A new crystalline modification of 5-fluoro-1-(tetrahydro-2 - furyl) uracil and complex compounds based on it having antitumor action

 

(57) Abstract:

The invention relates to a new crystalline modification of 5-fluoro-1-(tetrahydro-2-furyl)uracil, as well as complex compounds of this form with 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine or licorice root extract (Radices Glycyrrhzae). This form characteristics different from previously known modifications of this compound and has high antitumor activity and is used in medicine. A new form of sustainable and can form a stable molecular complexes with biologically active substances which exhibit similar properties. Technical result: higher activity and stability of the obtained compounds. 2 C. and 8 C.p. f-crystals, 14 tab., table 2.

The technical field

The invention relates to the field of Oncology, specifically to polymorphic modifications of anti-cancer drugs and complex compounds with synergistic antitumor effect. The object of the invention is a new physically stable crystalline modification ftorafura (INN - tegafur) - 5-fluoro-1-(tetrahydro-2-furyl)uracil with enhanced antitumor activity compared to previously and the persistent molecular complexes.

Prior art

We know a significant number of medicinal substances and their combinations, which is the result of a comprehensive research and development of anticancer agents. In clinical practice apply effective against malignant tumors chemotherapeutic agents. Although the results of such therapy in recent years has improved significantly, it should be noted that the efficiency in many cases remains low or insufficient to achieve the desired degree of suppression of tumor growth and a significant extension of life of patients. In addition, most anticancer drugs are characterized by high toxicity, which negatively affects the healing process.

Ftorafur - 5-fluoro-1-(tetrahydro-2-furyl)uracil (INN - tegafur) synthesized by C. A. Giller with co-workers (U.S. patent 1168391) as a precursor of 5-fluorouracil (5-FU) is an effective anticancer drug and is widely used in the treatment of various tumors, particularly of the gastrointestinal tract and breast cancer.

Since tegafur is quite toxic compound repeatedly ENT is sootvetstvujushij FS 42-1182-86) characterized by powder diffraction pattern following interplanar distances d and the relative intensity of the reflexes I:

d - I

8,917 - 64

7,199 - 13

6,102 - 14

5,808 - 69

5,388 - 25

4,845 - 43

4,677 - 90

4,522 - 100

4,139 - 13

4,085 - 48

4,013 - 24

3,949 - 48

3,715 - 17

3,620 - 26

3,572 - 75

3,450 - 86

3,248 - 32

3,131 - 84

2,907 - 25

2,842 - 17

2,798 - 34

2,328 - 17

2,308 - 15

2,171 - 19

1,748 - 71

The DSC curve of pharmacopoeial tegafur shown in Fig. 7, consists of two endothermic effect. First, a wide effect in the range of 84.8-128,1oAnd the second is the effect of melting in the range 172,3-192,0oC. UV spectrum shown in Fig.11.

In particular, for many years, attempts were made to modernize the molecule tegafur. So in Belgium patent 855121 described optically active isomers (2'R and 2'S) tegafur, which is chemically the racemate. However, studies conducted by different groups of scientists (e.g., M. Yasumoto et al. "J. Med. Chem.", 1977, vol.20, 12, 1592-1594 or Horwitz J. P. et al. "Cancer Res.", 20, 1975, vol.35, 1301-1304) showed that the biological activity of both isomers are almost identical and do not differ from the activity of the racemate. The toxicity of one or the other isomer also does not detect significant differences compared with the original substance.

In addition, processing the original tegafur (corresponding to JP XII) were allocated -,-,-,-modification. These crystalline modifications differ powder x-ray, IR spectra and DSC curves (differential scanning calorimetry). To obtain the form of tegafur was dissolved in warm acetone and left to crystallize at room temperature. Colorless columnar crystals were separated by filtration. Colorless prismatic crystals-shape made of a saturated solution of methanol by evaporation of the solvent using a rotary evaporator. The crystal form was obtained by heat-shape when 130oC for 1 hour. The crystal forms were isolated by recrystallization from a solution of methanol (very slow evaporation of methanol) at room temperature. However, none of these modifications has no significant therapeutic advantage.

Based on the above we can conclude that the task of enhancing the activity of tegafur with synthesis of isomers or obtain polymorphic modifications to the present time has not been solved.

Parallel research was conducted on the music search - synergistic mixtures containing tegafur as the active substance.

The opening combination of drugs is tabliture and loses activity in the body, perhaps the use of uracil for the inhibition of these processes (U.S. patent 5534513). It turned out that although uracil itself does not show antitumor activity, he has the ability to potentiate the antitumor effect. Study of the efficacy of the mixture of tegafur and uracil (molar ratio tegafur : uracil 1:4) and is described for example, in the work of Y. Kagawa et al. "Cancer Investigation", 1995, vol. 13, 5 470-474.

In addition, was obtained and studied composition containing tegafur, uracil and folic acid (Sanchiz f, Milla A., "Jpn. Journal Clin. Oncol", 1994, vol. 24, 6, 322-326).

In such combined preparations is extremely important is the question about the optimal dose as an active component, and a substance which causes potentiation of activity. It is desirable that the substance-potentiator used in minimum doses (to reduce their own toxic effect) or the substance itself almost has no toxic effect. Currently known synergistic products containing the active ingredient - tegafur - and substance-potentiator not always optimized for qualitative composition of components and their quantitative value. For example, uracil (which is typically used is compared with other substances, can potentiate the action of tegafur, thymine, thymidine or uridine (Fujita X. Experimental and clinical pharmacotherapy. Century 12, Riga, 1983, page 205).

Thus, the current state of cancer therapy needs to be improved drugs used in Oncology, and the development of drugs having a high antitumor activity along with minimized toxicity.

Disclosure of the invention

The objective of the invention is to provide a physically stable form of tegafur with enhanced pharmacological activity. As a result of experiments, it was unexpectedly discovered that high specific activity along with physical stability over a long period of time, sufficient for commercial use, has a new, previously unknown, metastable crystal modification of tegafur (hereinafter referred to as a V shape).

A new form of V is a light, airy white powder.

Form V is characterized by powder diffraction pattern following interplanar distances d and the relative intensity of the reflexes I:

d - I

9,035 - 5

3,730 - 20

3,626 - 25

3,588 - 42

3,473 - 60

3,437 - 50

3,255 - 30

3,143 - 36

2,915 - 23

KZT 2,382 - 16

2,336 - 20

Conducted thermal analysis has revealed a new form three pronounced endothermic peak on the DSC.

The first type _ transition in the range 96,6-102oC. the Second and third peaks represent the superposition of two endothermic effects: transition _ in range 157,1-174,2oWith and superimposed on it the effect of melting-shape with a maximum temperature of 174oC. the Point of overlap of the second and third effects is in the area 167,6oC.

UV-spectrum of the form V tegafur shown in Fig. 10.

Form V tegafur obtained by dissolution of the pharmacopoeial substance of tegafur or individual polymorphic modifications in water, alcohol or alcohol-water mixture. The solvent is preferably pre-heated to a temperature of 40-65oC. the resulting solution is injected into a container cooled to a temperature of not less than 10oWith Antibacterials (for example, dimethyl ether, diethyl ether or chloroform). The precipitate is separated, remove the remaining solvents and get crystalline powder form V.

New kristallicheskimi carriers or fillers, that allows its use in medicinal preparations. However, it has been unexpectedly discovered that the above form of V has the property to form molecular complexes with some organic molecules, including possessing biological activity. In particular, the received complex compounds with 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine (hereinafter methyluracil) and biologically active plant extracts, obtained in particular from licorice root (Radices Glycyrrhizae).

Complex compounds can be obtained under certain technological conditions, leading to the formation of non-valence bonds between molecules of tegafur and molecules of organic compounds entering with tecaform in the interaction of this sort.

The synthesis of complex compounds is possible in three ways. The first path involves the simultaneous transfer of a physical mixture of tegafur and other organic molecules, which are scheduled to be included in the composition of complex, high-energy (metastable) state. As it was found under these conditions, tegafur turns into a V-shape, are capable of forming stable molecular complexes.

The translation of physical mixtures in highly what I education of the form V tegafur.

Such methods can be, for example, co-micronization (in particular, grinding or other known methods of influencing the energy of the molecule.

The second way of obtaining complexes consists in mixing the prior of the form V tegafur with the rest of the complex is an individual substance or mixture of substances which, at the time of mixing are thermodynamically stable state.

The third way of obtaining complexes consists in mixing the prior of the form V tegafur and the second component of the complex that is already in the high-energy state.

To obtain complexes can be used, in particular, methyluracil (M. D. Mashkovsky. Drugs, 1997, Kharkov, so 2, S. 168), is a form of methyluracil (hereinafter Betamecil) with reduced toxicity (U.S. patent 5543147), various extracts of licorice, for example Extractum Glycyrrhizae siccum (M. D. Mashkovsky. Drugs, 1997, Kharkov, T. 1, S. 345-346).

Molecular complex of tegafur-methyluracil in a molar ratio of 1:2 (compound 1A) is a white crystalline powder and is characterized in powder diffraction pattern with>/BR>7,234 - 32

6,883 - 100

5,864 - 13

4,831 - 27

4,571 - 13

4,197 - 25

3,627 - 15

3,448 - 18

3,254 - 26

3,192 - 13

3,149 - 6

2,933 - 13

2,448 - 8

2,300 - 8

The DSC curve of compound 1A shown in Fig. 8. It is a two endothermic effect. The first effect of type _ is in the range 117,1-132oC. the Second effect melting-form - interval 149,9-167,1oC.

The UV spectrum of the compound 1A, characterizing his personality, is shown in Fig. 12.

Molecular complex of tegafur-methyluracil in a molar ratio of 1:1 (compound 1b) is a white crystalline powder and is characterized in powder diffraction pattern following interplanar distances d and the relative intensity of the reflexes I:

d - I

7,187 - 53

6,841 - 100

4,806 - 41

4,181 - 37

3,669 - 20

3,474 - 21

The complex tegafur-licorice root extract (compound 2) is x-ray amorphous form and is an easy lumps powder yellow with a brownish tinge.

The DSC curve of compound 2, shown in Fig. 9, is a combination of two endothermic effects: wide - interval The UV spectrum of the compound 2, confirming the identity of the substance, shown in Fig. 13.

Form V is superior in solubility formerly known modifications of tegafur. In addition, a new form of tegafur compared with previously known polymorphic forms has a high specific activity. Complex compounds are even more significant specific activity (compared not only with pharmacopoeial tecaform, but compared to the new form V), i.e., there is a potentiation of pharmacological action.

The new crystalline modification of tegafur and complex compounds based on it can be widely used in medicine for the treatment of cancer. This will expand the Arsenal of means acting on the tumor cells, and thereby improve the efficiency of treatment of patients suffering from malignant tumors.

Brief description of drawings

Fig.1 is a powder x-ray of the claimed form V tegafur.

Fig.2 is a powder x-ray Pharmacopoeia of tegafur.

Fig. 3 is a powder x-ray molecular complex tegafur-methyluracil in the ratio 1:2.

Fig. 4 - p is Raskova radiograph complex compounds of tegafur-licorice root extract.

Fig.6 is a DSC curve of the claimed form V tegafur.

Fig.7 is a DSC curve of pharmacopoeial tegafur.

Fig. 8 is a DSC curve of the molecular complex of tegafur-methyluracil in the ratio 1:2.

Fig. 9 is a DSC curve complex compounds of tegafur-licorice root extract.

Fig.10 - UV spectrum of the claimed form V tegafur.

Fig.11 - UV spectrum of pharmacopoeial tegafur.

Fig. 12 - UV spectrum of molecular complex tegafur-methyluracil in the ratio 1:2.

Fig. 13 - UV spectrum of the complex compounds of tegafur-licorice root extract.

Fig.14 - results of the study the specific activity of pharmacopoeial tegafur, form V of tegafur, complex compounds 1A and complex compounds 2.

Examples: the Best option for carrying out the invention

1. The form V tegafur.

Obtaining crystalline modification of tegafur according to this invention is as follows.

At a temperature of 45oTo prepare a saturated solution of the original component Pharmacopoeia of tegafur (corresponding to FS 42-1182-86) in water. The resulting solution in a volume of 0.5 l was dispersed in a container of chloroform, pre-cooled to 2is OK filtered off, remove the remainder of the solvent under reduced pressure (10-1mm RT.CT.) and get the final product. The output of the form V tegafur is 62% of the original pharmacopoeial substance.

2. Obtaining complex tegafur-methyluracil (1:2).

At a temperature of 100oTo prepare 0.5 l of 0.1 M solution of the form V tegafur in water and 0.5 l of 0.2 M solution Betamecil in the water. The obtained solutions are gently mixed and left in a thermostat at a temperature of 60oWith 1.5 hours. Then the solution is cooled to 2oWith deposited precipitate is filtered off, dried under reduced pressure (10-1mm RT.CT.) and get the final product. The output is 71%.

3. Obtaining complex tegafur-methyluracil (1:1).

At a temperature of 100oTo prepare 0.5 l of 0.2 M solution of the form V tegafur in water and 0.5 l of 0.2 M solution methyluracil in the water. The obtained solutions are gently mixed and left in a thermostat at a temperature of 60oWith over 3 hours. Then the solution is cooled to 2oWith deposited precipitate is filtered off, dried under reduced pressure (10-1mm RT.CT.) and get the final product. The output is 68%.

4. Obtaining complex tegafur and the mixture of organic components of licorice root extract.

At a temperature of 40oWith dissolved in 0.25 l of water 10 g of the form V tegafur, and in another vessel at the same temperature in 0.1 l of water was dissolved 5 g of dry extract of licorice root. The resulting solutions are mixed and left in a thermostat at a temperature of 40oC for 30 minutes. Then the solution is quickly cooled to 2oWith deposited precipitate is filtered off and dried, yielding the final product. The yield is 75%.

Received a new modification of tegafur and complex compounds based on it were investigated by powder x-ray diffraction.

X-ray phase analysis was performed on an automated powder diffractometer. Shooting conditions: radiation CuK, graphite monochromator on the secondary start, intervals of angles from 4 to 64 2a step of 0.1othe scanning speed of 2oand overlapping at him wide reflex polymer film center about 11 2.

The results are presented in Fig. 1-5.

Research conducted by differential scanning calorimetry shown in Fig. 6-9 demonstrate the novelty of the proposed drug compounds. DSK features a V shape substantially different from pharmacopoeial sample tegafur (corresponding to FS 42-1182-86) and from previously known polymorphic modifications.

Thermo analytical studies were conducted thermoanalyzer STA-409 company NETZSCH (Germany), which allows to simultaneously study the methods of thermogravimetry (TG) and dierential scanning calorimetry (DSC). Studies were performed in the atmosphere of dried helium (1 ATM) at a scan rate of temperature of 10 deg/min When conducting experimental DSC curve, was determined by the point of intersection of the line corresponding to the base line, and straight line which is tangent at the inflection point upward peak.

To determine the sensitivity coefficients linking the area under the curve of the DSC with a heating effect, carried out the calibration India and Sapphira in terms identical to the working conditions of the experiments. Integration of the peaks on the DSC curve and the calculation of thermal effects produced by the programs, which is part of the software of the device STA-409.

UV spectra (Fig. 10-13) shot on spectrophotometer "Aminec". Solutions with a concentration of 0.02% was prepared in 0.1 M phosphate buffer with pH 6.8.

Industrial applicability

Determination of solubility of the studied drugs and tegafur

Determination of solubility were carried out in accordance with the requirements of article "Solubility", USPXXIII (1995, p. 2071).

As can be seen from the data given in table. 1, the solubility of the inventive preparations: form V tegafur, complex compounds 1A and 1b is higher than that of tegafur Pharmacopoeia, the solubility of the complex compound 2 could not be determined because of the vegetative component of the extract of licorice root, forming a cloudy, opalescent to rostranenie with tecaform pharmacopoeial on cell cultures of cervical cancer

The determination was performed according to the method (Mosmami N. T. J. Immunoloey Methods, 1983, vol.65, 55 to 63, Carmichael J. et al. Cancer Res, 1987, vol.47, 936-946) on the cell culture of cancer of the cervix, the cells were grown at 37oWith medium RPMI 1640 with the addition of 10% fetal cow serum and 200 u/ml of gentamicin, the CO2in the atmosphere of the incubator was 10%. Cells in exponential growth phase, suspended by trypsin and the number 4x103were sown in each well of 96-well plate to monolayer cultures. Solutions of the samples of the study drug was prepared by dissolving 23 mg of each drug in 10 ml of culture liquid, thus obtaining the solutions of concentration 10-2M. These solutions served as the source for obtaining a solution of lesser concentration by diluting their culture liquid. Before adding fluids to the cells they were sterilized by filtration through millerovskie filters. Twenty-four hours after seeding the cells in each well of the tablet was added to solutions of the samples of the studied drugs in predetermined concentrations, after which the cells were grown for another 4 days.

All were tested on 9 concentrations of each of the 4 samples of the studied drugs.

To the-2-yl)-2,5-diphenyltetrazolium (MTT). MTT has a selective ability to be metabolized in the mitochondria of cells with formation of a colored product formazan having maximum absorption at a wavelength of 530-570 nm, while there is a correlation between the degree of inhibition of mitochondria and color cells. To each well of the tablet was added to 0.5 mg/ml for 4 hours before the end of culturing cells. After incubation, the culture fluid from the wells was removed, the crystals formazan was dissolved and the cells were scanned on an automatic reader Multiscan MCC/340P at a wavelength of 540 nm. The results were calculated in percent absorption cell at 540 nm, exposed to the study drug, in relation to the acquisition of control cells.

The effect of each concentration of the studied drugs on cancer cells was assessed by the results of 4-6 independent experiments, the results were processed using the methods of mathematical statistics. Data received research are given in table. 2 and in Fig. 14.

As can be seen from the data table. 2 and the graph shown in Fig. 14, all the studied drugs have different cytotoxic effects on cancer cells. However, the inventive preparations, namely, a V-shape of tegafur and starting cells. So, tegafur in the concentration range 10-6-10-4M has no effect on the proliferation of cancer cells. Form V tegafur inhibits cell proliferation at a concentration of 510-5M, at a concentration of 10-4M the drug inhibits proliferation by 70% harder than tegafur. Compound 1A (tegafur-methyluracil) has a dampening effect on the proliferation of cells, starting with a concentration of 10-6M, the same applies to the integrated connection 2 (tegafur-licorice root extract), it should be noted that the complex compound 1A of the form V tegafur is less than 1/2, and in connection 2 - 1/3, thus, in this case, there is a pronounced cytotoxic effect.

1. Crystalline modification of 5-fluoro-1-(tetrahydro-2-furyl) uracil, characterized in powder diffraction pattern following interplanar distances d and the relative intensity of the reflexes I:

d - I

9,035 - 63

7,237 - 23

6,149 - 19

5,839 - 100

5,413 - 17

4,704 - 42

4,551 - 62

4,104 - 36

4,041 - 28

3,966 - 25

3,730 - 20

3,626 - 25

3,588 - 42

3,473 - 60

3,437 - 50

3,255 - 30

3,143 - 36

2,915 - 23

KZT 2,382 - 16

2,336 - 20

2. The complex compound is a tract of licorice root (Radices Glycyrrhizae).

3. Complex connection on p. 2, characterized in that the 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin is Metamucil.

4. Complex connection on p. 2, characterized in that the medicinal substance represents 5-fluoro-1-(tetrahydro-2-furyl)-uracil, 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin when the molar ratio 1:2.

5. Complex connection on p. 4, characterized in that characterized in powder diffraction pattern following interplanar distances d and the relative intensity of the reflexes I:

d - I

9,090 - 19

7,234 - 32

6,883 - 100

5,864 - 13

4,831 - 27

4,571 - 13

4,197 - 25

3,627 - 15

3,448 - 18

3,254 - 26

3,192 - 13

3,149 - 6

2,933 - 13

2,448 - 8

2,300 - 8

6. Complex connection on p. 2, characterized in that the medicinal substance represents 5-fluoro-1-(tetrahydro-2-furyl)-uracil, 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin when the molar ratio of the components is 1:1

7. Complex connection on p. 6, characterized in that characterized

on powder diffraction pattern following interplanar distances d and the relative intensity of the reflexes I:

d - I

7,187 - 53

6,841 - 100

9. Complex connection on p. 8, characterized in that the medicinal substance represents 5-fluoro-1-(tetrahydro-2-furyl)-uracil and licorice root extract in the ratio of 2:1 (by weight).

10. Complex connection on p. 9, characterized in that the powder diffraction pattern expressed no reflexes inherent to crystalline forms.

 

Same patents:

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to new arylpyrimidines compounds of formula I having the effect of antagonist 5HT2B-receptor, and pharmaceutical compositions

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to derivatives of 3-N-1,2,3-triazolo-[4,5-d]-pyrimidine of the General formula I, in which a represents O or CH2; X is selected from NR1R2, SR1and C1-C7-alkyl; Y is chosen from SR1, NR1R2and C1-C7-alkyl; R1and R2each independently represents N or C1-C7-alkyl, or R1represents C1-C7-alkyl, optionally substituted in the alkyl chain one atom of O or S or one or more halogen, and R2is hydrogen; R3and R4both represent hydrogen or together form a bond; a is COOH, C(O)NH(CH)pCOOH, C(O)N[(CH2)q-COOH]2WITH(ABOUT)NНСН(COOH)(CH2)rCOOH or 5-tetrazolyl, in which p, q and r each independently is 1, 2 or 3, as well as their pharmaceutically acceptable salts or esters

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to intermediate compounds used in the synthesis of CIS-nucleosides, their analogues and derivatives of nucleosides of high purity, the method of obtaining these intermediate compounds

The invention relates to new derivatives of benzofuranyl, possess valuable biological properties, in particular to derivatives of N-(3-benzofuranyl)urea, mixtures of their isomers, or individual isomers and their salts

The invention relates to new N1-[2,2-dimethyl-1S-(pyridin-2-ylcarbonyl)propyl] -N4-hydroxy-2R-isobutyl-3S-methoxybenzamido or its pharmaceutically acceptable salt, hydrate or solvate

The invention relates to medicine, namely to Oncology, and can be used for the treatment of malignant brain tumors

The invention relates to pharmacology, and relates to pharmaceutical compositions containing the benzimidazole derivative of the formula I, where R, R2X, Y and n have the meanings indicated in the claims, which inhibits the growth of tumors and cancers in mammals

The invention relates to medicine, namely to clinical pharmacology, in particular to the development of a new drug and method of reducing and/or eliminating the side effects of anticancer agents

The invention relates to organic synthesis, in particular it concerns a method for obtaining 2-[bis-(2-chloroethyl)amino] tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide, monohydrate, known in the pharmaceutical industry as anticancer drug cyclophosphamide

The invention relates to medicine and relates to a new composition for treating or preventing prostate cancer, containing as the active ingredient N-[1-methyl-1-(4-methoxyphenyl)ethyl] -3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, and method of treating or preventing prostate cancer using the composition

The invention relates to chemistry, in particular to pharmaceutical chemistry, and can be used for the production of anticancer drug

The invention relates to the field of medicine and pharmacology, and relates to pharmaceutical compositions for the prevention and treatment of tumors associated with human papilloma virus, namely dysplasia and cervical cancer and laryngeal papillomatosis
Powder makarova // 2194509
The invention relates to medicine, namely to pharmacology, and can be used in surgery, infectious diseases and dermatology
Up!