Composition for injections containing hydroxychloroquine for local application in treating cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an injectable therapeutic anti-cancer formulation administered into cancer cells directly. The formulation contains 5-25% (wt/vol) of hydroxychloroquine or hydroxychloroquine sulphate, Lidocaine concentrated 1-2% (wt/vol), Riboflavin concentrated 0.1-0.5% (wt/vol) and physiologic saline.

EFFECT: invention provides the formulation which exhibits cytotoxic effect on the cancer cells without involving normal cells, and which is administered into the cancer cells directly.

2 cl, 3 tbl, 4 dwg, 4 ex

 

Area of technology

The present invention relates to an injectable composition for local application containing hydroxychloroquine as an active ingredient, which composition must be injected directly into cancer cells to manifest anticancer effect.

Background of the invention

As a rule, the tumor is a disease in which abnormal cells continuously multiply, interfering with the function of normal cells. In accordance with histopathological and clinical criteria tumors are divided into benign and malignant, and so-called cancer refers to malignant tumors.

Cancer is the leading cause of death in Korea, but also worldwide. The cause of cancer or his treatment method is still unclear. Cancer treatment developed to date, reflect the problems associated with lethal side effects, expression of drug resistance, destruction of lymphocytes and bone marrow etc. during their clinical use. Thus, there is an urgent need to develop new anticancer drugs that exhibit cytotoxic activity without affecting normal cells.

Today in the body of a man found about 270 types of cancer. Cleto�s line, which reportedly was used in the study of these cancers include cells of sarcoma-180 cells, cells of melanoma, adenoma cells, cell adeno-carcinoma, the cells of ascitic Ehrlich tumor cells and carcinoma Walker. Among these cells, the cells of sarcoma-180 represent a cell line tumors derived from axillary cancerous growths in male white mice, it is also known that sarcoma-180 can be reseeded in the ascites to exist both in solid and ascitic form, and has no species specificity for the transplant.

Meanwhile, hydroxychloroquine is currently used for the prevention and treatment of rheumatoid arthritis, a chronic and systemic lupus erythematosus, skin diseases associated with photosensitivity, and malaria. Lately, there have been documented studies of hydroxychloroquine to suppress damage of the kidneys and the safe removal of glioma.

Korean patent registration number 10-0390332 provides information about the anticancer composition, which allows the introduction of such joint anti-cancer drugs like doxorubicin or cisplatin, hydroxychloroquine, chloroquine, primaquine, etc., often used as antimalarial drugs, thereby reducing the 50% inhibitory concentration (IC50) anticancer deterge�VA and suppressing the resistance of cancer cells to drug, caused by anticancer agents. With an antimalarial drug such as hydroxychloroquine, used as auxiliary substances to suppress the resistance of cancer cells anti-cancer agent for the purpose of improving anti-cancer effects of anti-cancer drugs, and anticancer agent exerts its effects through system administration in a variety of ways such as oral and parenteral route.

Hitherto it was not known that hydroxychloroquine has anti-cancer effects. Thus, have been reported the anti-cancer agent based hydroxychloroquine.

Technical problem

The object of the present invention is the use of hydroxychloroquine as an anticancer agent for local application. In particular, the object of the present invention is to provide an anticancer composition for local application that exhibits cytotoxic activity against cancer cells without affecting normal cells, and which must be injected directly into cancer cells.

Technical solution

To accomplish the above objective, the present invention provides an injectable anticancer composition for local application containing hydroxychloroquine or �th Sol.

Anticancer composition of the present invention may be injected directly into cancer cells. Preferably, the anticancer composition of the present invention also contain a local anesthetic, such as lidocaine, and/or an antioxidant, such as Riboflavin.

The present invention aims to make possible the introduction of a composition on the basis of hydroxychloroquine directly to cancer cells, thus showing anti-cancer effects. The composition for local application containing hydroxychloroquine, is injected directly into the affected area to inactivate local tissue, thus blocking the metabolism of local tissues. The metabolism of cancer cells faster than normal cells, so when you lock the metabolism of cancer cells hydroxychloroquine tissue cancer cells are inactivated, resulting in tissue death of cancer cells.

The desirable content of hydroxychloroquine in the composition of the present invention is 5-25% (weight/volume) and 20-25% (weight/volume). If the content of hydroxychloroquine is less than 5% (weight/volume), he did not exhibit therapeutic effects, but if the content of hydroxychloroquine for more than 25% (weight/volume), it can cause death of normal tissues surrounding the cancer cells.

According to the present invention, the injectable composition for local application�ia local anesthetic is used for pain relief during application by injecting the composition directly into cancer cells. Preferably use a local anesthetic lidocaine in a concentration of 1-2% (weight/volume). Antioxidant also serves to stabilize the composition. As an antioxidant Riboflavin is used in a concentration of 0.1-0.5% (weight/volume).

Also, taking into account the solubility of hydroxychloroquine in the water, you can use salt hydroxychloroquine. In particular, preference is given to hydroxychloroquine sulfate.

Injectable anticancer composition for local application according to the present invention can be prepared according to any conventional method for the preparation of injectable preparations.

According to the present invention, injectable anticancer composition for local application is preferably administered directly to the cancer cells. The composition of the present invention can be administered repeatedly at intervals of 3-4 days for several weeks, depending on the condition of the patient, or can be repeated at intervals of 1-2 days, depending on the size and development of cancer cells, whereby it is possible to suppress the proliferation and metabolism of cancer cells to inactivate the cancer cells in the short term.

Description of drawings

FIG.1 is a graphical diagram showing the results of the impact assessment of the composition of the present invention on the growth of the cells DNA.�Noah the line of sarcoma-180 in comparison with the control drug by using the MTT assay.

FIG.2 is a graphical diagram showing the effect of the composition of the present invention on the differentiation of cell lines of sarcoma-180 in albino mice compared with the control drug.

FIG.3 is a graphical diagram showing the effect of the composition of the present invention on the growth of solid cancer caused by cells of sarcoma-180 in albino mice.

FIG.4 is a graphical diagram showing the effect of the composition of the present invention to increase the lifetime of albino mice after injection of ascitic cancer tumors in mice by means of cells of sarcoma-180.

The best option

Hereinafter the present invention will be described in more detail with reference to examples. It should be understood, however, that these examples are given for illustrative purposes and are not intended to limit the scope of the present invention.

Test method

(1) Preparations for the introduction

Anticancer composition of the present invention that was used in this test was prepared as a drug for topical application, by injection directly into cancer cells. In particular, hydroxychloroquine was added to the physiological saline for injection to a concentration of 20% (weight/volume) and 20% ethanol as a solvent was added at a concentration of 10-20% based on�e volume of the obtained composition. The mixture was dissolved by heating in a water bath. Then put the lidocaine and Riboflavin in an amount of 2% (weight/volume) and 0.1% (weight/volume), respectively, thereby preparing the injectable composition for local application.

Cisplatin, used as a positive control drug, was purchased from Sigma. (Sigma Co.) (USA).

(2) Cancer cell line

Cancer cell line used in this example was sarcoma-180 (KCLB 4066), obtained from the Korean cell Bank lines.

As the environment of the cultivation of the cell lines was RPMI 1640 containing 10% fetal bovine serum (ABS), supplemented with streptomycin (100 µl/ml) and penicillin (100 µl/ml).

The cell line of sarcoma-180 was reseeded in 5% CO2incubator at 37°C for 48 hours and was used during the test.

For tests on animals cell line sarcoma-180 was introduced into the abdominal cavity albino mice at a concentration of 2×107cells/ml after About 2 weeks, the ascites was collected and centrifuged at 2000 rpm, and the pellet was washed twice and then marked with a blue trypsin and 0.4%, thus there was obtained 2×1077cells/ml.

(3) animal Testing

White outbred mice aged 5 weeks were purchased and acclimatized � for 1 week before use in the test. Animals were kept at a temperature of 22±2°C and 50% relative humidity, 12 hours light /12 hours in the dark.

Example 1: Measurement of cytotoxicity against sarcoma-180

To assess the effect of the composition of the present invention on the cytotoxicity, we used the MTT assay. The MTT assay is a laboratory test method to measure cell viability, and can be considered as standard colorimetric analysis. Using the MTT assay can accurately measure the distribution and the number of living cells, it is an integral procedure in the field of Biosciences, in particular in the field of biology of tumors.

Prior to testing on living organisms such as animal testing, for the detection of exposure for the development of new anti-cancer drugs or explore sensitivity to existing anti-cancer drugs, it has to apply outside of the body, objectively demonstrating that the drug slows tumor growth.

Cell line sarcoma-180, reported to a cell concentration of 1×105cells/ml was added to each well of 96-well plates and cultured in 5% CO2incubator at 37°C for 24 hours. After 24 hours of cultivation, the composition of the invention diluted to 8 concentrations from 1.0 µl to 0 μl was added to each well. While Cipla�Ying also diluted in a similar manner and added to each well.

Then the cells were cultured in 5% CO2incubator at 37°C for 24 hours, and added 50 µl of MTT reagent with a concentration of 2 mg/ml. the cells were Then maintained in the incubator at 37°C for 4 hours.

Cell culture was centrifuged to remove the supernatant, and add 200 ál of DMSO to each well to dissolve the colored MTT precipitate, after the value of the OD540was measured using a reading unit enzyme-linked immunosorbent assay at a wavelength of 540 nm.

50% inhibiting concentration (IC50was defined as the concentration of drug that resulted in 50% cell viability, and the value of IC50was used as an indicator of antitumor effects of the drug.

FIG.1 is a graphic diagram showing the results of the impact assessment of the composition of the present invention on the growth of cell lines of sarcoma-180 in comparison with the reference preparation using the MMT analysis.

The composition of the present invention was added to a suspension cell line sarcoma - 180 with a cell concentration of 2×107cells/ml, and then its anti-cancer activity compared with the reference drug cisplatin. As a result, as can be seen in FIG.1, the value of IC50the composition of the invention has been shown with 0.01 l or less.

In other words, the value of IC50the composition of the invention in from�Oseni sarcoma-180, determined by the MTT assay on living organisms was approximately 10 times lower than that of cisplatin, indicating that the composition of the present invention has excellent cytotoxic effect.

Example 2: Inhibitory effect on the differentiation of cancer cells

To observe anti-cancer composition of the present invention in albino mice, mice were inoculated with cells of sarcoma-180, and an evaluation of the impact of the composition of the present invention on the differentiation of cells of sarcoma-180.

In particular, as shown in table 1 below, the animals adapted to the conditions of detention were eventually divided into 6 groups (G1-G6), each of which consisted of 12 animals. Table 1 shows the creation of the experimental groups and the concentration of the drug.

[Table 1]
GroupDoseThe number of animals
G 1N (normal group)012
G 2With (control group)012
G 3 L in the group receiving low-dose)Of 16.6 µl/kg12
G 4M (the group receiving high dose)83,3 µl/kg12
G 5N (the group receiving higher dose)Of 166.6 µl/kg12
G 6Cis (cisplatin)20 mg/m212

Cell suspension of sarcoma-180 with a cell concentration of 2×107cells/ml was implanted by subcutaneous injection in the groin of all groups except normal group, thereby causing solid cancer. The composition of the present invention was installed on a small dose (of 16.6 μl/kg), medium dose (83,3 µl/kg) and higher dose (of 166.6 µl/kg of body weight), each dose of the composition administered to mice with 3-day intervals for 6 weeks immediately after stimulation ascites cancer, at the same time, we evaluated the impact of the composition of the invention to the vaccine and differentiation of cancer cell lines and compared with those of the cisplatin.

On the last day of the test animals underwent biopsy, and the number of animals in which the cells of the sa�coma-180 steadily increased, these cells were measured and used as an anticancer index. The same test was carried out twice, the results of the two measurements were averaged.

FIG.2 is a graphical diagram showing the effect of the composition of the present invention on the differentiation of cell lines of sarcoma-180 in albino mice compared with the control drug. In FIG.2, L: a small dose of the composition of the invention; M: middle dose of the composition of the invention; H: high dose of a composition of the invention; cis: cisplatin; N: normal group; and C: control group.

As described above, after completion of the test, the presence or absence of cancer cells in the inguinal region was determined by biopsy. As a result, as shown in FIG.2, the cancer cells of 9.5 was observed in animals in the group receiving low-dose, 7,5 animals in the groups that received the medium and higher dose, and 4.5 to animals for control of the drug cisplatin.

In other words, the inhibitory effect of the composition of the present invention on the differentiation of cancer cells was slightly higher than in the control group, but not higher than in the cisplatin group.

It is believed that the reason that the effectiveness of the composition of the present invention was different to living organisms and outside of organisms that the diffusion length of hydroxychloroquine was limited because hydrox�chloroquine is not soluble at room temperature.

Test example 3: Antitumor effect on solid cancer.

To observe the anticancer activity of the composition of the present invention in albino mice, white outbred mice entered the cells of sarcoma-180 for the induction of solid cancers, and then evaluated the impact of injectable composition for cell death in sarcoma-180.

According to Table 2 below, the animals adapted to the housing conditions, were divided into 4 groups (G1-G4), each of which consisted of 10 animals. Table 2 below shows the definition of the test groups and the concentration of the medication.

[Table 2]
GroupDoseThe number of animals
G1Control group010
G2The group receiving weak dose83 µl/kg10
GBThe group receiving high dose166 µl/kg10
G4 Group, receiving a strong dose415 µl/kg10

Suspension of washed cells of sarcoma-180 with a cell concentration of 2×107cells/µl was transplanted by subcutaneous injection in the groin to all groups in this regard have received solid cancer. The composition of the present invention installed in the doses indicated in Table 2, each dose of the composition administered to mice twice a week with 3-day intervals for 6 weeks after 1 week after transplantation of the cancer cell line, was observed when the degree of induction of solid cancers.

On the last day of the test by biopsy was carried out visual inspection, the weight of tumor cells was measured and used as an anticancer target.

FIG.3 is a graphical diagram showing the effect of the composition of the present invention on the growth of solid cancers induced by cells of sarcoma-180 in albino mice. In FIG.3, G1: control group; G2: 83 entered μl/kg weight of the injection composition (20% hydroxychloroquine); G3: 166 entered μl/kg weight of the injectable composition; and G4: 415 entered μl/kg weight of the injection composition.

As a result, as can be seen in FIG.3, average weight of tumor cells amounted to 4.81±1,69 g in the control group, which was not introduced generic�about, in the group G2 - 4,16±1,68 g (administered injectable composition (20% of hydroxychloroquine)), in the group G3 was 3.92±1.00 g, 3,31+0,72 g in the group G4, indicating that the composition of the present invention reduced the weight of solid cancers, depending on the dosage.

Test example 4: Monitoring anti-cancer activity on Ehrlich ascites cancer

In mice with Ehrlich ascites carcinoma induced by transplantation of cells of sarcoma-180, were evaluated the anticancer effect of the composition of the present invention and impact of the composition to increase the lifetime of mice.

According to Table 3 below, the animals adapted to the housing conditions, were divided into 3 groups (G1-G3), each of which consisted of 10 animals.

Table 3 below shows the formation of test groups and the concentration of the medication.

[Table 3]
GroupDoseThe number of animals
G1Control group010
G2The group receiving high dose166 µl/kg10
G3830 µl/kg10

Suspension of washed cells of sarcoma-180 with a cell concentration of 2×107cells/µl was introduced into the abdominal cavity of all groups for induction of Ehrlich ascites cancer. The composition of the present invention installed in the doses indicated in Table 3, and each dose of the composition administered to animals with 3-day intervals for 6 weeks after the induction of ascites cancer, while observations were made for mortality rate, which was compared with mortality in the group which was administered cisplatin.

FIG.4 is a graphical diagram showing the effect of the composition of the present invention on the lifespan of albino mice after induction of Ehrlich ascites cancer in albino mice by cells of sarcoma-180. In Fig.4, G1: control group; G2: 166 entered μl/kg weight of the injection composition (20% of hydroxychloroquine); and G3: entered 830 μl/kg weight of the injection composition.

Mortality of animals from Ehrlich ascites cancer was studied until the last day (day 42) test. As a result, in the control group dead animals began to appear with 9 days and 21 days, about half of the animals were dead on day 42 one animal survived, but I believe that surviving animal was not infected ascitic cancer, or degree inducts�and ascitic cancer in this animal was insufficient.

In the group G2 dead animals began to appear on day 13, a little later than in the control group, on day 26 half of the animals died, but as of the last day of the study 3 animals survived. However, in the group G3 all animals were dead on the first day after drug administration. These results suggest that the composition of the present invention prolongs the lifespan of animals with Ehrlich ascites carcinoma.

Industrial applicability

As described above, an injectable medicinal composition for topical application of hydroxychloroquine, in accordance with the present invention, shows the value of IC50against cells of sarcoma-180, which is about 10 times lower than that of cisplatin, as determined by a laboratory MTT test, with the assumption that the composition of the present invention has excellent cytotoxic effect. The composition of the present invention shows a dose-dependent effect on solid cancer induced by cells of sarcoma-80 in the body. In addition, the composition of the present invention has an effect on extending the lifespan of patients with ascites carcinoma induced sarcoma cells-80.

1. Injectable anticancer medicinal composition for administration directly into cancer cells, comprising 5-25% (wt./about.) hydroxychloroquine or �of Ulfat hydroxychloroquine, lidocaine at a concentration of 1-2% (wt./vol.), Riboflavin in a concentration of 0.1-0.5% (wt./about.) and saline.

2. The composition according to claim 1, in which the content of hydroxychloroquine is 20% (weight/volume).



 

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FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely represents a method for the therapy of respiratory symptom. The method involves administering a liquid composition containing a gel former and/or a mucoactive polymer, a non-menthol cooling substance; and contacting the oral mucosa with the liquid composition. The invention also describes liquid compositions applicable in the method for the therapy of a respiratory disease.

EFFECT: implementing the method provides improving the cooling properties of the cooling agent N-(4-cyanomethylphenyl)-n-menthane carboxamide in the liquid composition by combining the non-menthol cooling substance with the gel former.

14 cl, 2 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to the field of pharmaceutics and deals with a pharmaceutical composition, which contains feline erythropoietin as an active ingredient, to which two or more polyethyleneglycol molecules with a non-branched chain are attached, with a water-soluble long-chain molecule having the molecular weight, constituting not less than 30 kDa and producing the haemopoietic effect. A haemopoietic medication and a medication for the treatment of anaemia are based on the said composition.

EFFECT: group of inventions provides the haemopoietic effect, which lasts for not less than seven days, when introduced to humans and/or animals.

8 cl, 4 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention represents a composition for preventing and treating allergic conjunctivitis and keratoconjunctivitis, containing cromoglicic acid, boric acid and water-soluble polymers specified in a group of: carbomer, hypromellose, macrogol and polyvinylpyrrolidone with the components of the composition taken in specific relations, g in 1 ml of the mixture.

EFFECT: invention provides the better reduction of the inflammatory process and symptoms of the disease; there are also ensured ease of use with a smaller frequency of administration, prolonged action and no side effects.

5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with a crystalloid cardioplegic solution, which contains salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and a structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=CH3, Y=H, Z=OH. The group of inventions also deals with the crystalloid cardioplegic solution, containing salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=H, Y=NO2, Z=NH2.

EFFECT: group of inventions provides the recovery of the coronary flow, cardiac contractile and pump function in case of the reperfusion and the reduction of injury to membranes of cardiomyocytes.

2 cl, 2 dwg, 8 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is a pharmaceutical, ear, sterile, preservative-free composition in the form of a transparent aqueous solution, containing 0.01-0.025 % of fluocinilone acetonide optionally in a combination with 0.1-0.8% of ciprofloxacin or its pharmaceutically acceptable salt, a non-ionic surface-active substance, a tonicity-regulating agent and a viscosity-increasing agent.

EFFECT: composition is useful for the prevention and/or treatment of ear inflammation, optionally accompanied with a bacterial infection, and for the introduction of a single dose from a package.

15 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention represents a balanced infusion solution containing sodium, potassium and magnesium chlorides, a solvent and sodium L-arginine succinate of formula: Na+[NH=C(NH2)NH(CH2)3CH(NH2)COOH]+[OOC(CH2)2COO]2-. The ingredients in the solution are found in certain proportions, wt %.

EFFECT: invention provides enhanced detoxification activity, low toxicity and wide range of clinical applications.

11 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to production of medications for treating dermatosis. Medication according to invention, made in form of cream, contains mometasone furoate, preservative, hydrophilic no-aqueous solvent, emulsifying agent of 1st kind, emulsifying agent of 2nd kind, emollient, disodium edetate (trilon B), pH-regulating agent, and purified water in quantities, given in invention formula.

EFFECT: invention can be applied for treating inflammatory diseases and itching in case of dermatosis, yielding to glycocorticosteroid therapy.

9 cl, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiac surgery, and represents cardioplegic solution, which contains sodium chloride - 3.41-3.62, potassium chloride - 1.092-1.156 g, magnesium chloride - 3.190-3.485 g, calcium gluconate - 0.0105-0.0130 g, mannite - 4.365-4.520 g, L-carnosine - 20.1504-24.1650 g, N-acetylcarnosine - 8.056-11.032 g, L-histidine - 0.705-0.820 g, water for injections to 1000 ml.

EFFECT: invention ensures prevention of reduction of amplitude, speed of front and speed of pulse-wave reduction, as well as increase of diastolic pressure in left heart ventricle during reperfusion with preservation of buffer capacity and osmolarity of cardioplegic solution with physiological pH parameters.

4 tbl, 2 ex

Transdermal plaster // 2553350

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine. Described is matrix layer, suitable for application in plaster for transdermal delivery, aimed at introduction of biologically active compounds, which includes phosphate compound of tocopherol and polymer carrier. Also described is transdermal plaster and method of its production.

EFFECT: plaster makes it possible to efficiency introduce biologically active compounds.

48 cl, 15 tbl, 13 dwg, 12 ex

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