Pharmaceutical compositions comprising polysaccharide conjugates for inhibition of metastasis or prophylaxis in malignant tumor relapse

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions used for inhibition of metastasis or prophylaxis of malignant tumor relapse after the topical therapy. As an active component, compositions contain derivative of polysaccharide comprising polysaccharide with carboxyl group bound with an active substance possessing anti-tumor activity through amino acid or peptide consisting of from 2 to 8 amino acids that are similar or different, or its salt wherein this active anti-tumor substance is represented by derivative of camptothecin of the formula (I) by claim 1 or compound of the formula (II) by claim 1 given in the invention description. The topical therapy involves surgery, radiation therapy, thermotherapy, cryotherapy or laser-burning therapy. Proposed compositions allow providing the high concentration of active substance in tumor metastasis region and prophylaxis of relapses of malignant tumor after carrying out the topical therapy.

EFFECT: valuable medicinal properties of pharmaceutical compositions, improved method of treatment.

9 cl, 1 dwg, 4 tbl, 6 ex

 

The technical field to which the invention relates.

The present invention relates to pharmaceutical compositions for the inhibition of metastasis or prevent recurrence of a malignant tumor. In particular, the present invention relates to pharmaceutical compositions for the inhibition of metastasis or prevent recurrence of a malignant tumor, which contains as active ingredient a derivative of the polysaccharide, comprising the polysaccharide with carboxyl group associated with the active substance having antitumor activity, for example, a derivative of camptothecin formula (I) or (II)as mentioned below, through amino acid or a peptide comprising 2 to 8 amino acids, which are the same or different, or its salt.

The level of technology

Malignant tumors are one of the main causes of death in developed countries, and the majority of deaths associated with malignant tumors, occur due to metastasis to distant organs or relapse, followed by metastasis to distant organs after local therapy. Metastases in distant organs can be caused by hematogenous metastasis or lymphogenous metastasis and it is known that patients with lymphogenous metastases who are at high risk of recurrence of malignant tumors after local terap is I. The main bodies for relapse are the brain, lung, liver and bone. In particular, the tumor in the digestive organs, such as colon cancer that affects a large number of patients, can invade and spread to the liver, and breast cancer and lung cancer are also often invade and spread to the liver. Next, lymphoma and lymphatic leukemia can spread mainly in the lymphatic system and there are reports that the autopsy reveals metastases in the liver with a high frequency.

In order to inhibit the recurrence, including metastasis to distant organs, such as metastasis to the liver, and to prolong life, use chemotherapy and other methods of maintenance therapy after local treatment, but chemotherapy is more toxic and cannot be used for regular use. In addition, almost no has been reported that the lifetime in the more extended use of supportive care in chemotherapy than one local therapy. For example, in experiments on chemotherapy on the patient, who was the object of surgical interventions for extensive gastric cancer, one of the cancers of the digestive organs, conducted clinical trials of various agents against malignant tumors, but no therapeutic meth is d, demonstrating significantly better survival than one surgery, has not been set.

Under these circumstances it would be desirable to find a new agent, effective for the inhibition of the recurrence or to prolong life after local therapy, applicable in respect of metastases to lymph nodes and distant organs with little side effects and is suitable for continuous administration.

On the other hand, WO 94/19376, WO 97/46260, WO 97/38727, JP-A-10-72467 and JP-A-10-95 802 reveal polysaccharide derivative, including a polysaccharide that is associated with the active substance with antitumor activity through amino acid or peptide.

However, these publications disclose the use of these polysaccharides for the treatment of cancers by their accumulation in the tumor and kill tumor cells, but it is nowhere specified activity against inhibition of metastasis or prevent recurrence of a malignant tumor.

Disclosure of inventions

The object of the present invention to provide a new pharmaceutical composition for the inhibition of metastasis or prevent recurrence of malignant tumors.

There have been numerous studies and it was found that a derivative of the polysaccharide, comprising the polysaccharide with carboxyl group associated with having antitumor the th activity of the active substance through amino acid or peptide, has an excellent effect in the inhibition of metastasis and/or preventing recurrence of a malignant tumor, allowing the present invention. Thus, the present invention relates to pharmaceutical compositions for the inhibition of metastasis or prevent recurrence of a malignant tumor, which comprises as an active ingredient derived polysaccharide, comprising the polysaccharide with carboxyl group associated with the antitumor activity of the active substance through amino acid or a peptide comprising 2 to 8 amino acids, which are the same or different, or its salt.

Brief description of figures

The drawing shows the number of days after implantation of the tumor and the number of surviving animals in models of liver metastasis M 5076.

The implementation of the invention

The polysaccharide with carboxyl group in accordance with the present invention includes the same polysaccharides, which are disclosed in the aforementioned WO 94/19376 and WO 97/46260, and includes polysaccharides with carboxyl groups, which initially contains in its structure (for example, hyaluronic acid, pectic acid, alginic acid, chondroitin, heparin, etc), and polysaccharides, initially containing no carboxyl group (for example, pullulan, dextran, Mann is h, chitin, monoglycol, chitosan and so on), but which are inserted in them, and polysaccharides, having initially carboxyl group in its structure, but in which carboxyl groups are introduced after the formation of the polyalcohol (for example, the polysaccharide polisport having a carboxyl group).

Polysaccharide, having initially carboxyl group, but which introduces carboxyl group, means polysaccharides, which is obtained by substitution of hydrogen atom part or all of hydroxyl groups of polysaccharides, having initially carboxyl group, carboxy-C1-4is an alkyl group.

In the present invention the polysaccharide includes those polysaccharides which are obtained by processing the polysaccharide did not initially have a carboxyl group using a reducing agent, followed by substitution of the hydrogen atom of part or all of hydroxyl groups of the resulting compound on the carboxy-C1-4is an alkyl group.

Polysaccharide polisport having a carboxyl group includes, for example, carboxy-C1-4-alkylpolyglucoside polisport, which is obtained by processing the polysaccharide did not initially have a carboxyl group, consistently with periodates sodium and sodium borohydride according to the method described in WO 97/46260, obtaining the polysaccharide polisport, which is then treated with haloge the new 1-4-alkalicarbonate acid.

The alkyl portion of the carboxy-C1-4is an alkyl group that replaces a hydrogen atom of hydroxyl groups of the above-mentioned polysaccharide (including a polysaccharide polisport)may or alkyl group with a linear chain, or alkyl group branched chain.

Preferred carboxy-C1-4is an alkyl group are, for example, carboxymethyl group, 1-carboxyaniline group, 3-carboxypropyl group, 1-methyl-3-carboxypropyl group, 2-methyl-3-carboxypropyl group, 4-carboxybutyl group, etc. and carboxymethyl group is most preferred.

In the present invention, the polysaccharide having a carboxyl group, preferably represents a carboxy-C1-4-alkyldimethyl or carboxy-C1-4-alkyldimethyl polisport, and carboxy-C1-4-alkyldimethyl is especially preferred.

The degree of education of polysperma (by successive oxidation periodates sodium and restore the sodium borohydride) at the stage of obtaining carboxy-C1-4-alkylpolyglucoside polisport mentioned above, is not defined, but intermediate the polysaccharide polisport preferably obtained by treatment of the polysaccharide under conditions allowing essentially almost complete education polisport.

Bol is e, in the present invention, the polysaccharide having a carboxyl group, preferably represents karboksimetilirovaniya dextran or karboksimetilirovaniya the dextran-polisport, and among these particularly preferred polysaccharides is dextran having an average molecular weight of from 20,000 to 500,000, and dextran having an average molecular weight between 50,000 to 350,000, is the most preferred (specified average molecular weight determined by gel permeation chromatography (GPC), Shinseikagaku, Jikken Koza, Vol.20, R, Tokyo-Called-Dojin, 5.11.1991).

With the introduction of carboxialkilnuyu groups in polysaccharides degree of its introduction is expressed as "degree of substitution", which is determined by the number carboxialkilnuyu groups (including groups of the peptide chain, the input of these groups per sugar residue. This is expressed by the following equation.

When carboxialkilnuyu group is carboxymethyl group, the degree of substitution is sometimes expressed by the degree of karboksimetilirovaniya (CM-degree).

When the polysaccharide is a dextran, the degree of substitution is preferably in the range of from 0.3 to 0.8. When the polysaccharide is a dextran-polisport, the degree of substitution is preferably in the range from 0.3 to 0.5.

The amino acid or peptide of nastoyascheevremya play the role of a spacer (link), existing between the polysaccharide having a carboxyl group, and an active substance having antitumor activity, and an amino acid or amino acid, forming the specified peptide includes natural amino acids and synthetic amino acids (including D-amino acids, L-amino acids, their mixture), and also includes both neutral amino acids, basic amino acids and acidic amino acids. In addition, the amino acid of the present invention can be not only α-amino acid, but also β-amino acids, γ-amino acids, ε-amino acids, etc.

Examples of amino acids are glycine, α-alanine, β-alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, lysine, citrulline, arginine, phenylalanine, tyrosine, Gastein, tryptophan, Proline, hydroxyproline, γ-aminobutyric acid, ε-aminocaproic acid, etc.

The peptide of the present invention includes a peptide comprising 2 to 8 amino acids, preferably 2-5 amino acids, which are the same or different. Examples of peptides are glycyl-glycyl-L - or D-i.e. phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, L-or D-i.e. phenylalanyl-glycine, L - or D-tyrosyl-glycine, L - or D-leucyl-glycine, L-or D-i.e. phenylalanyl-citrulline and L - or D-poured-citrulline (N-end of these peptides vvedeno in the carboxyl group of the polysaccharide).

Among these peptides are preferred glycyl-glycyl-L - or D-i.e. phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine and L - or D-i.e. phenylalanyl-glycine.

Active substance having antitumor activity of the present invention may contain various compounds known as an antitumor agent, and may be a cytotoxic agent or cytostatic agents. The cytotoxic agent is preferably a derivative of camptothecin and derivatives taxane, and the cytotoxic agent is a preferred angiogenesis inhibitors, inhibitors of the EGF receptor. More preferably, the cytotoxic agent is a derivative of camptothecin and cytotoxic agent is an inhibitor of angiogenesis.

Examples of derivative camptothecin are the compounds of formula (I)disclosed in JP-A-10-72467:

where R1represents a substituted or unsubstituted lower alkyl group, X1represents a group of formula: -other2(R2represents a hydrogen atom or a lower alkyl group) and Alk represents a C1-6-alkylenes group with a linear chain or branched chain, having PR is necessary in the chain an oxygen atom. Among them, preferred is a compound 10-(3'-aminopropoxy)-7-ethyl-(20S)-camptothecin.

Other examples of derived camptothecin are the compounds of formula (II)disclosed in JP-A-10-95802:

where two groups of numbers from R2to R6that are adjacent to each other, combined with the formation of the lower alkalinous group, and one of the carbon atoms indicated lower alkalinous group, substituted amino group, and the remaining three groups of numbers from R2to R6represent a hydrogen atom, a lower alkyl group or halogen atom. Among them, preferred is the compound (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo [de]pyrano [3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione, etc.

Examples of derivatives taxane are Taxol, Taxotere, 13-[(2'R,3'R)-3'N-tert-butyloxycarbonyl-3'-cyclopropyl]-10-deacetylbaccatin III, etc.

The active ingredient of the present invention the ratio of the polysaccharide and the active substance having antitumor activity, can be selected in accordance with the form of the polysaccharide, which should be used, but when the polysaccharide is dextran or dextran polisport, then the content of the active substance having antitumor activity, preferably is in the range from 0,to 20% by weight, more preferably in the range from 2 to 10% by weight calculated on the total weight of the active ingredient.

Among the active ingredients of the present invention are preferred polysaccharide derivatives or their salts in which the amino acid or a peptide comprising 2 to 8 amino acids, which are the same or different, is introduced into a portion or all of carboxyl groups of the polysaccharide having a carboxyl group, through acid-amide bond, and the remaining part or all of amino groups or carboxyl groups that are not involved in binding with the carboxyl groups of the above-mentioned peptide linked to carboxyl groups, amino groups or hydroxyl groups of the active substance having antitumor activity, through acid-amide bond, or a complex of essential communication.

Particularly preferred active ingredient is a derivative of the polysaccharide, in which the polysaccharide having a carboxyl group is karboksimetilirovaniya acid, the active substance having antitumor activity, is 10-(3'-aminopropoxy)-7-ethyl(20S)-camptothecin and the peptide is glycyl-glycyl-glycine or its salt. Especially preferred is a derivative of the polysaccharide, in which the polysaccharide having a carboxyl group is karboksimetilirovaniya a code of the Russian Academy of Sciences, having an average molecular weight from about 60,000 to 200,000, and a degree of karboksimetilirovaniya it is in the range from 0.3 to 0.8, or its salt.

Other preferred active ingredient is a derivative of the polysaccharide, in which the polysaccharide having a carboxyl group is a carboxy-C1-4-alkyldimethyl polisport, active substance having antitumor activity, is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]-quinoline-10,13(N,15 NM)-Dion and the peptide is glycyl-glycyl-L - or D-i.e. phenylalanyl-glycine, or its salt, and particularly preferred is a derivative of a polysaccharide or its salt, in which the polysaccharide having a carboxyl group is a carboxy-C1-4-alkyldimethyl polisport having an average molecular weight of from 200,000 to 400,000, and the degree of substitution is in the range from 0.3 to 0.5.

Derived polysaccharide or salt of the active ingredient of the present invention can be obtained according to the methods disclosed in WO 94/19376, WO 97/46260, WO 97/38727, JP-A-10-72467 and JP-A-10-95 802.

The pharmaceutical composition of the present invention can actively accumulate in the website, such as lymph node or liver, which can spread the cancer can release the active substance with the appropriate sconosciuta, to view the active substance is barely touched on normal cells and inhibited the growth of tumor cells, and therefore, the pharmaceutical composition of the present invention is applicable for the inhibition of metastasis or to prevent recurrence of a malignant tumor. The pharmaceutical composition of the present invention is particularly applicable for the inhibition of metastasis lymph node or liver metastasis, in particular, are useful for inhibiting metastasis of lymph nodes. In addition, among the metastasis of lymph nodes present pharmaceutical composition suitable for inhibiting metastasis in lymph nodes from colon cancer or metastasis in the lymph nodes of the lung.

In addition, the present pharmaceutical composition may have an effect not only before the appearance of metastases, but also after the start of the formation of metastases. Therefore, the present pharmaceutical composition is also applicable for the inhibition of metastasis or prevent recurrence of malignant tumors after local therapy (e.g. surgery, radiotherapy, thermotherapy, cryotherapy, laser-burning therapy etc). In addition, the present pharmaceutical composition is also suitable for repeated dosing over a long period of time and can be used in conjunction with the local therapy.

The present pharmaceutical composition is preferably introduced parenteral (e.g. intravenous injection) and is normally introduced in the form of a liquid composition, such as solution, suspension, emulsion, etc.

The present pharmaceutical composition is preferably prepared in the form of injections or drip infusions, using distilled water for injection, physiological saline, aqueous glucose solution.

The dosage of the present pharmaceutical composition may vary depending on the route of administration, age, weight or condition of the patients and so on, but it is usually in the range of 0.002 to 50 mg/kg, more preferably in the range from 0.01 to 5 mg/kg, single dose, in terms of the amount of the active substance.

In the present description lower alkyl group and lower alkalinous group may be a group having from 1 to 6 carbon atoms, preferably having from 1 to 4 carbon atoms, and the halogen atom is fluorine atom, chlorine atom, bromine atom, iodine atom, etc.

Examples

Experiment 1 (model of liver metastasis M 5076)

One million cells M 5076 (cell sarcoma ovarian mouse) implanted male BDF1 mice (5 weeks of age, 8 animals per group) into the tail vein. The test compound (compound A, compound, obtained as described below in the section Preparation is t 1, and irinotecan (CPT-11)) dissolved in physiological saline, and each quantity specified in Table 1, as mentioned below, is injected mice on the 4th, 8th and 12th day after implantation, mice see within 120 days after implantation of the tumor. In the control group (untreated test compound) is injected only physiological saline. Observed survival time (days) in groups treated test compounds, and in the control group, and the level of life extension calculated according to the following equation. The results are shown in Table 1 and in the drawing.

Table 1
Dose (mg/kg)Days of lifeStandard errorThe level of life extension (%)
Control12,515,001,24-
Connection37,575,27150,5
2543,135,98187,5
5048,715,33of 224.8
Irinotecan8022,500,550
/p>

As shown in Table 1, the compound obtained as described below in the section Preparation 1 (compound A), shows excellent activity against life extension on models of liver metastasis M 5076. It should be noted that irinotecan is not known as a means for inhibiting metastasis, or prevent recurrence of a malignant tumor, and he was just tested as a drug from a number of derivative camptothecin.

Experiment 2 (metastatic model HT-29)

Segment (2 mm2) HT-29 cells (colon cancer person) are implanted into the vermiform Appendix in the female mouse 100NCr PI/PI (5-6 weeks of age, 10 animals per group). The test compound (compound A, compound, obtained as described below in the section Preparation 1, the connection; the connection is obtained, as mentioned below in the section Preparation 4, and irinotecan (CPT-11)) dissolved in physiological saline, and each number given in the following Table 2, is injected mice on the 15th, 19th, 23rd and 25th day after implantation of the tumor. On the other hand, the control group (untreated test compound) is injected only physiological saline. The presence or absence of metastasis of each body check on the 84 day after implantation of the tumor. The results are shown to follow the it Table 2.

1
Table 2
GroupThe number of animalsLymph nodeLiverEasyOther organs ***The number of animals with metastases
MI*P**MI*P**MI*P**MI*P**P**
Connection And

(40 mg/kg)****
100<0,0101,000,2101,00<0,01
Connection And

(20 mg/kg)****
101<0,0101,010,5801,02<0,01
Connection And

(10 mg/kg)****
1081,001,021,001,081,0
Connection And

(5 mg/kg) ****
1060,301,00,5821,060,30
Connection

(5 mg/kg) *****
100<0,0101,000,2101,00<0,01
Connection

(2.5 mg/kg) *****
1060,3011,010,5811,060,3
Irinotecan

(40 mg/kg)
1070,5801,010,5811,070,58
Irinotecan

(20 mg/kg)
1091,021,021,001,091,0
Control109-1-3-00000001-9-
*: MI refers to the frequency of metastasis.

**: P means standard deviation, where all the treated groups compared to the control is by using Fisher's exact test.

***: Including the diaphragm, the abdominal cavity and the chest cavity.

****: Dosage in terms of 10-(3'-aminopropoxy)-7-ethyl-(20S)-camptothecin.

***** Dosage per (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione.

Experiment 3 (metastatic model HT-29)

Segment (2 mm2) cells HT-29 (colon cancer person) are implanted into the vermiform Appendix to the female mouse 100NCr PI/PI (5-6 weeks, 10 animals per group). Because lymph node metastases observed in 49 day after implantation of the tumor, the test compound (compound A, compound, obtained as described below in section 1 Drug, irinotecan - (CPT-11)) dissolved in physiological saline, and each quantity specified in the mentioned below Table 3, is injected mice 51-th and 55 th, 59 and 63, the third day after implantation of the tumor. On the other hand, the control group (untreated test compound) is injected only physiological saline. The presence or absence of metastases in each organ were examined in 84-day after implantation of the tumor. The results are shown in the following Table 3.

Table 3
GroupThe number of alive is data Lymph nodeLiverEasyOther organs ***The number of animals with metastases
MI*P**MI*P**MI*P**MI*P**P**
Compound A (40 mg/kg)****1000,0101,000,2121,020,01
Compound A (20 mg/kg)****1020,0101,000,2111,030,01
Irinotecan

(40 mg/kg)
1081,011,000,2111,081,0
Control109-1-3-1-9-
*: MI refers to the frequency of metastasis.

**: P means standard the deviation, where all the treated groups were compared with controls using Fisher's exact test.

***: Including the diaphragm, the abdominal cavity and the chest cavity.

****: Dosage in terms of 10-(3'-aminopropoxy)-7-ethyl-(20S)-camptothecin.

Experiment 4 (metastatic model N)

Segment (2 mm2) cells N (human lung cancer) implanted in the left lung in female mice 100NCr PI/PI (5-6 weeks, 10 animals per group). Because metastases observed on the 14th day after implantation of the tumor in the other control group, the test compound (compound A, compound, obtained as described below in the section Preparation 1, the connection; the connection is obtained, as mentioned below in the section Preparation 4, and irinotecan (CPT-11)) dissolved in physiological saline, and each quantity specified in the mentioned below Table 4, is injected mice on the 14th, 18th, 22nd, and 26th day after implantation of the tumor. On the other hand, the control group (untreated test compound) is injected only physiological saline. The presence or absence of metastases of each body check on the 36th day after implantation of the tumor. The results are shown in the following Table 4.

DRUGS

The drug 1

Getting the CM-dextran-7-ethyl-10-[3'-(glycyl-glycyl-glycylamino is)propyloxy]-(20S)-camptothecin:

(CM-dextran means carboxymethylation, hereinafter the same)

(1) Hydrochloride 10-(3'-aminopropoxy)-7-ethyl-(20S)-camptothecin (500 mg) dissolved in acetonitrile (25 ml), then there is successively added tert-butoxycarbonylmethyl-glycyl-glycine (345 mg), N-methylmorpholin (121 mg), N-hydroxybenzotriazole (161 mg), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (228 mg) and the mixture is stirred over night. Precipitated precipitated product is collected by filtration, purified by chromatography on a column of silica gel, to obtain the powder pale yellow color, similar to the foam, which is recrystallized from n-propanol to obtain 7-ethyl-10-[3'-(tert-butoxycarbonyl-glycyl-glycyl-glycylamino)propyloxy]-(20S)-camptothecin (663 mg) as colorless crystals.

TPL: 157-159°C.

(2) 7-ethyl-10-[3'-(tert-butoxycarbonyl-glycyl-glycyl-glycylamino)propyloxy]-(20S)-camptothecin (3,86 g) emuleret in purified water (64 ml) and there is added 6N aqueous solution of hydrochloric acid (32 ml) and conducting the reaction at room temperature under stirring for 2 hours. The solvent is concentrated and to the residue is added n-propanol to precipitate a powder product. The obtained powdery product is collected by filtration and recrystallized from water-is-propanol to obtain hydrochloride of 7-ethyl-10-[3'-(glycyl-glycyl-glycylamino)propyloxy]-(20S)-camptothecin (2,56 g) as yellow crystals.

(3) Sodium salt of CM-dextran (CM-degree=0,44, 50 g) dissolved in water (2.5 liters), and the pH value is brought to a value of 5.0 with 0,2N aqueous solution of hydrochloric acid under stirring at a temperature of 15°and to it add the hydrochloride of 7-ethyl-10-[3'-(glycyl-glycyl-glycylamino)propyloxy]-(20S)-camptothecin (4,01 g). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 g), and the pH value of the reaction solution is maintained at 5.0-5.5 using 0,2N hydrochloric acid. The mixture reacts at a temperature of 15°under stirring for one hour, after which it was diluted with purified water to a total volume of 10 liters. While the pH value is supported above 4.0, low molecular weight fractions are removed using ultrafiltration module (ACP-1010, released Asahi Kasei Industries, Ltd.) and the pH value adjusted to 8 using a 0.1 N aqueous solution of sodium hydroxide and then treated with ion exchange resins MSC-I (Na-form, issued by the company Dowex). Fractions containing the target compound, concentrated and passed through a filter (0.45 µm). The resulting product is mixed with ethanol (10 liters) with stirring, and thereto is added dropwise 3M brine (40 ml) under stirring. The precipitate is collected by filtration and dissolved in purified water (21 liter). The pH value of the solution adjusted to pH 4.0, using 0,2N aqueous races is the thief of hydrochloric acid and again subjected to ultrafiltration, during which the pH value is maintained at the level of 4.0. The solvent is concentrated to a total volume of 1.5 liters and filtered through a filter (0.45 µm). The resulting product is mixed with ethanol (9 liters), then with stirring is added dropwise 3M brine (35 ml). The precipitate is collected by filtration and washed successively with ethanol and acetone, concentrated under reduced pressure, giving the target compound (54,9 g) in the form of a powder pale yellow color. The content of the hydrochloride 10-(3'-aminopropoxy)-7-ethyl-(20S)-camptothecin was 4.2%, as confirmed by the absorption at 367,5 nm. In accordance with analysis using GPC (helpanimals chromatography) with an average molecular weight of the target product 121 kDa and degree distribution (MW/mn) was 1.47.

The product 2

Getting the CM-dextran-13-[(2'R,3'S)-3'-N-tert-butoxycarbonyl-3'-phenyl-2'-O-L-i.e. phenylalanyl-glycyl-azaserine]-10-deatil-baccatin III:

(Bz denotes benzoyloxy group, hereinafter the same)

CM-dextran (2008 mg CM-degree: 0.47, the average molecular weight of 170 kDa) was dissolved with stirring in purified water (90 ml), then add mesilate 13-[(2'R,3'S)-3'-N-tert-butoxycarbonyl-3'-phenyl-2'-O-L-i.e. phenylalanyl-glycyl-azaserine]-10-deatil-baccatin III (119 mg) and dimethylformamide (90 ml)and the mixture is then displaced is more to dissolve. To the mixture is added with stirring 2-ethoxy-1(2H)-quinoline-carboxylic acid (4.0 g) and the mixture is stirred at room temperature overnight. To the reaction solution with stirring, add ethanol (720 ml), and then with stirring, dropwise 3M brine (1.8 ml). The precipitate is collected by centrifugation and dissolved in water (200 ml), the pH value of the solution was adjusted to a value of 7 with 0,2N aqueous sodium hydroxide solution. The solution is poured with stirring in ethanol (800 ml) and added with stirring dropwise ZM brine (4 ml). The obtained precipitate was separated by centrifugation and purified in the same manner as in the section Preparation of 1-(3), which gives the target compound (600 mg) as white powder. The content of the active substance 2,4% (UV method (λ=276 nm)

Drug 3

Getting the CM-dextran-2'-O-i.e. phenylalanyl-glycyl-Taxol:

CM-dextran (1,294g, CM-degree: 0.47, the average molecular weight of 170 kDa) was dissolved with stirring in purified water (70 ml), and then there is added mesilate 2'-O-phenyl-alanyl-licitacao (77 mg) and dimethylformamide (70 ml) and the mixture is stirred until dissolution. To the mixture was added with stirring 2-ethoxy-1(2H)-quinoline-carboxylic acid (2,59 g), followed by reaction under stirring overnight. The reaction solution was added to ethanol (70 ml) under stirring, and there under stirring is added dropwise 3M brine (1,4 ml). The precipitate was separated by centrifugation, dissolved in water (240 ml) and mixed with ethanol (1200 ml) under stirring. To the mixture with stirring is added dropwise 3M brine (4.8 ml) to precipitate. In the same way the precipitation was repeated three times, which gives the target product (746 mg) as white powder. The active substance of 4.8% (UV method (λ=273 nm).

The product 4

Getting carboxymethyloxime-polisport-(1S,9S)-1-(glycyl-glycyl-L-i.e. phenylalanyl-glycylamino)-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]-pyrano [3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione:

(1) preparation of (1S,9S)-1-(tert-butoxycarbonyl-glycyl-glycyl-L-i.e. phenylalanyl-glycylamino)-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione:

To a solution of hydrochloride (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione (167 mg; 0,354 mmol), tert-butoxycarbonyl-glycyl-glycyl-L-i.e. phenylalanyl-glycine (463 mg; 1.06 mmol) and monohydrate 1-of hydroxybenzotriazole (NOVT) (143 mg; 1.06 mmol) in dimethylformamide (DMF) (10 ml) was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (270 mg; of 1.42 mmol), triethylamine (148 μl; 1.06 mmol) and 4-dimethylamino ridin (DMAP) (5 mg; 0.04 mmol). The reaction mixture was stirred at room temperature for 15 hours and the solvent concentrated under reduced pressure. The residue is dissolved in chloroform and the mixture is washed, dried, and the solvent is evaporated under reduced pressure. The residue purified using column chromatogaphy on silica gel (solvent-chloroform: methanol=50:1 to 10:1), which gives the specified connection (228 mg, 75%yield) as a solid pale yellow color.

IR (Nujol); 3290, 1710, 1655 cm-1

ESI-MS; 854 (M+N)

(2) Obtain (1S,9S)-1-(glycyl-glycyl-L-phenyl-alanyl-glycylamino)-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione:

To a solution of (1S,9S)-1-(tert-butoxycarbonyl-glycyl-glycyl-L-i.e. phenylalanyl-glycylamino)-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione (220 mg; 0,258 mmol) in dioxane (4 ml) is added 4N solution of hydrogen chloride in dioxane (6 ml) under stirring in an ice bath. The mixture continued to stir at room temperature for 16 hours. To the reaction mixture is added diethyl ether (30 ml) and the mixture is again stirred at room temperature for one hour. The precipitate is collected by filtration and dried, giving a named connection (176 mg, yield 86%) in VI is e powder yellow color.

IR (Nujol); 3250, 1745, 1660, 1605, 1535 cm-1

ESI-MS; 754 (M+N)

(3) Receiving dextran of polysperma (RA-Dextran):

Acetate buffer (0.1 M, pH 5.5, 1000 ml) is placed in a three-neck round bottom flask (capacity 3 liters). Dextran T-500® (10.0 g, from the company Amersham Pharmacia Biotech AB) is added in small portions to the buffer specified above for 30 minutes at room temperature. The mixture is stirred for about 30 minutes until the solution becomes transparent, and then the mixture is cooled at a temperature of 5°C (internal temperature) in the bath.

Separately into the flask (1 liter) add periodate sodium (33,0 g) and water (1000 ml)and the mixture stirred at room temperature, and then cooled at a temperature of 5°C.

To the above solution of dextran added under stirring to the above solution periodate sodium at a temperature of 5°and the mixture is left at a temperature of 5°C for 5 days in a dark place. Excess periodate sodium is removed by the addition of ethylene glycol (10 ml), after which the mixture is optionally stirred at a temperature of 5°C for 2 hours. The reaction mixture is cooled to a temperature of 3°and to it was added 8M aqueous sodium hydroxide solution, and the reaction temperature kept lower than 6°With (until the pH value of the reaction mixture does not become higher than pH 9). Then to the reaction mixture Bo is sodium hydride (14 g) in small portions under stirring, then the mixture is stirred at a temperature of 5°With during the night. In order to remove the excess of sodium borohydride, the pH value of the reaction mixture to reduce the pH below 5.5 by the addition thereto of acetic acid at a temperature of from 3 to 6°and the mixture is then stirred for another 2 hours. The pH value of the reaction mixture is brought approximately to 7.8 with 8M aqueous sodium hydroxide solution. The mixture was subjected to dialysis against water (membrane Spectora®/Por 3, limit exceptions molecular weight <3500) and freeze-drying that yields a dextran-polisport (a 8.34 g) as amorphous powder.

(4) Obtaining carboxymethylcysteine polysperma (CM-RA-Dextran):

Water (155 ml) placed in a three-neck round bottom flask (500 ml) and to it was added with stirring, a dextran-polisport (5,18 g) at room temperature for more than 10 minutes. The mixture is stirred for about 10 to 30 minutes, until it becomes transparent, and then to the dextran solution of polisport with stirring in small portions, add sodium hydroxide (pellets, 97,0%, 21.8 g), while the temperature inside is maintained at a level of from 30 to 40°in an ice bath. The flask with the reaction mixture is placed in a bath and the mixture is stirred at a temperature of 30°C. With stirring in small portions add monochloracetic acid (31.1 g) in the reaction mixture is PR the temperature from 30 to 40° C. After complete addition, the mixture is stirred at a temperature of 30°in the bath for 20 hours. Then the reaction mixture is cooled in a bath of ice and neutralized by adding acetic acid under stirring (i.e., the pH value is brought to a value below 9).

To the mixture add water (160 ml) and subjected to dialysis against water (membrane Spectora®/Por 3, limit exceptions molecular weight <3500), and lyophilized, giving carboxymethylated polisport (6,53 g) as amorphous powder.

(5) Obtaining carboxymethyloxime-polisport-(1S,9S)-1-(glycyl-glycyl-L-i.e. phenylalanyl-glycylamino)-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione:

Water (40 ml) was placed in a round bottom flask (capacity 100 ml) and to it was added carboxymethylated polisport (1.0 g) at room temperature under stirring for 5 minutes. The mixture is then stirred for about 30 minutes, until the mixture becomes transparent. To the mixture is added with stirring a solution of (1S,9S)-1-(glycyl-glycyl-L-i.e. phenylalanyl-glycylamino)-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-dione in dimethylformamide (100 mg/10 ml) and then dimethylformamide (15 ml), then the mixture stirred for another 10 minutes. To the mixture is added dropwise with stirring a solution of 2-ethoxy-1-atoxic ronil-1,2-dihydroquinoline (EEDQ) in dimethylformamide (1.0 g/10 ml) at room temperature and the mixture is additionally stirred for 18 hours. The reaction mixture was subjected to dialysis (membrane Spectora®/Por 3, limit exceptions molecular weight <3500) and then purified using a cation exchange column (column of BioRad AG® MP-50, Na-form, 30 ml). The main fraction is subjected to dialysis (membrane Spectora®/Por 3, limit exceptions molecular weight <3500) and freeze-drying that yields a crude product which is triturated with acetone, collected by filtration and dried, obtaining the target product (904 mg) in the form of a powder pale yellow color.

Industrial applicability

The pharmaceutical composition of the present invention can highly accumulate in such place as lymph node or liver, which may be effected by cancer, and to act overwhelmingly on the growth of cancer cells, does not act on normal cells and, therefore, the pharmaceutical composition of the present invention are useful for inhibiting metastasis, especially for the inhibition of metastasis of lymph node or liver metastasis, or to prevent recurrence of malignant tumors.

In addition, the present pharmaceutical composition can exhibit its effect not only before the formation of metastases, but also after they were formed. Thus, the present pharmaceutical composition also climbed the and for inhibiting metastasis, or prevent recurrence of malignant tumors after local therapy (e.g., surgery, radiation therapy, thermotherapy, cryotherapy, laser-burn therapy and so on).

1. Pharmaceutical composition for inhibiting metastasis, or prevent recurrence of malignant tumors after local therapy, containing as active ingredient a derivative of the polysaccharide, comprising the polysaccharide with carboxyl group associated with the antitumor activity of the active substance through amino acid or a peptide comprising 2 to 8 amino acids, which are the same or different, or its salt, where the specified active substance having antitumor activity, is derived camptothecin formula (I)

in which R1represents a substituted or unsubstituted lower alkyl group, X1represents a group of formula: -other2(R2represents a hydrogen atom or a lower alkyl group) and Alk represents a C1-6-alkylenes group with straight chain or branched chain, having a chain optionally an oxygen atom, or a compound of the formula (II)

in which two groups of numbers from R2to R6that are related to each other, merged to form the lower alkyl is OIC group, and one of the carbon atoms indicated lower alkalinous group, substituted amino group, and the remaining three groups of numbers from R2to R6represent a hydrogen atom, a lower alkyl group or halogen atom.

2. The pharmaceutical composition according to claim 1, where the local therapy is a surgery, radiotherapy, thermotherapy, cryotherapy or laser-sigauke therapy.

3. The pharmaceutical composition according to claim 1 or 2, in which the polysaccharide having a carboxyl group is a carboxy-C1-4-alkyldimethyl or carboxy-C1-4alkyldimethyl polisport.

4. The pharmaceutical composition according to claim 1 or 2, in which the polysaccharide having a carboxyl group is a carboxy-C1-4-alkyldimethyl.

5. The pharmaceutical composition according to claim 1, in which the peptide is a member selected from the group comprising glycyl-glycyl-L-or D-i.e. phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, L - or D-i.e. phenylalanyl-glycine, L - or D-tyrosyl-glycine, L - or D-leucyl-glycine, L - or D-i.e. phenylalanyl-citrulline and L - or D-poured-citrulline.

6. The pharmaceutical composition according to claim 1, in which the polysaccharide having a carboxyl group is karboksimetilirovaniya acid, the active substance having protivo the holeva activity is a 10-(3'-aminopropoxy)-7-ethyl-(20S)-camptothecin, and the peptide is glycyl-glycyl-glycine.

7. The pharmaceutical composition according to claim 1, in which the polysaccharide having a carboxyl group is a carboxy-C1-4-alkyldimethyl polisport, active substance having antitumor activity, is a (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,N-benzo[de]-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(N,15 NM)-Dion and the peptide is glycyl-glycyl-L - or D-i.e. phenylalanyl-glycine.

8. The pharmaceutical composition according to claim 1, which represents a pharmaceutical composition for inhibiting metastasis of a malignant tumor.

9. The pharmaceutical composition according to claim 1, which represents a pharmaceutical composition for preventing recurrence of a malignant tumor after local therapy.



 

Same patents:

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine, in particular angiogenesis prophylaxis and treatment.

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5 cl

FIELD: organic chemistry, medicine, pharmacy.

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9 cl, 5 sch, 36 tbl, 70 ex

FIELD: oncology.

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2 ex

FIELD: organic chemistry, pharmacy.

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36 cl, 4 sch, 1 tbl, 21 ex

FIELD: medicine.

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EFFECT: valuable medicinal properties of medicine agents.

10 cl, 3 dwg, 7 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

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3 dwg, 2 ex

FIELD: medical engineering.

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3 cl

FIELD: medicine.

SUBSTANCE: after keeping during pharmaceutically acceptable period oxaliplatinum is placed in transparent, colorless and residue-free solution at concentration of, at least, 7 mg/ml, and a solvent contains sufficient quantity of, at least, one hydroxylated derivative chosen among of 1.2-propandiol, glycerol, maltite, saccharose and inositol. The innovation describes the way to obtain such a preparation. The preparation is stable during pharmaceutically acceptable period of time, that is it remains transparent, colorless and free of any residue within the range of 2-30 C that could be available during its transportation, storage and/or any handling.

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14 cl, 6 ex, 4 tbl

FIELD: medicine, oncology, immunology.

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EFFECT: valuable properties of antibody.

14 cl, 3 tbl, 13 dwg

FIELD: immunology.

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34 cl, 1 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides novel triterpenoid derivatives having general formula:

(I), wherein, as polymer carrier, are used water-soluble copolymers of N-vinylpyrrolidone with α,β-(methyl)acrylic acid alkyl esters and quaternary ammonium salts thereof having general formula: (II), in which formulas A represents triterpenoid residue belonging to series of acids: betulinic {1}, betulonic {2}, glycyrrhetinic {3}, glycyrrhisic {4}, ursolic {5}, ursonic {6}, oleanolic {7}, oleanonic {8}, meristothropic {9}, diketomeristothropic {10}, macedonic {11}, diketomacedonic {12},equinocystic {13}, or mixture of above-indicated carboxyl-containing triterpenoids, where R1 and R2 are hydrogen or methyl; R3 methyl or ethyl; R4 is C6-C16-alkyl; Hal is iodine, bromine, or chlorine atom; k = 65-95 mol %; l = 0.1-34 mol %; n = 0.5-5.4 mol %; molecular weight is equal to (7-100)·103. Polymer derivatives of above-defined triterpenoids are prepared by reaction of terpolymer II, wherein k = 65-95 mol %; l = 0.1-34 mol %; x = 1.0-34.9 mol %; R1-R4, Hal and molecular weight as above. Reaction is carried out in organic solvent at concentration of terpolymer 1 to 30%, concentration of triterpenoid 0.05 to 3.4%, and molar ratio of motif containing quaternary nitrogen to triterpenoid between 1 and 10. Products are isolated by removing solvent.

EFFECT: expanded synthetic possibilities.

FIELD: medicine.

SUBSTANCE: invention relates to new polycation-based bioconjugates of general formula I useful in delivery of various kinds of active substances into organism.

EFFECT: conjugates of increased activity and low toxicity.

36 cl, 4 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: rectal- and vaginal-administration suppositories contain 1,3-diethylbenzimidazolium triiodide as active principal, polyvinylpyrrolidone as solubilizer and stabilizer, and lipophilic base with specified proportions of components.

EFFECT: extended therapeutical activity and reduced occurrence of side effects.

4 cl, 2 ex

FIELD: organic chemistry, polymers, medicine.

SUBSTANCE: invention describes lidocaine polyacrylate eliciting the prolonged topical anesthetic effect of the general formula: wherein n means (number of links) = 50-70; means a link of polyacrylic acid; means N,N-diethylaminoacetic acid 2,4-dimethylanilide.

EFFECT: valuable medicinal properties of compound.

1 cl, 2 tbl, 1 ex

FIELD: biochemistry, pharmaceutical chemistry.

SUBSTANCE: invention relates to preparing conjugate of naturally occurring or recombinant urate oxidase (uricase) bound covalently with poly-(ethylene glycol) or poly-(ethylene oxide) (both are designated as PEG) wherein in average from 4 to 10 PEG strands are conjugated with each subunit of uricase and molecular mass of PEG is about between 20 and 40 kDa. Prepared PEG-uricase conjugates are nonimmunogenic practically and retain at least 75% of uricolytic activity of nonmodified enzyme.

EFFECT: improved preparing method, valuable properties of conjugates.

22 cl, 17 dwg, 12 ex

The invention relates to genetic engineering and can be used for therapeutic purposes, in particular in the treatment of neoplastic processes

The invention relates to experimental medicine, cardiology

The invention relates to pharmaceutical compositions comprising a stable water-insoluble complex, consisting of stable amorphous form of the therapeutically active compound dispersed on a molecular level in the water-insoluble ionic polymer

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to medicinal agent for treatment of solid tumors. Agent comprises dispersion of paclitaxel microparticles stabilized with albumin in physiological solution wherein microparticles are taken in the concentration 2-8 mg/ml of this solution. Medicinal agent doesn't comprise surface-active substances and can be administrated safely into arteries directly that supply tumor-associated region sensitive to paclitaxel for short administration time in the range of some minutes, and this administration can be repeated some times.

EFFECT: valuable medicinal properties of agent.

2 cl, 5 ex

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