Pharmaceutical composition based on doxorubicine and phospholipid nanoparticles for treatment of oncologic diseases

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to pharmaceutical composition for treatment of oncologic diseases in form of phospholipid nanoparticles with size 10-30 nm, which includes phosphatidelcholin, maltose and doxorubicine with the following ratio of components, wt. %: phosphatidelcholin 20-43, maltose 55-78, doxorubicine 2-8. Composition is accumulates in tumour tissue more actively and slows down tumour growth in mice with carcinoma LLC more efficiently in comparison with free doxorubicine.

EFFECT: composition represents freeze-dries powder, stable in long storage, which dissolving in water gives nanophpospholipid particles with included doxorubicine.

3 dwg, 5 tbl

 

The invention relates to medicine and pharmacology, and relates to stable storage and effective for its specific action of drug composition, which consists of nanoparticles on the basis of vegetable phospholipids, including the anticancer drug doxorubicin.

Doxorubicin is a well-known antitumor anthracycline antibiotic series, its chemical name is (8S-CIS)-10-(3-amino-2,3,6-trideoxy-alpha-L-oxohexanoyl)hydroxy-7,8,9,10-Tetra-hydro-6,8,11-trihydroxy-8-(hydroxyacetic)-1-methoxy-5,12-naphthacenedione, Brutto-formula C27H29NO1. The doxorubicin molecule consists of a tetracyclic antrahinonove aglycone of doxorubicine, United glycosidic bond with the amino sugar daunosamine

Doxorubicin has more than 30 years is used for treating hematological cancer, and solid tumors of different localization [1, 2].

Its cytotoxic effect is due to the binding to DNA of tumor cells, overwhelming their growth and proliferation [3]. The drug can be introduced between the layers of the base pairs of DNA, inhibiting DNA-dependent RNA synthesis.

Doxorubicin is used only in the form of solutions for intravenous and intravesical administration. It is administered intravenously at 60-75 mg/m22once a week for 3-4 weeks. After/in the introduction doxorubicin is rapidly disappears from the blood spread to the organs and tissues of the body: kidneys, myocardium, spleen, lungs. In the liver, it is metabolized to form the active metabolite doksorubitsinola. The half-life of doxorubicin 20-48 hours, with 40% of it is excreted in the bile as unchanged within 7 days, the urine within 5 days displayed 5-12% of doxorubicin and its metabolites.

A limitation to therapeutic use of doxorubicin is its toxicity to normal tissues, primarily cardiotoxicity manifested in severe heart failure. An effective way of reducing is the use of doxorubicin is not in free form and in the composition of the medicinal compositions: doxorubicin and carrier (transport system)that affect the biodistribution of drugs in the body and, in particular, reducing the possibility of its receipt in the heart [4].

In this regard, in recent years it doxorubicin devoted a large amount of research and development of new dosage forms of doxorubicin with delivery system in the body.

The main requirement for such forms of doxorubicin is maintaining or increasing therapeutic antitumor de the effects while reducing side effects. The most common delivery system - liposomal form, based on lipids [4-6]. The advantages of liposomal forms are now well known and are associated primarily with improved pharmacokinetics and reduced side effects. For doxorubicin this form turns out to be very productive, as encapsulated in liposomes medicine almost misses healthy tissue, penetrating only through the defective capillaries tumors, and amphiphilic phospholipid membrane of liposomes, interacting with the cell membrane, can contribute to the interaction of drugs with cell-target, thus increasing its effect. In this regard, significant is the amount of phospholipid carriers maximum reduction will facilitate penetration into tumors, including intracellular supply of medicines, as well as to increase the resistance against the capture of particles by the reticuloendothelial system (RES).

There are several liposomal form of doxorubicin with an average diameter of from 100 to 400 nm, which are two groups of drugs. The most commonly used drug doxil (doxyl)calix (caelyx), manufactured in the USA [6]. The drug is approved for use in Russia. He is a stabilized polyethylene glycol (PEG) liposomes containing doxorubicin. DL is getting them a mixture of lipids (hydrogenated soy phosphatidylcholine, cholesterol and distearoylphosphatidylcholine with attached Peg in the ratio of 56:39:5) are suspended in a solution of 250 mm ammonium sulfate, and then subjected to extrusion (i.e. homogenization filtered under pressure). Unencapsulated public ammonium sulfate is removed (for example, using column chromatography), add doxorubicin and incubated at 55-60°C. In this case, because the resulting pH gradient medicine is inside liposomes, forming a salt with the captured sulfate anion, which stabilizes it in the inner space of the liposomes. After the boot stage, the mixture is cooled. On the same principle, but using mostly egg phosphatidylcholine, designed preparation lipodoks (Ukraine) [7]. At the same time, the presence of such drugs Page can lead to additional adverse interactions.

Known also another form of liposomal doxorubicin, not containing PEG. This drug Myocet (TLC D-99 produced "The Lyposome Company, USA), representing the liposomes of phosphatidylcholine to cholesterol containing citrate doxorubicin, with a ratio of drug:lipid 0,28 [8]. To obtain first prepare a single-layer liposomes average diameter of 180 nm of a mixture of egg phosphatidylcholine to cholesterol (55:45) in citrate buffer, and incubated them when shaken with freshly made what astora chloride doxorubicin with methylparaben at 55-60°C. The disadvantage of this unstabilized form is the rapid uptake of liposomes by cells of the RES, which contributes to their relatively large size is greater than 150 nm, in combination with an unprotected surface.

Thus, each of the commercially available liposomal form of doxorubicin has certain disadvantages: low stability or additional side effects. In connection with the foregoing in ongoing research and development of new optimized lipid dosage forms. Thus, there have been incorporating doxorubicin in phospholipid nanoparticles comprising the injectable form of the drug "Phosphogliv with particle size of ~50 nm [9]. The addition of doxorubicin (100 mg) was added to a mixture of original substances of the drug "Phosphogliv": 5 g of soybean phosphatidylcholine (Lipoid S100, the firm Lipoid, Germany), 2 g trinational salts of glycyrrhizic acid (China) and 20 g of maltose monohydrate. Added 100 ml of water for injection, was stirred on a vibrating mixer and the resulting aqueous suspension was subjected to homogenization using a homogenizer high pressure RANNIE MiniLab 7.30 VH (Denmark) for 5 minutes. The resulting solution was subjected to sterilizing filtration using filters with a pore diameter of 0.22 μm at a pressure of nitrogen of 1.5-2 ATM, poured into sterile vials 10 ml and liofilizirovanny using freeze drying Liolab F. The drug showed a more pronounced antitumor and antimetastatic activity in mice with carcinoma of the LLC compared with free doxorubicin. Also described liposomes with a diameter of ~135 nm of phosphatidylcholine, cholesterol and oleic acid, from 0.19 moles of doxorubicin per mole of lipid obtained by injection of an ethanol solution [10], solid lipid nanoparticles of monolaurin, octadecylamine and oleic acid [11], temperature-sensitive liposomes [12]. Developed targeted liposomes with doxorubicin containing as a ligand estrone [13] or interleukin-13 [14] - increased expression of receptors, which manifests itself according to some data on the number of tumor cells. Also described receiving "nanoassembly" phosphatidylethanolamine with PEG with a size of 10-20 nm, exhibiting a pronounced therapeutic effect on the model carcinoma LLC in mice [15]. At the same time, not to mention that none of these works did not pay attention on the intracellular penetration of doxorubicin, administered in new transport forms, on its interaction with DNA, which is the basis of the cytotoxic actions, and particular importance in the transition of nanoscale particles that can deliver the drug not only to the cell membrane, but also to penetrate into the cell.

The present invention suitable for all kinds of which is the development of nairboi phospholipid composition of doxorubicin with an average diameter of the nanoparticles 10-30 nm, with reduced toxicity compared to the free drug, while maintaining specific cytotoxic actions that can withstand long-term storage and to carry out the transport of doxorubicin in the tumor tissue, ensuring its high bioavailability.

The problem is solved by creating a pharmaceutical composition for the treatment of oncological diseases in the form of phospholipid nanoparticles with a size of 10-30 nm, including phosphatidylcholine vegetable origin, maltose and doxorubicin in the following ratio of components, wt.%:

Phosphatidylcholine20-43
Maltose55-78
Doxorubicin2-8

Used phosphatidylcholine is a major component of high-purity vegetable soybean phospholipid content of not less than 73-95% wt. Other phospholipid components may be contained in amounts not exceeding the allowable (effective absorption with added up to 4% wt., trace amounts of other phospholipids).

As a subsidiary pharmacologically acceptable substances composition contains maltose, which is a cryoprotectant at a stage of subl the awareness drying. Adding maltose gives the possibility of obtaining freeze-dried, able after rehydration to fully restore its structure, in particular the particle size.

According to the proposed composition of the invention allows to obtain a pharmaceutical preparation with a large accumulation of doxorubicin in tumor tissue compared to the original drug.

The method of obtaining the phospholipid composition of doxorubicin as follows.

Materials and methods

We used the following materials:

1. Soybean phospholipid firm Lipoid GmbH, Germany, with the content of phosphatidylcholine 78-95%.

2. Maltose monohydrate, MERCK, Germany.

3. Water for injection (FS No. 42-4587-95).

4. Doxorubicin, substance (FS 42-02402570-02).

Example 1. Receiving Doxorubicin in the phospholipid composition of particles

A. Obtaining a coarse emulsion

25 g of maltose dissolved in 200 ml of water with a temperature of 45°C. until complete dissolution). In the resulting solution of maltose add 625 mg of doxorubicin and 6.25 g of the phospholipid. Using a household blender spend homogenization of the mixture and bring the volume to 250 ml

B. Receiving Doxorubicin in the composition of phospholipid nanoparticles

The obtained crude emulsion is passed through a homogenizer (MiniLab 7.3 VH, Rannie, Denmark) at a pressure of 800 bar. Register of svetopropusknaya the s at 660 nm. Filter the product through the filter of 0.22 micron. Re-register the transmittance at 660 nm, see it increase. Determine the size of particles in the product. Analyze the content of doxorubicin in the obtained drug by high performance liquid chromatography (HPLC). Pour the preparation into 10 ml vials and freeze-dried.

The contents of the vial are dissolved in 10 ml of purified water and determine the particle size after reconstitution lyophilized powder of the drug. Carry out the determination of the particle size in a day, and two week storage of dissolved drug at the temperature of 4°C.

The characteristic composition of doxorubicin in the composition of phospholipid nanoparticles

Analysis of particle size by using a Beckman instrument N5 (see table 1) shows that more than 96% of the particles have a size (20,0±2,0) nm. Injection of doxorubicin in phospholipid nanoparticles is about 96%.

Table 1
The distribution of particle size in the drug doxorubicin as part nanophotonic particles
N dimensionThe measurement area, nmThe distribution of particles
size, nmcontent, %the standard deviation, nm
13,0-450,019,595,171,3
23,0-450,021,396,501,2
33,0-450,021,196,342,1
43,0-450,020,695,971,6
53,0-450,019,797,211,4

The definition of a medicinal substance in the phospholipid preparation was carried out by HPLC. To do this, to the drug and added a 9-fold excess of methanol, carefully mixing in the mixer. HPLC analysis of an aliquot of the solution prepared in (1-10 ál) was performed on the instrument Agilent Technology 1200 (US) or "milikhrom" (Novosibirsk) using a linear gradient of acetonitrile in 0.1% aqueous solution TFU, from 1% to 60%, with the rate of elution of 200 µl/min and detected is eaten in the range 220-360 nm. To determine the concentration used calibration curve of the dependence of the peak area from the number of the respective standard samples of substances.

According to HPLC injection of doxorubicin in phospholipid nanoparticles is about 96%. After rehydration of lyophilized drug doxorubicin in the composition of phospholipid nanoparticles (NP-doxorubicin) and the distribution of particle size and size main size fractions of particles does not change: more than 96% of the particles have a size (20,0±2,0) nm. During storage of dissolved drug at 4°C for 7 days, the size of the particles is preserved.

95,73
Table 2
The distribution of particle size in solution NP doxorubicin at the time of release, after 4 and 7 days of storage
N dimensionShelf lifeThe measurement area, nmThe distribution of particles
size, nmcontent, %the standard deviation, nm
123 456
in the moment3,0-450,0
1release19,596,331,3
218,997,131,6
319,696,431,9
420,196,872,1
4 days3,0-450,0
120,397,261,6
219,596,371,7
319,496,962,0
419,696,531,8
7 days3,0-450,0
119,896,211,7
220,496,151,9
319,795,982,3
420,91,4

According to the proposed composition of the invention allows to obtain a pharmaceutical product with a greater availability of doxorubicin in relation to tumor tissue in comparison with the free drug.

To assess the validity of the obtained pharmaceutical composition of doxorubicin in experimental animals, its accumulation in the tumor and distribution in fractions of blood and plasma was necessary at the first stage to practice the method of extraction of doxorubicin from the tissues, which allows to monitor not only the free drug, but associated with the cells, in particular in the complexes with DNA.

List of drawings

Figure 1 - binding to erythrocytes of free doxorubicin and doxorubicin in the phospholipid composition of the nanoparticles during incubation in vitro with heparinized blood.

Figure 2 - distribution between the fractions of lipoproteins in blood plasma of free doxorubicin and doxorubicin in the phospholipid composition of the nanoparticles after incubation of plasma in vitro with blood plasma.

Figure 3 - the release of Triton X-100 doxorubicin (detected after ultrafiltration) in plasma, incubated with free or with NF-doxorubicin.

The choice of method of extraction of doxorubicin

Was selected extraction of doxorubicin with a mixture of methanol and 0.5% triflorum what usnei acid (TFU) and shows the completeness of the extraction of the drug from complexes with DNA (table 3). This was performed the following procedure:

to 100 μl of DNA solution (10 µg/ml) was added to 100 ál of prediluted (1:100) solution of doxorubicin;

- selected 50 μl of the solution of the complex of doxorubicin - DNA was added to 450 μl of extractant: a) methanol and b) methanol with 0.5% TFU (i.e. the total concentration of doxorubicin in each sample was 1000 ng/ml);

the solutions were mixed on the vibrator, centrifuged and each solution was collected and 20 μl for analysis of doxorubicin by HPLC, in each sample the number of doxorubicin corresponded to 10 ng of the drug in its complex with DNA.

Table 3
The completeness of the extraction of doxorubicin complexes with DNA
ExtractionThe detected amount of doxorubicin in the extract (20 ál), ngThe original amount of doxorubicin in the sample, ngThe percentage extraction of doxorubicin from DNA complex
1234
Methanol110 10%
Methanol with 0.5% TFU1010100%

Because treatment with a mixture of methanol with 0.5% TFU leads to a complete extraction of doxorubicin, this system was selected for the subsequent extraction of doxorubicin from the tissues.

The action of free doxorubicin and doxorubicin in the composition of phospholipid nanoparticles on mice with inoculated tumor

Comparison of the accumulation of drugs in tumor tissue and in the liver

The experiment

Used mice with inoculated with adenocarcinoma Lewis LLC.

Tumor volume ~5000 mm3

The weight of mice ~20-25 g

Drugs doxorubicin was administered to mice intraperitoneally at a dose of 15 mg/kg of body weight.

After 4 hours the animals were scored, drew the liver and tumor.

Tissue samples homogenized in a mixture of methanol with 0.5% TFU, in the ratio of 100 mg tissue in 900 ml of solvent. The homogenate was centrifuged; the supernatant was determined by the concentration of doxorubicin using HPLC. The results are shown in table 4.

Table 4
The content of doxorubicin in the liver and tumors of mice with a tumor after administration of free doxorubicin and NF-doxorubicin
ClothThe amount of doxorubicin, µg/ g tissue
after the introduction of the free doxorubicinafter the introduction of the NF-doxorubicin
Liver2,53,1
Tumor1,2of 5.4

From the presented data it follows that in the case of NF-doxorubicin in the tumor (the target tissue) is adjudged to be 4.5 times more drugs than when doing it in a free form.

Comparison of specific antitumor activity of free doxorubicin and doxorubicin in the composition of phospholipid nanoparticles

The solutions of both forms of doxorubicin was administered intraperitoneally to mice with LLC tumor at a dose of 5 mg/kg of Drugs were introduced, starting from the 7th day after transplantation of the tumor, once a week for a total of three infusions). To determine the size of tumors after 3 and 15 days after the start of treatment. The results of the experiment are given in table 5.

Table 5
The inhibition of tumor growth when administered to mice doxorubicin and NF-doxorubicin
GroupnThe average volume of tumors, mm3
The day after the start of treatment
After 3 days after 1 St introductionAfter 15 days (i.e. after the 3rd injection)
Control131156 [769÷1543]6713 [5082÷8344]
Taxonomizing10834 [541÷1127]5390 [4161÷6619]
Hormogonia tumor growth, %2820
NF-doxorubicin10349 [199÷499]2934 [2358÷3510]
The inhibition of tumor growth, %70*56*
* - significantly in relation to the group of animals treated with free drug, p<0,05.

With the introduction of a specific mode NF-doxorubicin causes a much more pronounced inhibition of tumor growth than the s with the free drug.

Thus, doxorubicin in the phospholipid composition of the nanoparticles has a higher antitumor activity in experimental tumor compared with free doxorubicin, which is manifested in the increased accumulation of the drug in tumor tissue and more intense inhibition of tumor growth.

To characterize the properties of doxorubicin in the phospholipid composition of the nanoparticles, which may have an impact on its specific activity, experiments were carried out in vitro by incubation of NP-doxorubicin with heparinized blood taken from rats male Wistar weighing about 400 g Were considered the distribution of the drug in the blood between erythrocytes and plasma, and plasma between the separate classes of lipoproteins in healthy animals.

Distribution of free doxorubicin and doxorubicin in the phospholipid composition of the nanoparticles in the blood

The distribution between blood cells and plasma

There is literary evidence that doxorubicin, due to high nonspecific absorption activity when introduced into the blood associated largely with erythrocytes [16]. This reduces the proportion of active drug in the plasma, reducing the overall therapeutic effect. Therefore, when developing composition of the NF-doxorubicin was considered useful to assess the possible changed the e such nonspecific binding in a new dosage form.

The experiment:

1) to 900 ml of heparinized blood was added 100 μl of a solution of doxorubicin or NF-doxorubicin concentration of 2 mg/ml (which corresponds to the concentration of the drug in the blood sample of 200 μg/ml);

2) were incubated at 37°C under stirring for 30 or 60 minutes;

3) selected 50 μl of blood was added to 450 μl of a mixture of methanol with 0.5% TFU, stirred on the vibrator, centrifuged and supernatant was collected for analysis;

4) 100 μl of blood from the same tubes were centrifuged to precipitate formed elements. To 50 μl of plasma was added to 450 μl of a mixture of methanol with 0.5% TFU, stirred on the vibrator and centrifuged, selecting the supernatant for analysis;

5) in the resulting sour-methanol extracts of whole blood and plasma was determined by the content of doxorubicin using HPLC. The results were calculated on the content of drug in 1 ml of the original whole blood (figure 1). The content of doxorubicin in structural elements were determined by difference.

On the drawing, you can see that with the inclusion of doxorubicin in the composition of phospholipid nanoparticles (NP-doxorubicin) reduced the percentage of drugs associated with uniform elements of blood. This increases the relative proportion of free drug that can have a therapeutic effect.

The distribution of doxorubicin in plasma for the freedoms of the CSOs drugs and NF-doxorubicin

In recent years clearly shows the impact on the pharmacokinetics and distribution of drugs in the body the way it is distributed in plasma, i.e. binding to the separate classes of lipoproteins and plasma proteins (primarily albumin). Since 2002, the Administration for control of food and drugs (FDA) the U.S. this study is required when registering new drugs, including lipophilic components [17]. It was therefore deemed appropriate to characterize this aspect and NF-doxorubicin.

The experiment:

1) in a test tube with heparin collected the blood of rats (8 ml blood by 1.6 ml of heparin solution), centrifuged and collected in two tubes of 3.8 ml plasma;

2) was added 200 μl of a solution of doxorubicin or NF-doxorubicin to plasma concentration 0.1 mg/ml;

3) were incubated for 30 minutes at 37°C;

4) for fractionation of lipoproteins by density) was added to 2 g of crystalline NaBr, was stirred until complete dissolution of salt and just added 6 ml of a solution of NaBr density 1,019 g/ml;

5) was centrifuged in an ultracentrifuge Optima L90K Beckman at 41000 rpm in the angular rotor 65 at 4°C for 2 hours;

6) collected fractions from the top to the height of the tube, 1-2 ml, corresponding to the lipoproteins of very low lipoproteins (VLDL), low (LDL) and high density and ostavshuusa the bottom of the protein fraction (without lipoproteins);

7) an aliquot of each fraction was treated with 9-fold volume of methanol, separating the precipitated proteins by centrifugation (10 min at 3000 rpm), and analyzed methanolic extracts using HPLC. The results are presented in figure 2.

From the submitted drawing shows that when using the NF-doxorubicin distribution of drugs is shifted from the albumen fraction of the plasma to the lipoproteins, mainly to HDL, which may also be partly responsible for increasing its penetration into the tumor tissue.

Assessment of the relative strength of binding of doxorubicin in the composition of the nanoparticles of the composition of the NF-doxorubicin

Additional description of the medicinal composition of doxorubicin is also the duration of the retention of drug in the composition nanofactories particles. The criterion would be the extent of binding of free drugs with plasma proteins - in the case of incubation of plasma with a free or NF-doxorubicin. To detect this binding was used ultrafiltration preincubating plasma in combination with treatment with Triton X-100, a destructive protein complexes, with the release of the free drug.

The experiment:

1) to 900 ál of plasma was added free or NF-doxorubicin to the concentration of doxorubicin 0.5 mg/ml and incubated for 4 hours at room te is the temperature;

2) was added Triton X-100 to a concentration of 1% and incubated for 10, 30 or 90 minutes.

3) plasma after incubation with Triton X-100 was subjected to ultrafiltration, the ultrafiltrates were treated with methanol as described above, and methanol extracts was determined by the concentration of doxorubicin using HPLC. The results are presented in figure 3.

Due to the fact that during ultrafiltration of plasma proteins are retained and do not pass into the filtrate, the absence of doxorubicin indicates the absence of plasma free drug, in both cases. In the case of a plasma with free doxorubicin his appearance in the processing of Triton, up to almost full output, suggests that doxorubicin source was in a complex with components of the plasma, destroyed by Triton. In plasma, incubated with NF-doxorubicin, the release of free drug is 1.5 times slower. Thus, we can conclude that a significant portion of the medication during the 4-hour incubation was protected from complexing with plasma proteins, as she was part nanofactories particles.

Indicators of the degree of toxicity of free doxorubicin and doxorubicin in the composition of phospholipid nanoparticles

Comparative evaluation of the toxicity of both forms of doxorubicin was performed on mouse on the x-male BDF1, weighing not less than 18-20, Was set LD50after a single intravenous injection:

LD50for NF-doxorubicin - 12,4 mg/kg;

LD50for drug free doxorubicin (LANCE Pharm) - 12,8 mg/kg

Tolerability was comparable: in none of the groups was not observed in the animals ' death.

Thus, doxorubicin in the composition of the phospholipid composition in the form of nanoparticles 10-30 nm to actively accumulate in tumor tissue and effectively inhibits tumor growth in mice with adenocarcinoma of the LLC. In vitro experiments for this composition (code name "localip") shows a large proportion does not bind to blood cells, doxorubicin, and redistribution in the plasma of the blood from the protein fraction to lipoproteins. Shows the stability of the particles of docsalive by incubation with blood within 4 hours. Indicators of toxicity maxolip compared with free doxorubicin production LENS Pharm.

LITERATURE

1. Doxorubicin hydrochloride, the European Pharmacopoeia. Sixth Edition, 2005, 1389-1390.

2. Register of medicines of Russia, M., 2000

3. Terasaki T., Iga, T., Sugiyama Y., Sawada Y., Hanano M. Nuclear binding as a determinant of tissue distribution of adriamycin, daunomycin, adriamycinol, daunorubicinol and actinomycin D. J. Pharmacobiodyn. 1984, 7(5), 269-277.

4. Abraham S.A., Waterhouse D.N., L.D. Mayer, P.R. Cullis, T.D. Madden, Bally M.B. The liposomal formulation of doxorubicin. Methods Enzymol. 2005, 391, 71-97.

5. Drummond D.C., C.O. Noble, M.E. Hayes, J.W. Park D.B. Kirpotin Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development. J Pharm Sci. 2008, 97(11), 4696-4740.

6. Pérez-López M.E., Córiel So, Gymez J.G., Jorge M. Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer. Anticancer Drugs. 2007, 18(5), 611-617.

7. Kaplun A.P., Le Bang Sean, Krasnopolsky, Y.M., Shvets V.I. Liposomes and other nanoparticles as a means of drug delivery. The matters. The honey. Chemistry, (1999) 45, 1-12.

8. Cowens J.W., Creaven P.J, Greco W.R., D.E. Brenner Doxorubicin Encapsulated in Liposomes. Initial Clinical (Phase I) Trial of TLC D-99. Cancer Research 1993, 53, 2796-2802.

9. Ipatov O.M., Zykova MG, Targovska TI, Medvedev, NV, Prozorovsky NR. The possibility of using phospholipid nanosystems with glycyrrhizic acid (Phosphogliv) to optimize drug, for example, doxorubicin and budesonide. Biomedical chemistry, 2009, 55(2), 185-194.

10. Sonar, S., D'souza SE, K.P. Mishra A simple one-step protocol for preparing small-sized doxorubicin-loaded liposomes. J Environ Pathol Toxicol Oncol. 2008, 27(3), 181-189.

11. Ying X.Y., Y.Z. Du, W.W. Chen, Yuan H., Hu, F.Q. Preparation and characterization of modified lipid nanoparticles for doxorubicin controlled release. Pharmazie. 2008, 63(12), 878-882.

12. Morita K., Zywietz F., Kakinuma K., Tanaka R., Katoh M. Efficacy of doxorubicin thermosensitive liposomes (40 degrees C) and local hyperthermia on rat rhabdomyosarcoma. Oncol Rep. 2008, 20(2), 365-372.

13. Rai, S., Paliwal R., Vaidya C., K. Khatri, A.K. Goyal, Gupta P.N., Vyas S.P. Targeted delivery of doxorubicin via estrone-appended liposomes. J Drug Target. 2008, 16(6): 455-463.

14. A.B. Madhankumar, Slagle-Webb C., X. Wang, Q.X. Yang, D.A. Antonetti, P.A. Miller, J.M. Sheehan, J.R. Connor Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model. Mol Cancer Ther. 2009 Mar; 8(3): 648-54.

15. Tng N., Du G., Wang, N., Liu C., Hang, H. W. Liang Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin. J Natl Cancer Inst. 2007, 99(13), 1004-1015.

16. Marczak, A., Kowalczyk A., Wrzesień-Kus A., Robak, T., Jóźwiak Z. Interaction of doxorubicin and idarubicin with red blood cells from acute myeloid leukaemia patients. Cell Biol Int. 2006, 30(2), 127-132.

17. Wasan C.M., D.R. Brocks, Lee S.D. Impact of lipoproteins on the biological activity and disposition of considered are hydrophobic drugs: implications for drug discovery. Nat. Rev. Drug Discov. 2008; 7(1): 84-99.

Pharmaceutical composition for treatment of cancer in the form of phospholipid nanoparticles with a size of 10-30 nm, including 78-95%phosphatidylcholine vegetable origin, maltose and doxorubicin in the following ratio, wt.%:

Phosphatidylcholine20-43
Maltose55-78
Doxorubicin2-8



 

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54 cl, 412 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new polyprenylated 1,4-benzoquinones of formula 1 or formula 3 or polyprenylated 1,4-hydroquinones of formula 2 or formula 4, or to their pharmaceutically acceptable salts exhibiting anticarcinogenic activity 1, 2, 3, 4. In formulae 1-4 each of R1 and R2, irrespectively of others, can be a hydrogen radical or (C1-C6)-alkoxy-group; each of R3 and R4 irrespectively of others, can be a hydrogen radical or (C1-C6)-alkyl group; n can be equal to 2 or 3.

EFFECT: provided application of new compounds and some common 1,4-benzoqunones and 1,4-hydroqunones for preparing a drug, a based pharmaceutical composition, development of a method of oncotherapy, a method of inducing AP-1-dependent or NF-kB-independent transcription activity or both activities simultaneously in a cell and a method of inducing apoptosis in a cell, as well as separating glabruquinones.

21 cl, 3 tbl, 28 dwg, 26 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in chemotherapy of hepatic metastases. The method involves radio-frequency thermal ablation followed by treating hepatic tissue within a necrosis region with an aqueous solution of 5-fluorouracil. The solution contains 5-fluorouracil 0.087 wt %, water for injections 1.754 wt %, low-molecular polyethylene 67.114 wt %, emulsifier T-2 16.778 wt %, microcrystalline gelatine 6.717 wt %, oil olive 7.550 wt %.

EFFECT: invention provides prevention of general toxic effect and malignant cell enlargement ensured by prolonged release 5-fluorouracil for 4 weeks.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is sugar-cholestanol compound, which can be easily synthesized, and which demonstrates sufficient anti-tumour activity.

EFFECT: claimed is anti-tumour medication, which as active ingredient, contains cholestanol compound, represented by the following formula (1) or cyclodextrin complex of inclusion, which contains said compound.

6 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel additive salt of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino-1H-pyrazole-3-carboxylic acid and acid, where said salt is obtained with application of acid, selected from metasulfonic acid and acidic acid and their mixtures. Invention also relates to methods of obtaining additive salt of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid and acid with acid, to method of obtaining of pyperidin4-ylamide of 4-(2,6-dichlorbenzoylamino-1H-pyrazole-3-carboxylic acid, to method of obtaining intermediate compound of formula (XIII), to novel intermediate compound of formula (XII), to method of obtaining pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to method of prevention and treatment of disease or disease state mediated by cyclin-dependent kinase or glycogen synthase-3 kinase, to method of state alleviation or reduction of manifestations of disease or disease state, mediated by cyclin-dependent kinase or glycogen synthase-3 kinase, to method of treatment of disease or state, which includes abnormal cell growth or resulting from abnormal cell growth in mammal, to method of alleviation of state or reduction of manifestations of disease or state, which includes abnormal cell growth or resulting from abnormal cell growth in mammal, to method of treatment of disease or state, which includes abnormal cell growth or resulting from abnormal cell growth in mammal, to application of additive salt with acid of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to method of treating B-cell lymphoma, diffuse B-large cell lymphoma or chronic lymphocytic leukemia, to method of diagnostics and treatment of disease or disease state, mediated by cyclin-dependent kinase, to application of additive salt with acid of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to method of inhibiting tumour growth in mammal, as well as to method of inhibiting tumour cell growth.

EFFECT: obtaining novel biologically active compounds, which possess anti-proliferative activity.

75 cl, 19 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel additive salt of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino-1H-pyrazole-3-carboxylic acid and acid, where said salt is obtained with application of acid, selected from metasulfonic acid and acidic acid and their mixtures. Invention also relates to methods of obtaining additive salt of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid and acid with acid, to method of obtaining of pyperidin4-ylamide of 4-(2,6-dichlorbenzoylamino-1H-pyrazole-3-carboxylic acid, to method of obtaining intermediate compound of formula (XIII), to novel intermediate compound of formula (XII), to method of obtaining pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to method of prevention and treatment of disease or disease state mediated by cyclin-dependent kinase or glycogen synthase-3 kinase, to method of state alleviation or reduction of manifestations of disease or disease state, mediated by cyclin-dependent kinase or glycogen synthase-3 kinase, to method of treatment of disease or state, which includes abnormal cell growth or resulting from abnormal cell growth in mammal, to method of alleviation of state or reduction of manifestations of disease or state, which includes abnormal cell growth or resulting from abnormal cell growth in mammal, to method of treatment of disease or state, which includes abnormal cell growth or resulting from abnormal cell growth in mammal, to application of additive salt with acid of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to method of treating B-cell lymphoma, diffuse B-large cell lymphoma or chronic lymphocytic leukemia, to method of diagnostics and treatment of disease or disease state, mediated by cyclin-dependent kinase, to application of additive salt with acid of pyperidin-4-ylamide of 4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxylic acid, to method of inhibiting tumour growth in mammal, as well as to method of inhibiting tumour cell growth.

EFFECT: obtaining novel biologically active compounds, which possess anti-proliferative activity.

75 cl, 19 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula I, as well as to their diastereoisomers, enentiomers and/or pharmaceutically acceptable salts, which possess inhibiting action with respect to cyclin-dependent kinases and/or tyrosinekinases of VEGF receptor. In compound of general formula (I) Q stands for group where D, E, G, L, M and T in each case represent carbon, R1 represents hydrogen, halogen or CF3, R2 represents C1-C10-alkyl, which can optionally be disrupted with one group-C(O), C2-C10-alkinyl, C3-C10-cycloalkyl or phenyl, which is optionally substituted in one or more places in similar or different way by hydroxyl, halogen, C1-C6-alkoxy, C1-C6-alkyl, C3-C10-cycloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl or -COR8, X represents oxygen, sulphur or group -NH-, R3 represents hydroxy, halogen, CF3 or C1-C6-alkoxy, m represents 0-4, R4 represents hydrogen or group -COR8, NO2 or -SO2R7, or represents C1-C10-alkyl or C3-C10-cycloalkyl, R5 represents C1-C10-alkyl, which can be optionally substituted in one or more places, in similar or different way, by hydroxyl or C3-C10-cycloalkyl, or C3-C10-cycloalkyl, R7 represents C1-C10-alkyl, which is optionally substituted by group trimethylsilanyl (TMS), R8 represents C1-C6-alkyl, C1-C6-alkoxy. Invention also relates to intermediate compounds.

EFFECT: compounds can be applied for obtaining medication intended for treatment of cancer, selected from Kaposhi's sarcoma, Khodgkin's disease, leukemia or solid tumour, such as carcinoma of mammalian gland, kung, large intestine or prostate gland, autoimmune disease, such as psoriasis, and/or proliferative diseases, such as hemangioma or angiofibroma.

21 cl, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in order to prevent cancerogenic action of methylnitrosourea in experimental animals, methylnitrosourea is introduced to experimental animals subcutaneously in combination with anticancerogen. Introduction of anticancerogen starts from the first day of experiment with forage simultaneously with methylnitrosourea. Methylnitrosourea is introduced in dose 2.5 mg per a rat in 0.2 ml of injection water five times with one week interval during 1.5 months into tissue of the same mammalian gland at the base of left front paw. As anticancerogen, curcumin is given with forage in dose 200 mg/kg of forage 4 times per week during 8 months.

EFFECT: method ensures prevention of cancerogenic action of methylnitrosourea in experimental animals, which includes application of polyphenol compound of curcumin in phase of cancerogenesis promotion, when process of healthy cell transformation into tumour cell takes place.

3 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to an immunoliposomal form of a photosensitiser form on the basis of tetra-3-phenylthiophthalocianine aluminium hydroxyl which is used in photodynamic therapy of malignant tumours. The immunoliposomal form contains said photosensitiser (0.011 g), egg phosphatidylcholine (2.2 g), cholesterol (0.264 g), mPEG2000-DSPE [methoxy(polyethylene glycol-2000)] 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N (0.0528 g), (pNP-PEG3400-DOPE) 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine-N-[n-nitrophenylcarbonyl (polyethylene glycol-3400)] (0.0176 g), triple-substituted sodium citrate (0.53 g) and anti-CD5 MCA (ICO-80) (anti-CD5 monoclonal antibodies) (0.00237 g).

EFFECT: high phototoxic effect.

3 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: method for producing immobilised bilayer vesicles is ensured by processing a carrier containing graft polymer chains, with a bilayer vesicle suspension in water or a water-salt solution. In implementing said method, the carrier is presented with modified solid surfaces or modified disperse particles. The given carriers contain at least one cationic or anionic graft polymer of polymer density not less than 200 polymer chains per one square micron of a carrier surface. The bilayer vesicles are anionic or cationic vesicles consisting of at least one amphiphile surface-active substance and carrying a surface charge opposite in sign to a charge of the polymer-modified carrier surface.

EFFECT: simplified method for producing immobilised bilayer vesicles.

2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel surfactants of formula III and their use in obtaining nanoparticles which serve as vectors for biologically active ingredients. , and , where R3 is selected from group IV or V; Y is a sulphur atom or -NH-CO-(CH2)n-X-; X is a sulphur atom or -CH2-; n and y are integers from 0 to 10; R is a hydrocarbon, fluorinated hydrocarbon or thioalkyl; W is -NH- or CH2-; p is an integer from 1 to 50; m is an integer from 0 to 9; and if X = CH2, 0 < m+n < 6; x is an integer from 0 to 30; R1 is selected from the following radicals: where R' is H or polyhydroxylated hydrocarbon; R2 is an identification group which has affinity to a biological target; Z is a spacer group.

EFFECT: design of novel surfactants and nanoparticles based on the said surfactants.

22 cl, 9 ex, 2 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to carbohydrate-containing polycationic amphiphiles (1-3) which are trihydrochlorides of rac-N-[6-(β-D-glycopyranosyloxy)hexyl]-N-[2,3-di(tetradecyloxy)prop-1-yl]-4-[(12-amino-4,9-diazadodec-1-yl)amino-succinylamino]benzenesulfonamide of the given general formula , where A is a 1,2-di-O-tetradecyl-rac-glycerin residue, B is a galactose residue (for (1)), galactose (for (2)) and mannose (for (3)), C is a spermine residue, n= 6, m = 2.

EFFECT: obtaining compounds which are capable of delivering nucleic acid into mammal cells.

1 cl, 4 tbl, 2 dwg, 11 ex

FIELD: medicine.

SUBSTANCE: invention relates to application of compositions for local application which contain epidermal growth factor. Invention is aimed at application of efficient amount of epidermal growth factor, incapsulated or bound with deformable or ordinary liposomes, for production of pharmaceutical composition for local application for treatment of diabetic foot ulcers of IV and V severity degree in patients with diabetes.

EFFECT: invention ensures high EGF bioavailability in tissues deeply lower than affection nodes and allows to prevent amputation caused by diabetic foot.

8 cl, 8 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and cosmetology and represents derivatives of hyaluronic acid structurally organised with unilamellar liposomes or in them, for injection as soft tissue filler and/or for correction of skin defects and/or for integration into synovial fluid or for replacement of synovial fluid in case of intra-articular treatment of osteochondrosis, where said derivatives are selected from group including esters, internal esters, amides, O-sulphated derivatives, percarboxylised derivatives and deacetilated derivatives, where molecular mass of hyaluronic acid is within the range from 50000 to 3×106 Da, liposomes are formed by phospholipids and concentration of phospholipid is within the range from 0.1 to 50 mg/ml.

EFFECT: invention relates preservation of said fillers during long time in the area of their application, which considerably reduced necessity of their frequent introduction with preservation of properties of biocompatibility, safety and easiness of processing.

12 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention belongs to medicine and pharmacology, notably to stable in storage nanosystem with particle size up to 10-30 nm which includes plant-based phosphatidilcholine and maltose and designed for inclusion of medication into phospholipid particle, to method of nanosystem producing, to phospholipid composition of medication in form of phospholipid nanoparticles 10-30 nm, including phosphatidilcholine, maltose and medication, and to method of mentioned nanosystem manufacture.

EFFECT: storage stability of the system.

12 cl, 3 dwg, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and medical therapy, to sphere of ultrasound therapy. Fluocarbon emulsion activator for highly-intensive focused ultrasound therapy (HIFU therapy) is described, which can increase sound therapy deposition at the target during HIFU therapy. The activator contains an internal phase consisting of nuclear substance encapsulated in membrane forming substance and continuous phase consisting of water medium. Internal phase is uniformly dispersed in continuous phase, particle size in the internal phase being within 0.1-1 mcm; the amount of membrane forming substance in the activator being 0.1-100 g/k; nuclear substance consists of liquid with liquid-gas transition within the range of 38-100°C, and nuclear substance in the activator amounts to 5-200 ml/l. The result is improved clinical HIFU therapy potential in cancer cells removal without affecting healthy tissues within the ultrasound path.

EFFECT: invention discloses application of fluocarbon emulsion activator for HIFU therapy in the course of HIFU therapy.

16 cl, 6 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention is a pharmaceutical composition for psoriasis and eczema treatment, containing trailing mahonia extract in loposomal delivery system. The extract content in the composition is 5-20% of the composition total weight. The invention also concerns method for production of trailing mahonia extract.

EFFECT: pharmaceutical composition is especially effective for psoriasis and eczema treatment among patients of various degrees of disease.

8 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, namely to creation of a new inter- and intra- multilayer vesicular composition containing a drug dithranol used for psoriasis treatment. A controlled release vesicular composition used for drug delivery containing a set of dispersed concentric two-layer vesicles with an external layer enclosing an aqueous hydrocolloid gelling agent, and an internal layer being a lipid phase. Both layers have a drug dispersed in the concentration 70-80% in the internal layer and 20-30% in the external layer. Particularly, the composition contains as follows, %: dithranol 0.25-1.0; phospholipid 8-12; cholesterol 3-7; butylated hydroxytoluol 0.1-0.5; hydrocolloid gelling agent 0.5-3.0; a phosphate salt buffer - the rest. The average vesicle size in the composition varies in the range 1-10 micron. The hydrocolloid gelling agent possesses thixotropic rheological characteristic and particularly represents methyl cellulose. Besides the invention concerns application of said composition for drug delivery for treatment of dermal problems, particularly psoriasis. The invention improves efficiency of molecules of the drug in a reduced dose, makes the composition more acceptable with relation to rheology, and stable, provides the absence of irritation and stains formation, is easily applied (remains on an injured area). The declared composition can contain the increased amount of the drug without irritation and stains formation when severity of disease requires increased doses.

EFFECT: product is characterised by improved therapeutic properties of dithranol combined with some other favourable properties.

6 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is sugar-cholestanol compound, which can be easily synthesized, and which demonstrates sufficient anti-tumour activity.

EFFECT: claimed is anti-tumour medication, which as active ingredient, contains cholestanol compound, represented by the following formula (1) or cyclodextrin complex of inclusion, which contains said compound.

6 cl, 2 ex, 1 tbl

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