3
R=1,4
4.5part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0,0045 parts Na-CMC (aq.)3
R=2,3
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and 0,0045 parts Na-CMC (aq.)3
R=1,5
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0,0045 parts Na-CMC (aq.)3
R=1,2
4.0part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0,004 is t, Na-CMC (aq.) 3
R=2
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and 0.004 parts of Na-CMC (aq.)3
R=1,3
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0.004 parts of Na-CMC (aq.)3
R=1
3.5part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0,0035 parts Na-CMC (aq.)3
R=1,8
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and 0,0035 parts Na-CMC (aq.)3
R=1,2
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0,0035 parts Na-CMC (aq.)3
R=0,9
3.0part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0.003 parts of Na-CMC (aq.)3
R=1,5
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and 0.003 parts of Na-CMC (aq.)3
R=1
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0.003 parts of Na-CMC (aq.)3
R=0,8
2.5part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0.0025 parts of Na-CMC (aq.)3
R=1,3
1 part aSO 4·2H2O2, 3 parts CaSO4·1/2H2O, and 0.0025 parts of Na-CMC (aq.)3
R=0,83
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0.0025 parts of Na-CMC (aq.)3
R=0,63
2.0part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0.002 parts of Na-CMC (aq.)3
R=1
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and 0.002 parts of Na-CMC (aq.)3
R=0.67
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0.002 parts of Na-CMC (aq.)3
R=0,5
1.5part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0.0015 parts of Na-CMC (aq.)3
R=0,75
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and 0.0015 parts of Na-CMC (aq.)3
R=0,5
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0.0015 parts of Na-CMC (aq.)3
R=0,38
1part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and 0.001 parts of Na-CMC (aq.)3
R=0,5
part 1 CaSO4·2H2O2, 3 parts CaSO4the 1/2H 2O, and 0.001 parts of Na-CMC (aq.)3
R=0,33
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and 0.001 parts of Na-CMC (aq.)3
R=0,25
0.95part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and
0,00095 parts Na-CMC (aq.)3
R=0.48
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and
0,00095 parts Na-CMC (aq.)3
R=0,32
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and
0,00095 parts Na-CMC (aq.)3
R=0,24
0.85part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and
0,00085 parts Na-CMC (aq.)3
R=0.43
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and
0,00085 parts Na-CMC (aq.)3
R=0,28
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and
0,00085 parts Na-CMC (aq.)3
R=0,21
0.75part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and
0,00075 parts Na-CMC (aq.)3
R=0,38
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and
000075 parts Na-CMC (aq.) 3
R=0,25
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and
0,00075 parts Na-CMC (aq.)3
R=0,19
0.65part 1 CaSO4·2H2O22 parts CaSO4·1/2H2O, and
0,00065 parts Na-CMC (aq.)3
R=0,33
part 1 CaSO4·2H2O2, 3 parts CaSO4·1/2H2O, and
0,00065 parts Na-CMC (aq.)3
R=0,22
part 1 CaSO4·2H2O2, 4 parts CaSO4·1/2H2O, and
0,00065 parts Na-CMC (aq.)3
R=0,17
1All parts are parts by weight.
2CaSO4·1/2H2O = the hemihydrate of calcium sulfate; CaSO4·2H2O = particles dihydrate calcium sulphate .
3Na-CMC (dissolved in water) is given as part Na-CMC.
R = mg Na-CMC/g CaSO4·1/2H2O.

Each of the above embodiments may further comprise an active substance, such as, for example, flutamide, 2-hydroxyflutamide and/or bikalutamid, including combinations thereof. The concentration of the active substance is usually in the range from about 0.01% wt./mass. to about 75% wt./mass. from arosca the hemihydrate of calcium sulfate and/or particles of the dihydrate of calcium sulfate, such as, for example, from about 0.01% wt./mass. to about 50 wt%./mass., from about 0.01% wt./mass. up to about 40% wt./mass. from about 0.05% wt./mass. up to about 30% wt./mass., from about 0.05% wt./mass. up to about 20% wt./mass. or from about 0.1% wt./mass. up to about 10% wt./mass.

Specific ready-to-use composition according to the invention contain

1 part (for example, 0.33 g) CaSO4·2H2O with the active substance,

1 part (for example, 0.33 g) CaSO4·1/2H2O with the active substance,

1 part (for example, 0.33 g) CaSO4·1/2H2O without the active substance and

from about 0,0015-0,0027, preferably 0,0022-0,0025, parts of Na-CMC, namely Blanose 9M31XF (aq.) (for example, 0.6 to 0.9, preferably of 0.7-0.8, g 0,30% aqueous solution). Alternatively, for example, of 0.7 to 1.0, preferably from 0.8 to 0.9 g of 0.25% aqueous solution can be used.

Ready-to-use composition according to the present invention has good Miscibility and will squeeze out of the syringe for 10-15 minutes or more through a needle size 15-17G or less.

Other ready-to-use compositions can contain

2 parts (for example, 0.50 g) CaSO4·2H2O with the active substance,

1 part (for example, 0.25 g) CaSO4·1/2H2O with the active substance,

1 part (for example, 0.25 g) CaSO4·1/2H2O without the active substance and

from about 0,0015-0,0027, predpochtitelno 0,0018-0,0023, parts Na-CMC, namely Blanose 9M31XF (aq.) (for example, 0.6 to 0.8, preferably about 0.6-0.7, g 0,30% aqueous solution).

Each of the above compositions may optionally contain an active substance, such as, for example, flutamide, 2-hydroxyflutamide and/or bikalutamid, including combinations thereof, in the range of from about 0.01% wt./mass. to about 75% wt./mass., such as, for example, from about 0.01% wt./mass. to about 50 wt%./mass., from about 0.01% wt./mass. up to about 40% wt./mass. from about 0.05% wt./mass. up to about 30% wt./mass., from about 0.05% wt./mass. up to about 20% wt./mass. or from about 0.1% wt./mass. up to about 10% wt./mass.

The paste thus obtained (for example, ready-to-use composition) has a good Miscibility in the syringe and will be squeezing in for 10-15 minutes or more through a needle size 15-17G or more, such as, for example, 6G, 8G, 9G, 10G, 11G, 12G, 13G, 14G, 16G. Alternatively, the needle of smaller size may be used, such as 18G or 19G or 20G or smaller needle sizes, such as 21G, 22G, 23G, 24G and 26G.

The present invention also provides a kit for use in the method of treatment, compositions and use according to the invention, with appropriate limits, quantities and ratios of all components, as disclosed here.

The set can contain

i) a first component containing a

(a) gemagic is at calcium sulphate (CaSO 4),

(b) may dihydrate calcium sulphate in solid or semi-solid form, and

ii) a second component containing a

(c) carboxymethyl cellulose, namely, sodium carboxymethylcellulose (Na-CMC),

where the ratio R of carboxymethylcellulose and calcium sulphate in the set is from about 0.1 mg carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulfate to about 8 mg of carboxymethylcellulose (calculated as Na-CMC)/g calcium sulphate.

Ratio is from about 0.5 mg of carboxymethylcellulose (calculated as Na-CMC)/g of the hemihydrate of calcium sulfate to about 3 mg of carboxymethylcellulose (calculated as Na-CMC)/g of the hemihydrate of calcium sulfate or the ratio R is from about 1 mg carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulfate to about 3 mg of carboxymethylcellulose (calculated as Na-CMC)/g calcium sulphate.

In addition, it is assumed that the second component further comprises the aquatic environment, including water, where carboxymethylcellulose in the second component dissolved in water, where the concentration of carboxymethyl cellulose in water is from about 0.05% wt./mass. to about 1% wt./mass.

The kit also can contain the active compound in the component (i) and/or component ii), where the active substance is antiandrogens or its derivatives, such as n the example, cyproterone, flutamide, 2-hydroxyflutamide or etc.

The kit can also contain a dihydrate of calcium sulfate present in component (ii) in compressed form, or particles, as discussed here, where these particles can optionally contain an active substance. The set in which the hemihydrate of calcium sulfate component i) is present in the mixture with the active substance. Perhaps the set does not contain acetic acid in the component (ii).

The composition according to the present invention can be used for local or systemic treatment of various diseases, including, but without limitation, for example, pain, neurological diseases (Alzheimer's disease, Parkinson's disease), autoimmune diseases, immunological diseases, and diseases that respond to immunological and together with immunomodulating therapy (hepatitis, MS, tumors), infections, inflammation, metabolic disorders, obesity, diseases of the urinary tract, cardiovascular disease (including blood pressure), hematological, anticoagulant, thrombolytic and antiplatelet disease, chemotherapy of parasitic infections, microbial diseases and related neoplasms diseases, hypercholesterolemia, dyslipidemia, hematological diseases, respiratory diseases (asthma, chronic obstructive lung), kidney disease, W is lubochna-intestinal diseases, liver disease, hormonal disorders, replacement and substitution, replacement and substitution of vitamins.

However, the specific embodiment of the invention is the treatment of diseases associated with the prostate gland, such as prostate cancer, benign prostatic hyperplasia, or acute or chronic inflammation of the prostate gland.

So, the option of carrying out the invention relates to a method of treatment of the above diseases, especially diseases related to the prostate, such as prostate cancer, benign prostatic hyperplasia, or acute and chronic inflammation of the prostate, by applying compositions of the present invention. Another aspect of the invention relates to the above compositions for the preparation of drugs for the treatment of the above diseases, especially diseases related to the prostate, such as prostate cancer, benign prostatic hyperplasia, or acute and chronic inflammation of the prostate gland.

It is assumed that the composition of the present invention can be administered by injection into the tissue for the local treatment of the above diseases/conditions. Iny the Ktsia maybe for example, parenteral, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneally or direct injection into a specific organ/tissue such as the prostate gland. Other routes of administration are, for example, intrathecal, intra-arterial, intracranial, intraocular, oral, rectal or vaginal administration.

The following examples are given to further illustrate the invention. The examples should not be construed as limiting the invention.

Abbreviations used here are as follows:

Na-CMCSodium carboxymethylcellulose
2-HOF2-Hydroxyflutamide
MCMethycellulose
HAcAcetic acid

Examples

Example 1

Materials and methods

Table 1 provides an overview of all samples used in the examples. Samples were either purchased from Sigma-Aldrich (Sample 1), Apoteket AB (one sample Blanose®, Sample 8), or received as a gift from Hercules Inc. through Broste AB (nine samples Blanose®). A total of ten samples Blaose were used; the samples indicated in Table 1 PH, are relevant to the requirements of the monograph Ph. Eur. and USP/NF. The number of samples provided by Broste, four samples were used in the examples here.

Table 1
Data of different samples of Na-CMC used in examples.
Data of viscosity and degree of zamestnanosti taken from the certificate of analysis
No.ManufacturerTypeProduct nameThe batch numberViscosity1(mPas)The degree of zamestnanosti2
1Sigma-AldrichMedium viscosityS3CRated: 400-800 mPas (2%)Not defined
2HerculesLow viscosityBlanose 7LF PH7104442 (2%; 1; 60 rpm)0,78
3HerculesMedium viscosityBlanose 7M1F PH7232953 (2%; 1; 60 rpm)0,81
4HerculesMedium viscosityBlanose 7MF PH71042468 (2%; 2; 30 rpm)0,86
5HerculesMedium viscosityBlanose 7M8SF70425508 (2%; 2; 30 rpm)0,91
6HerculesMedium viscosityBlanose 9M31F701421680 (2%; 3; 30 rpm)0,95
7HerculesMedium viscosityBlanose 9M31CF712612170 (2%; 3; 30 rpm)0,73
8Hercule (through Apoteket) Medium viscosityBlanose 9M31XF PH604722620 (2%; 3; 30 rpm)0,92
9HerculesMedium viscosityBlanose 7M31C62667Not defined0,70
10HerculesHigh viscosityBlanose 7HF712411780 (1%; 3; 30 rpm)0,72
11HerculesHigh viscosityBlanose 7H4F923445940 (1%; 3; 30 rpm)0,85
1Viscosity (1 mPas = 1 cP) aqueous solution measured at specified parameters (concentration in percent by weight; Brookfield spindle number; and install in rpm).
2The average number carboxymethyl groups on anhydroglucose link the cellulose chain.
3Meets USP specifications tested in accordance with the manufacturer's data. Not defined = no data available.

Particularly important in this invention is that the used Na-CMC is used in aqueous solution. Aqueous solutions of Na-CMC were prepared by mixing the dry polymer powder with sizeofelement through the membrane water water (Milli-Q). The mixture stirred for several hours at room temperature and then placed in the refrigerator overnight for complete dissolution of the polymer material (dissolve any lumps formed during mixing). The obtained transparent more or less viscous solutions were stored in refrigerator until use, usually within weeks. All concentrations given here in the examples are percent by weight (wt./mass.).

In accordance with the specifications from Hercules aqueous solutions of Na-CMC have a pH in the range from 6.5 to 8.0. In the examples, the pH was brought.

As a control for Na-CMC used a mixture of 1.0% methylcellulose (MC) and 1.0% acetic acid (HAc) in water, prepared by Apoteket AB.

Different batches of hemihydrate calcium sulphate (CaSO4∙1/2 H2O) as a commercially available batch from Sigma-Aldrich (catalog No. 30,766-1, party 06106JD-046), and the party prepared to HV the domestic use LIDDS (marked CRVM), were used. The latter were based on dihydrate calcium sulphate (CaSO4∙2H2O) from Carl Roth GmbH, Germany, which rise in air at 200°C for 4 hours.

In addition, various parties compressed particles containing CaSO4∙2H2O and 2-hydroxyflutamide (2-HOF), was used in the test. Dense granules were produced by isostatic compression. To obtain compacted granules for each panel used the powder dry hemihydrate calcium sulphate/2-HOF in number 10, the Powder was placed in a two-way monoecious stamp for compression stainless steel. Punch that matches the stamp was placed on top of manually distributed powder layer. Under pressure by means of the axial mechanical pressure, approximately 2 tons of powder was pre-compacted in a dry bars. On each of the four long edges of the bar shed a certain amount of sterile water and waited for impregnation. Wet bar covered by the condom, tied a knot, trying to capture as little air as possible. Closed so the bar was placed in the receiver for samples cold isostatic press and exerted pressure 4000 bar for 60 minutes. After isostatic compression bars crushed and milled to the size of the granules 125-500 μm.

One of the commercially available pairs is s CaSO 4∙2H2O was used in Example 3 (Compactrol; party 06021C).

In Examples 2 and 3 were tested samples only with CaSO4∙1/2H2O, followed by Examples, where we used the samples from the compacted particles containing 2-HOF plus CaSO4∙1/2H2O, whereas the samples with 2-HOF in the pressed particles (extended release) and in the matrix (for immediate release or "booster dose, booster) were used in Examples 6-8.

Usually from about 0.1 mg to 8 mg Na-CMC/g CaSO4(i.e., the total quantity of calcium sulfate by weight (including as the hemihydrate and dihydrate), to which Na-CMC was added) were mixed to obtain a paste. The calcium part of the composition may contain different ratios of the hemihydrate of calcium sulfate and dihydrate, for example one part of the compressed particles CaSO4∙2H2O and two parts CaSO4∙1/2H2O, as additionally illustrated in Example 8.

To determine the properties of the obtained paste was used as plastic cups (using a spatula for mixing) and devices based on plastic syringes, both conventional and modified in various ways.

At the time of mixing the powder of the hemihydrate of calcium sulfate and/or dihydrate particles and a solution of Na-CMC was launched control the stopwatch. The result was a paste that has reached the elk through various means depending on the fixture, in which a test was conducted, i.e., first with a spatula, if used outdoor plastic Cup, or syringe conventional type (e.g., from Becton, Dickinson & Co. (BD) or Qosina Corp.), connected to each other through Swarovski tips and push their content back and forth several times.

For simplicity, the first tests were conducted in disposable plastic cups using conventional spatula stainless steel. During the mixing of the paste spatula was used to track the Miscibility and, therefore, vydavlivaete through imaginary syringe. Later tests were developed and conducted instead of glasses in the syringes to better simulate the actual method of preparation and mixing ready-to-use paste in the clinic, as well as to test vydavlivaete more accurate way.

The evaluation included observation of appearance, qualities, consistency, vydavlivaete and the time required for the thickening and hardening. All tests were performed at room temperature, about 20-25°C.

One way of estimating vydavlivaete composition consisted of 5 ml Plastipak syringe (BD) with a plastic cover on the side of the hole containing 1.0 g of powder mixture. To the powder mixture was then added to the test solution of Na-CMC, usually about 0.8 is l, and the resulting mixture was stir by hand using a plastic spatula until then, until he had a homogeneous paste. Then insert the piston and remove the cover. Then the paste was carefully squeezed through the hole of the syringe, making hand only moderate force. It was noted the time when the paste could not be extruded through the hole even after the application of higher forces. This time was defined as the time vydavlivaete. In addition, it was noted the time for the extruded paste is placed on a suitable flat surface and covered with, for example, aluminum foil required for solidification. Every 30 seconds were selected drop pasta with aluminum foil. When the "drop" was broken up after the load, for example by pressing the end of the finger, it was regarded as cured. This time was defined as the solidification time. Defined thus, the solidification time should be from about 5 to about 15 minutes.

Example 2

Test dilutions for the hemihydrate of calcium sulfate

In Tables 2 and 3 presents data showing that Na-CMC (aq.) as a solvent leads to a prolonged time of solidification CaSO4∙1/2H2O. it is Also clear that small changes in the concentration of Na-CMC easily make possible the regulation time is fordelene. Used in this Example, Na-CMC is C9481 from Sigma-Aldrich (marked No. 1 in Table 1).

Example 3

Test dilutions for sulfate hemihydrate and calcium sulfate dihydrate calcium

The data in Tables 4 and 5 below show a significant effect of Na-CMC (aq.) the degree of solidification of mixtures CaSO4∙1/2H2O CaSO4∙2H2O and the correlation between solidification time and the concentration of Na-CMC. Compared with the samples (No. 1 and 2 in Table 4), where the solvent used MC + HAc or water, the solidification time is considerably increased.

From the results shown in Table 4, it also follows that when the powder mixture is added CaSO4∙2H2O, the solidification time becomes shorter in comparison with mixtures, where the calcium sulfate is in the form of a hemihydrate (see Table 2). The reason for this is that CaSO4∙2H2O is the center of the crystal, which increases the speed of solidification.

Na-CMC used in this example is C9481 from Sigma-Aldrich (marked No. 1 in Table 1).

Example 4

Test dilutions for sulfate hemihydrate and calcium sulfate dihydrate calcium with pharmacologically active substances which m

The results presented below in Table 6, demonstrate dependent concentration the effect of Na-CMC (aq.) in the process of solidifying a powder composition containing as CaSO4∙2H2O and pharmacologically active substance, 2-hydroxyflutamide (2-HOF), and CaSO4∙1/2H2O. For comparison, the water and mix with HAc and MC lead to a shorter solidification time.

Na-CMC used in this example is C9481 from Sigma-Aldrich (marked No. 1 in Table 1).

Example 5

Test for solidification for the Na-CMC high viscosity

Table 7 presents data for a sample of Na-CMC from Hercules (Blanose® 7H4F No. 11 of Table 1). This sample had the highest viscosity among all samples used. Blanose 7H4F has a viscosity 5940 mPas and was added to the composition in an amount of about 0,63 mg/g of calcium sulfate, the composition was still fluid after 15 minutes. The application of the same concentration C9481 (having a viscosity of 400 to 800 mPas) has led to the fact that the composition is hardened after about 12 minutes (see Table 5).

Example 6

Vydavlivaete compositions containing sulfate hemihydrate and calcium sulfate dihydrate calcium and pharmacologically active substance

The results presented below in Tables 8 and 9 show that is possible is udevliat pasta through a thin needle size 17G, when the concentration of the drug reaches 75/100 as in compacted particles and used in the matrix.

Was used Na-CMC Blanose 7LF (No. 2 in Table 1).

The hemihydrate of calcium sulfate, marked "CRVM" means the powder obtained in the laboratory by heat treatment of the dihydrate of calcium sulfate. The dihydrate of calcium sulfate from Carl Roth (>98%, Ph. Eur. reinst Carl Roth, Germany) was used as a raw material. For the preparation of powder 250 g of dihydrate of calcium sulfate was placed in a 2000 ml crystallization tub. Crystallization bath incubated in an oven at 200°C for 4 hours. After cooling outside the furnace to room temperature, the powder was transferred into a 1000 ml flask with a wide neck and resuspendable in 200 g of isopropanol. Were added grinding balls (64 pieces, diameter 10 mm). The turbula shaker-mixer used for shake flask with a wide neck for 24 hours at 46 min-1. After grinding grinding balls removed and the suspension was placed in a 2000 ml crystallization tub. Crystallization bath incubated in a fume hood at room temperature until until isopropanol does not evaporate completely. The remaining powder was gently pressed through 450 µm sieve (for desagglomeration).

Example 7

Properties of various ratios dehydrate the calcium sulphate and the hemihydrate of calcium sulfate

The results presented below in Table 10, indicate that a high proportion of the compressed particles CaSO4∙2H2O to CaSO4∙1/2H2O (1:2 → 1:1) can be used when mixed with Na-CMC and squeezing the resulting paste through the hole of the syringe. These tests also indicate that the solvent No. 8 in Table 1 on the basis Na-medium viscosity CMC (Blanose 9M31XF) leads to improved consistency of the resulting paste compared to the low viscosity solvent No. 2 from Table 1 (Blanose 7LF). The data also show that the solidification time was reduced in the presence of CaSO4∙1/2H2O no 2-HOF with at least 20 minutes to less than 4 minutes.

Example 8

Properties of various ratios of sulfate dihydrate and calcium sulfate hemihydrate calcium

Presented below in Table 11 the results confirm that a higher ratio of compressed particles CaSO4∙2H2O to CaSO4∙1/2H2O 1:2 → 1:1 can be used when mixed with Na-CMC and squeezing the resulting paste through the hole of the used syringe, through the needle. These tests also confirm that the solvent No. 8 of Table 1, on the basis of Na-CMC medium viscosity, resulting in an acceptable consistency of the resulting paste. The data also show that the reduction in concentrations of from 0.30% to 0.5% leads to more rapid solidification, because the pasta was impossible to squeeze through a needle after about 7 minutes.

Example 9

Properties of various ratios of sulfate dihydrate and calcium sulfate hemihydrate of calcium and Na-CMC in relation to vydavlivaete

To study the effects of Na-CMC on the rheology of the paste, without de-serializing paste hydration (gradual salustiana), we conducted an experiment with mixing and studying vydavlivaete with nestorovski sulfates of calcium. Such a property are as the dihydrate of calcium sulfate, and anhydrous calcium sulfate. It was evident that there is a dispersion effect of Na-CMC, which is manifested in the fact that compared to pastes prepared with CMC or MC, CMC-paste are more fluid (less viscous.). This increased fluidity occurs after some mixing of the paste. The test included dispensed from the syringe, in some cases with a needle. The most difficult during extrusion is when the pasta is completely out of their syringe, and the transition moment of their wide body of the syringe in a much more narrow spout.

Tests were conducted to determine the suitability of different solvents for the preparation of injectable pastes of calcium sulfate. Dehydration powders of calcium sulfate was used to exclude the effects of solidification, camposol with the hemihydrate of calcium sulphate in the study of the properties of the pastes.

In the tests used three material calcium sulphate:

1. The dihydrate of calcium sulfate: Fluka, Product No. 21 246;

2. The dihydrate of calcium sulfate: Compactrol, party 06021 C;

3. Calcium sulfate (anhydrous): Sigma-Aldrich, Product # 237132.

It should be noted that anhydrous calcium sulfate may not be gidratirovana, and thus behaves similarly to dehydrate, in the sense that a mixture containing anhydrous calcium sulfate, does not harden.

Were tested and compared with deionized water two water solvent:

1. 0.25% wt./mass. Na-CMC;

2. 0,44% wt./mass. methyl cellulose (MC).

Water or an aqueous solution of the cellulose ether was added to the dry powder of calcium sulfate, and the mixture is vigorously stirred with a spatula. Some suspensions were treated in an ultrasonic bath at elevated temperature (40°C) for less than 1 minute, and then evaluated the appearance of the mist.

Some of the resulting suspensions were transferred into a 10 ml syringe, in some cases with needle (1,65/1,40×149 mm).

The results are summarized below in Table 12.

Table 12
No.PowderSolventResult
4,01 g anhydrous CaSO4+ 3,02 g of granulated material*3,99 g deionized H2OViscous suspension; it is difficult to squeeze through Swarovski hole 10 ml syringe
194,00 g anhydrous CaSO4+ 3,01 g of granulated material*4,01 g of 0.25 % Na-CMC (aq.)Less viscous, more fluid suspension than 18; squeezing through Swarovski hole 10 ml syringe with needle
204,01 g anhydrous CaSO4+ 3,02 g of granulated material*of 4.00 g of 0.44 % MC (aq.)Viscous suspension, which stabilizes the air bubbles; it is difficult to squeeze through Swarovski hole 10 ml syringe
217,00 g CaSO4∙2H2O (Fluka)4.35 g of deionized H2OViscous suspension. Usually squeezing through Swarovski hole 10 ml syringe
227,00 g CaSO4∙2H2O (Fluka)4.35 g of 0.25 % Na-CMC (aq.)Less viscous, more fluid VSUES is, than 21. Vydavlivaete in 21
237,01 g CaSO4∙2H2O (Fluka)4.35 g of 0.44 % MC (aq.)More dense than 21. Stabilizes the air bubbles. Vydavlivaete, as in 21
247,01 g CaSO4anhydrous4,37 g deionized H2OViscous slurry, extruding through Swarovski hole 10 ml syringe with needle
257,01 g CaSO4anhydrous4,34 g of 0.25 % Na-CMC (aq.)Less viscous, more fluid suspension than 24. Vydavlivaete, as in 24
267,01 g CaSO4anhydrous4.35 g of 0.44 % MC (aq.)Viscous suspension. Thicker than 24. Suspension contains air bubbles. Vydavlivaete, as in 24.
A7,00 g CaSO4∙2H2O (Compactrol)4.35 g of deionized H2OViscous slurry, extruding through Swarovski hole 10 ml syringe
B 7,00 g CaSO4∙2H2O (Compactrol)4,36 g of 0.25 % Na-CMC (aq.)Less viscous, more fluid suspension. Squeezing through Swarovski hole 10 ml syringe
C7,00 g CaSO4∙2H2O (Compactrol)4,37 g of 0.44 % MC (aq.)Viscous slurry, extruding through Swarovski hole 10 ml syringe. Contains air bubbles
D7,00 g CaSO4∙2H2O (Compactrol)of 3.95 g of deionized H2OSuch toothpaste twice. It is difficult to squeeze through Swarovski hole 10 ml syringe. Often blocked
E7,00 g CaSO4∙2H2O (Compactrol)of 3.95 g of 0.25 % Na-CMC (aq.)Less dense suspension than in D. Extruding through Swarovski hole 10 ml syringe. Rarely is locked
F7,00 g CaSO4∙2H2O (Compactrol)of 3.95 g of 0.44 % MC (aq.)A dense suspension. It is difficult to squeeze through Swarovski hole 10 ml syringe. Strongly stabilizes the air bubbles
*Dense granules, 125-300 μm, CaSO4·2H2O and 2-HOF.

Thus, some of these experiments (D, E, F) reproduce the conditions arising in ready-to-use composition when it reaches the point of solidification or partially solidified during the completion of injection.

In earlier experiments have shown that water Na-CMC solutions very effectively slow hydrating hemihydrate calcium sulphate. Solutions MC does not have this property.

Surprisingly, as shown in these experiments, besides the fact that it is very effective to slow the vehicle when the solidification of the hemihydrate of calcium sulfate, an aqueous solution of Na-CMC is also a very effective dispersing agent. By adding Na-CMC (aq.) improved conversion of the powder into a suspension and its further introduction. Non-ionic cellulose ether MC is the worst compared with Na-CMC in all respects; it is a poor dispersing agent, it stabilizes the air bubbles and does not slow down the solidification (hemihydrate calcium sulphate; not shown here).

As you can see here, Na-CMC gives appropriate rheological properties of aqueous suspensions of pasta CaSO4and inhibits the process of deposition and solidification.

1. The set contains two components
i) a first component containing the
(a) the hemihydrate Sul the veil of calcium
(b) compressed particles of dihydrate of calcium sulfate, optionally containing one or more therapeutically, prophylactically and/or diagnostically active substances, and
ii) a second component containing the
(c) sodium carboxymethylcellulose (Na-CMC) and the water environment, including water, where the ratio R of sodium-carboxymethylcellulose and calcium sulphate in the set is from 0.1 mg sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulfate 8 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulfate,
moreover, these two components form when mixing bioassays ceramic composition.

2. Set under item 1, where the ratio R is from 1 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulfate to 3 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g calcium sulphate.

3. Set according to any one of paragraphs.1-2, where the sodium carboxymethylcellulose in the second component dissolved in water at a concentration of from 0.05 wt. -%/mass. up to 1% wt./mass.

4. Set under item 1, where the active substance is antiandrogens.

5. Set on p. 4, where the active substance is cyproterone, flutamide, 2-hydroxyflutamide.

6. The set according to any one of paragraphs.1-5 for the treatment of a disease or condition associated with the prostate gland.

7. Ready-to-use composition is a paste form, for administration to the patient within a period of from 5 minutes to 1 hour before hardening obtained by mixing components (i) and (ii) as defined in any of paragraphs.1-5.

8. The cured composition containing
(a) the dihydrate of calcium sulfate and compacted particles of the dihydrate of calcium sulfate,
(b) sodium carboxymethylcellulose (Na-CMC),
where the ratio R of sodium-carboxymethyl cellulose to the total mass of calcium sulfate (weight of the hemihydrate of calcium sulfate, if present, plus the weight of the dihydrate of calcium sulfate) in the composition is from 0.1 mg sodium-carboxymethylcellulose (calculated as Na-CMC)/g of total calcium sulfate 8 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g total calcium sulphate/ and
(c) a therapeutically, prophylactically and/or diagnostically active substance, such as antiandrogen, cyproterone, flutamide or 2-hydroxyflutamide.

9. The composition according to p. 8, where the ratio R is from 1 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g total calcium sulphate 3 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g total calcium sulphate.

10. Set according to any one of paragraphs.1-5, further comprising a cannula or needle.

11. Method of preparation of ready-to-use composition, which is defined in paragraph 7, or preparation of the composition as defined in any of item is .8-9, where the method involves mixing of components i), ii) and iii) in the dispersion:
i) one or more fractions according to the size of the granules of the hemihydrate of calcium sulfate,
ii) one or more fractions according to size of compressed particles of dihydrate of calcium sulfate, optionally containing one or more therapeutically, prophylactically and/or diagnostically active substances,
iii) an aqueous solution containing sodium carboxymethylcellulose.

12. Composition according to any one of paragraphs.7 or 8 for use in the treatment of a disease or condition that relates to the prostate gland.

13. The composition according to p. 12, where the disease is benign prostatic hyperplasia, prostate cancer or inflammation of the prostate gland.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. What is presented is a polypeptide containing two binding fragments presented by antibodies; the first of them binds to CD3e(epsilon) chain epitope of a human or a primate, other than a chimpanzee, particularly Callithrix jacchus, Saguinus oedipus and Saimiri sciureus; the second one - to EGFR, Her2/neu or IgE of a human or a primate, other than a chimpanzee, with the above CD3e epitope containing the amino acid sequence Gln-Asp-Gly-Asn-Glu. There are also disclosed a coding sequence of the nucleic acid, a vector, a host cell and a method for preparing the above peptide, as well as a pharmaceutical composition and using the polypeptide in preventing, treating or relieving a proliferative disease, a malignant disease or an immunological disorder.

EFFECT: invention provides the clinical improvement of T-cell redistribution and the enhanced safety profile.

17 cl, 8 tbl, 26 dwg, 26 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to a novel compound, namely 2,2a,2a',3,5a,9b-hexahydrofluorene[9,1-bc]furan-8-ol of the formula 1 .

EFFECT: enhancement of antitumor activity.

2 dwg, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel fluorinated 1,4-naphthoquinone derivatives of general formula , where 1 R=C6H5, X=F; 2 R=2, 5-F2C6H3, X=F; 3 R=CH3, X=F; 4 R=C6H5, X, , possessing cytotoxic activity with respect to cancer cells, which can be applied in medicine.

EFFECT: claimed are novel compounds with anti-cancer activity for therapy of malignant neoplasms.

1 dwg, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to the field of biotechnology and cell technology. The claimed invention is aimed at the creation of pluripotent, multipotent and/or self-renewing cells, which are able to start differentiating in a culture into various types of cells and are capable of further differentiation in vivo. The claimed invention is also aimed at the creation of populations of the required differentiating cells, which can be transplanted to patients, genetic modification of endogenic cells and treatment of patients, suffering from diseases, intensity of which can be reduced by means of the said methods.

EFFECT: invention also claims methods of prevention, treatment or retardation of a disease, associated with an infection of immunodeficiency virus.

17 cl, 1 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein A1 represents N or C (A2); A2 represents H, F, Cl or CN; B1 represents H, OR1, SO2R1, NHR1, NHC(O)R1, F or Cl; D1 and E1 represents H or Cl; Y1 represents H, CN, NO2, F, Cl, Br, CF3, R17, OR17, SO2R17 or C(O)NH2; or Y1 and B1 together with atoms to which they are attached, represent 5- or 6-merous heteroarene having 2-3 nitrogen atoms, wherein heteroarene rings are unsubstituted or substituted by (O); G1 represents H; Z1 represents uncondensed phenylene substituted by OR41; R41 represents 6-merous heteroaryl having 1 N atom, wherein heteroaryl is condensed with R43A, R43A represents 5-merous heteroarene having 1 N atom; Z2 represents monocyclic 6-merous heterocycloalkylene having 1-2 N atoms and 0 double bonds; Z1A and Z2A are both absent; L1 represents -CH2-; Z3 represents R38 or R40; R38 represents uncondensed phenyl; R40 represents cycloalkyl, wherein cycloalkyl represents a monocyclic ring system having 3 to10 C atoms and 0 double bonds, cycloalkenyl, wherein cycloalkenyl represents monocyclic 6-merous ring having 1 heteroatom specified in a group consisting of O and N, and 1 double bond, wherein cycloalkenyl is uncondensed or condensed with R40A; R40A represents cycloalkane, wherein cycloalkane represents a monocyclic ring having 3-10 C atoms and 0 double bonds, or heterocycloalkane, wherein heterocycloalkane represents monocyclic 6-merous ring having 1 N atom and 0 double bonds (the rest substitutes are those as specified in cl. 1 of the patent claim). The invention also refers to compounds of formula

and a pharmaceutical composition containing an effective amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.

EFFECT: compounds of formula (I) or (II) inhibiting the activity of anti-apoptotic Bcl-2 proteins.

6 cl, 5 tbl, 378 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is a method of synthesising conjugates of glycoseaminoglycanes (GAG) with biologically active molecules of different origin, which include low molecular compounds and macromolecules. In particular the invention relates to conjugation of hyaluronic acid (HA) and its derivatives with polypeptides and proteins with the biological function, such as, for instance, interferons, erythropoietins, growth factors, insulin, cytokines, antibodies and hormones.

EFFECT: invention makes it possible to separate intermediate compounds, obtained by the partial or full interaction of GAG with protected aminoaldehydes in the method of conjugation Conjugates are able to increase the efficiency of a conjugated medication and support it in the course of time.

25 cl, 13 dwg, 15 ex

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