Injectable compositions for the postoperative treatment of malignant brain tumours

Abstract

The present invention discloses the use of local chemotherapy after laser hyperthermia treatment of a brain tumour. A pharmaceutical composition for local postoperative chemotherapy comprises a chemotherapy drug, in particular doxorubicin, loaded into nanoparticles obtained from a copolymer of amino acids that are natural metabolites in the brain.

Description

[0001] Injectable compositions for postoperative treatment of malignant brain tumors Field of technology

[0002] The invention relates to pharmacology and medicine and can be used to treat brain tumors.

[0003] State of the art

[0004] Every year, 10,000 new cases of primary malignant brain tumors are detected in the Russian Federation. Glioblastoma is one of the most malignant brain tumors, with a life expectancy of 14.6 months. Surgical treatment of glioblastomas alone results in an average life expectancy of 6 months, so radiation therapy and chemotherapy are also used. Each treatment method alone cannot be effective enough, so a comprehensive approach is used. The effectiveness of chemotherapy could be high, since the drug is theoretically capable of penetrating all areas of the brain and having a cytoreductive effect. However, parenteral or intravenous administration of chemotherapy drugs is limited by the ability of the drug to penetrate the blood-brain barrier (hereinafter referred to as BBB) to tumor cells. The list of drugs that can penetrate the BBB is very short, and tumor cells eventually become resistant to them.However, there is a list of drugs that are highly effective against brain tumors but are not able to penetrate the BBB and reach tumor cells. For good penetration through the BBB, the drug must be lipophilic and have a small molecular weight (less than 400 Daltons) to pass through the intercellular contacts of the BBB. Also, the concentration of the drug that has passed through the BBB must be sufficient so that the effective amount of the drug remains in the area of ​​interest and is not removed by the BBB transport systems that maintain brain homeostasis. The high concentration of capillaries in the brain with a step of 50 μm carries out strict supervision of homeostasis. Thus, insufficient passive diffusion and rapid elimination of the therapeutic agent that has penetrated through the BBB from the brain into the vascular bed is a limitation of the effectiveness of chemotherapy.

[0005] It is known from the state of the art that the chemotherapeutic drug Gliadel is used in the treatment of malignant intracerebral tumors. It is a biodegradable wafer containing the antitumor drug carmustine (Amade Bregy et al / The role of Gliadel wafers in the treatment of high-grade gliomas, Expert Rev Anticancer Ther. 2013 Dec;13(12):1453-61. doi: 10.1586 / 14737140.2013.840090). Gliadel was placed on the walls of the bed of a surgically removed tumor. Such local chemotherapy, on the one hand, made it possible to bypass the BBB, on the other hand, the diffusion of the active antitumor substance was very short from the placed wafer. And the tumor cells located at a distance that the drug did not reach remained untreated. Thus, Gliadel did not demonstrate a significant therapeutic effect and is also not without complications such as encephalitis and epileptic seizures.

[0006] A system for intracranial delivery of a diagnostic or therapeutic solid agent into the brain of a subject is known from the prior art, wherein said system includes: a device for introducing a diagnostic or therapeutic solid agent into the brain (US20090192487).

[0007] Thus, there is a need to develop new, more effective approaches to the complex therapy of malignant brain tumors.

[0008] Disclosure of invention

[0009] The objective of the present invention was to develop a pharmaceutical composition for postoperative local treatment of oncological disease of the brain, as well as a combined method for treating oncological disease of the brain, including surgical treatment, as well as local chemotherapy.

[0010] The technical result of the present invention consists in developing and creating a pharmaceutical composition for postoperative local treatment of oncological disease of the brain, in particular malignant tumor of the brain, based on nanoparticles, which is characterized by high efficiency in local chemotherapy of tumor disease of the brain, the composition according to the invention is capable of being displaced by the flow of cerebrospinal fluid to a sufficient distance from the injection site together with the gradual release of the active substance (chemotherapeutic drug) from the nanoparticles in the composition, and, as a result, a larger volume of the perifocal zone of the tumor is covered by treatment, which thereby contributes to increasing the efficiency of treatment of oncological disease of the brain.In addition, the composition according to the invention is characterized by the absence of local irritating and / or inflammatory manifestations, the nanoparticles in the compositions according to the invention are made of amino acids - natural metabolites of the brain. An essential aspect of the invention is the proposed two-component composition (nanoparticles with a drug in a gel-like solution of a polysaccharide), ensuring uniform distribution of nanoparticles, sedimentation stability and increased prolongation of action. At the same time, for the proposed gel-like solution with a temperature-controlled viscosity, both the convenience of introducing the system as a liquid (at room temperature) and its functioning in a gel state after administration at body temperature are realized.

[0011] In addition, the technical result of the present invention consists in developing a combined method for treating an oncological disease of the brain based on laser hyperthermia and local chemotherapy, which allows, along with high elimination of tumor cells in the tumor node due to laser hyperthermia, also to effectively eliminate tumor cells in the perifocal zone (along the periphery of the tumor node) by local chemotherapy using the composition according to the invention, as a result, the effectiveness of treating an oncological disease of the brain is increased. Laser hyperthermia of the tumor in the method according to the invention allows for cytoreduction and coagulation of the microcirculatory bed (capillaries), which in turn allows for disabling the function of the blood-brain barrier in the perifocal region.This is important to prevent or limit the elimination of a drug (chemotherapy drug) administered locally from the perifocal zone of the tumor, which allows it to circulate longer and move with the flow of cerebrospinal fluid at a distance from the site of its administration.

[0012] It is in the perifocal zone that continued tumor growth occurs in 80% of cases. Therefore, reducing tumor cells in the perifocal zone will stop or slow down further tumor development.

[0013] The specified technical result is achieved by means of a pharmaceutical composition for postoperative local treatment of oncological disease of the brain, which is a viscous gel-like solution of a polysaccharide, in which nanoparticles with a diameter of 100-300 nm are distributed based on a copolymer of L-glutamic acid or L-aspartic acid and L-phenylalanine or D-phenylalanine, or L, D-phenylalanine, or L, D-leucine, or 1_,O-isoleucine, containing 200-500 μg of a chemotherapeutic agent / mg of particles.

[0014] In particular embodiments of the invention, the chemotherapeutic agent is doxorubicin, docetaxel, paclitaxel, or irinotecan.

[0015] In particular embodiments of the invention, the polysaccharide is methylcellulose, hydroxyethyl starch or hyaluronic acid.

[0016] In particular embodiments of the invention, the gel-like solution of the polysaccharide is a solution of 5 mass % methyl cellulose or a gel-like solution of 3-20 mass % hydroxyethyl starch or a gel-like solution of 0.5-1 mass % hyaluronic acid.

[0017] In particular embodiments of the invention, the concentration of nanoparticles in the gel-like solution is 0.1-2.0 mg / ml.

[0018] In particular embodiments of the invention, the oncological disease of the brain is a glioblastoma, glioma, malignant glioma, malignant meningioma, or metastases of cancer in the brain.

[0019] In particular embodiments of the invention, the solvent in the gel-like solution of the polysaccharide is water or a physiological solution. In particular embodiments of the invention, the copolymer is a copolymer of L-glutamic acid and L-phenylalanine or a copolymer of [.-glutamic acid and D-phenylalanine or a copolymer of L-glutamic acid and L, D-phenylalanine.

[0020] In particular embodiments of the invention, the molar ratio of L-glutamic acid or L-aspartic acid units and L-phenylalanine or D-phenylalanine, or L, D-phenylalanine, or L, D-leucine, or L, D-isoleucine in the copolymer is in the range of 2: 1-3: 1.

[0021] In particular embodiments of the invention, the composition is intended for local injection into the brain, in particular into the perifocal zone of a brain tumor and / or directly into the tumor.

[0022] The subject of the present invention is also the use of the pharmaceutical composition according to the invention for postoperative local treatment of oncological disease of the brain.

[0023] In particular embodiments of the invention, the brain disease is a glioblastoma, glioma, malignant glioma, malignant meningioma, or brain cancer metastases.

[0024] In particular embodiments of the invention, the surgical treatment is laser hyperthermia.

[0025] The subject of the present invention is also a method for treating an oncological disease of the brain, comprising: a) laser hyperthermia of a brain tumor; b) local administration of a composition according to the invention into a brain tumor, in particular into the perifocal zone of a brain tumor and / or directly into the tumor.

[0026] In particular embodiments of the invention, the brain disease is a glioblastoma, glioma, malignant glioma, malignant meningioma, or brain metastases.

[0027] In particular embodiments of the invention, the composition is administered using a syringe or injector.

[0028] In particular embodiments of the invention, the composition is administered at the border of the coagulated tumor after stage a) and the perifocal zone.

[0029] In particular embodiments of the invention, laser hyperthermia of a tumor is carried out using infrared laser radiation with a power of 2 W.

[0030] The present invention also includes the preparation of compositions according to the invention.

[0031] Detailed disclosure of the invention

[0032] Brief description of the drawings Figure 1. In the figure, the darkest solid color indicates a laser-coagulated tumor, along the periphery of which is a perifocal zone where tumor cells are adjacent to brain cells. White balls indicate nanoparticles with doxorubicin.

[0033] Figure 2. Photo of a stage of laser hyperthermia of a tumor on the surface of a rat brain: 1 - wound skin; 2 - C6 glioma; 3 - rat cerebral cortex near the tumor node; 4 - laser fiber.

[0034] Figure 3. Rat brain 1 month after treatment: 1 - the site of the tumor with a depleted number of normal vessels; 2 - normal brain of the second hemisphere (the tumor was not implanted here).

[0035] Definitions (terms)

[0036] For a better understanding of the present invention, some terms used in the present description of the invention are provided below. The following definitions apply herein unless otherwise explicitly stated.

[0037] In the present description and in the following claims, unless the context otherwise requires, the words "have," "include," and "comprise," or variations thereof, such as "has," "having," "includes," "including," "contains," or "comprising," are to be understood as including the stated whole or group of wholes, but not excluding any other whole or group of wholes. These terms are not intended to be construed as "consists only of."

[0038] The term "and / or" means one, more, or all of the listed elements.

[0039] Also here, listing numeric ranges by endpoints includes all numbers within that range.

[0040] The term "gel-like solution" as used herein means a highly viscous solution that resembles a gel in appearance but, unlike the latter, has fluidity.

[0041] A copolymer is a type of polymer whose chains of molecules (macromolecules) consist of two or more different structural units. The copolymers according to the invention are characterized by a statistical distribution of monomer units in the chain.

[0042] Unless otherwise defined, technical and scientific terms in this application have the standard meanings generally accepted in the scientific and technical literature.

[0043] Implementation of the invention

[0044] The present invention discloses the use of local chemotherapy after laser coagulation of a tumor node. The pharmaceutical composition for local postoperative chemotherapy includes a chemotherapeutic agent, in particular doxorubicin, docetaxel, paclitaxel, irinotecan, loaded into nanoparticles obtained from a copolymer of glutamic acid or aspartic acid and phenylalanine or leucine, or isoleucine, which are natural metabolites in the brain. On the one hand, this prevents the brain's reaction and inflammatory complications. On the other hand, the use of particles according to the invention of nanosized 100-300 nm facilitates the diffusion of nanoparticles with the cerebrospinal fluid flow through the cerebrospinal fluid spaces over a greater distance from the injection site in the direction of the perifocal zone of the coagulated tumor. It is in the perifocal zone that continued tumor growth occurs in 80% of cases. Reducing tumor cells in the perifocal zone will stop or slow down further tumor growth.Migration of nanoparticles with release of a chemotherapeutic agent, in particular doxorubicin, docetaxel, paclitaxel, irinotecan, at a distance from the injection site in the perifocal zone has a therapeutic effect. In the closest space to the coagulated part of the tumor node, where the highest concentration of tumor cells is, the capillaries are coagulated. Accordingly, the elimination of the local chemotherapeutic agent by the BBB transport systems is limited, and it is able to circulate longer along the cerebrospinal fluid pathways to new territories with tumor cells and have a cytostatic or cytolytic effect.

[0045] According to the invention, when performing complex treatment of a tumor disease of the brain, the first stage is a cytoreductive operation using the method of laser hyperthermia of the tumor, which changes the tumor tissue along the periphery of the coagulation zone. Thus, in the coagulation zone, the tumor tissue is deprived of viability, and to the periphery of the coagulation zone, where the tumor cells are located, coagulation of microvessels, capillaries occurs and microcirculation stops. Termination of microcirculation in the perifocal zone of the tumor prevents the elimination of the therapeutic antitumor agent into the microvascular bed by the transport systems of the hematoencephalic and hematotumor barriers.Therefore, the chemotherapeutic agent, in particular doxorubicin, docetaxel, paclitaxel, irinotecan, released from nanoparticles in the composition according to the invention diffuses into the perifocal zone of the tumor together with the cerebral fluid, which facilitates long-term contact of the drug with tumor cells without its elimination into the microvascular bed by the BBB transport systems.

[0046] More specifically, the treatment of an oncological disease of the brain according to the invention includes a minimally invasive stereotactic surgery - laser hyperthermia of the tumor. The accuracy of targeting the tumor is ensured by a neuronavigation station. The operation is performed according to a plan created in the interface of the navigation station. The patient's head is fixed to the operating table with a Mayfield clamp in a motionless state. After registering the spatial position of the patient's head in the neuronavigation station, the point of application of the burr hole on the patient's head is found with its use. The operation is performed under general anesthesia in a neurosurgical operating room with standard equipment. Under aseptic conditions, after incision of soft tissues in the projection of the selected entry point into the skull, a burr hole with a diameter of 15 mm is applied (this diameter can vary depending on the clinical situation, size and number of foci in the tumor).Using a neuronavigation station, a stereotaxic introduction of a biopsy needle into the tumor is performed. After taking biopsy material with the needle, an optical fiber is introduced into the target to deliver laser radiation. Through the fiber introduced into the tumor, the first is irradiated with infrared laser radiation with a power of 2 W, the duration of continuous irradiation is, for example, 60 seconds, which leads to its heating and coagulation. Coagulation is characterized by the loss of viability of the coagulated tumor tissue, and the cessation of blood flow through the adjacent vessels of the microcirculatory bed of the coagulated tumor and the nearest perifocal zone. The second stage, with the purpose of cytoreduction of tumor cells located on the periphery of the coagulated tumor focus and infiltratively growing into the brain adjacent to the tumor, at the border of the coagulated tumor and the perifocal zone, a composition according to the invention is introduced through the needle.The number of points-sites for the introduction of the composition is determined by the doctor depending on the size and location of the tumor, commensurate with physiological accessibility. In case of primary multifocal tumors or multifocal relapses, the composition according to the invention can be stereotaxically placed in different foci located at a distance of several centimeters from each other, including in different lobes of the brain. Subsequently, nanoparticles with a chemotherapeutic agent, in particular, doxorubicin, docetaxel, paclitaxel, irinotecan, in the composition are capable of moving with the flow of cerebrospinal fluid to the perifocal zone. Thus, the contact of the drug with tumor cells is quantitatively increased, which increases its cytoreductive effect. And coagulation of the capillaries of the perifocal zone, achieved as a result of hyperthermia, levels out the elimination of the released drug by the BBB transport systems. This contributes to the movement of the drug to a greater distance from the site of introduction of the composition according to the invention.

[0047] Considering that the main tumor focus is subjected to coagulation and thus deprived of microcirculation, the therapeutic agent released from the biodegradable polymer is not removed by the BBB transport systems, but diffuses to the periphery from the tumor node with the natural flow of cerebrospinal fluid through the perineural and perivascular spaces. Thus, the nanoparticles and the active substance released from them over time - doxorubicin - are displaced with the flow of cerebrospinal fluid from the injection site to the perifocal zone of the coagulated tumor node. Since the ability of nanoparticles to migrate depends on their size and weight, the uneven sizes of the nanoparticles in the composition according to the invention contribute to their location at different distances from the coagulated tumor node, which contributes to the emergence of a more extensive perifocal area in which the active drug is present.Thus, the therapeutic agent is capable of being released from the biodegradable packaging at different time intervals and migrating to different distances with the flow of cerebrospinal fluid in the interstitial space of the perifocal zone of the tumor, reaching the tumor cells (Fig. 1).

[0048] Additionally, the method of treatment according to the invention can be combined with systemic administration of a traditional chemotherapeutic agent that penetrates the BBB. In this case, the effect of the traditional agent will be enhanced for the perifocal zone of the tumor due to the opening of the BBB in the perifocal zone after hyperthermia.

[0049] 1. Preparation of nanoparticles from a copolymer of L-glutamic acid and L / D / D,L-benzylalanine

[0050] To obtain nanoparticles, a copolymer with the following characteristics was used: average number molecular weight from 4000 to 10000, dispersion of 1.1-1.4, molar ratio of glutamic acid and phenylalanine units in the range of 2 / 1 -3 / 1. Nanoparticles were formed by the method of gradient phase inversion from organic (dimethylformamide) to aqueous (water), followed by lyophilic drying and redispersion in deionized water with short-term ultrasonic exposure (30 s) at a concentration of 1 to 5 mg / ml. The hydrodynamic diameter of the nanoparticles was 100-300 nm depending on the molecular weight of the copolymer and the phenylalanine enantiomer; the polydispersity index (IPD) was 0.2-0.3.

[0051] Polymer particles containing L-aspartic acid, or L,D-leucine, 1_,E-isoleucine are obtained according to the method above, but using the corresponding copolymers.

[0052] 2. Obtaining nanoparticles loaded with doxorubicin

[0053] To obtain doxorubicin-loaded nanoparticles (hereinafter DOX), an aliquot of doxorubicin solution in water was added to the nanoparticle dispersion obtained as described in Example 1 above at a rate of 200 to 500 μg doxorubicin per 1 mg of particles, followed by vigorous stirring for 30-60 seconds and left with moderate stirring for 30 min at room temperature. The resulting dispersion was then left overnight at 4 °C, after which it was freeze-dried and stored dry at 4 °C until use. After redispersion of the resulting nanoformulation in phosphate-buffered saline, the hydrodynamic diameter of the nanoparticles was in the range of 130-250 nm (IPD 0.28-0.35) for doxorubicin, depending on the initial loading. The efficiency of inoculation was 93-97% depending on the initial amount of doxorubicin used for loading.

[0054] After 10 days of incubation of encapsulated systems at physiological temperature (37 °C), the release of DOX is: - 5-7% in sodium phosphate buffered saline with pH 7.4 (initial loading 280 μg DOX / mg particles);

[0055] - 17-23% in sodium phosphate buffered saline acidified to pH 5.0 (initial loading 280 μg DOX / mg particles);

[0056] - 40-50% in human plasma (initial loading 280 μg DOX / mg particles). Release over 14 days (2 weeks) in plasma was 55-60%.

[0057] Thus, the rate of DOX release can be varied, prolonging or slowing down the release. The dosage and time of action will be determined by medical indications, the degree of tumor resection, the presence / absence of metastases in adjacent tissues.

[0058] 3. Obtaining injectable materials with cytostatic properties

[0059] Before obtaining the composition according to the invention, lyophilized nanoparticles loaded with doxorubicin are dispersed in a saline solution (0.9% NaCI) in a ratio of 100 μg of nanoparticles / 20-50 μl of saline solution under short-term ultrasound exposure (15-30 s). Next, the dispersion of nanoparticles is mixed with a pre-prepared viscous gel-like solution of the polysaccharide. The latter is prepared by adding the appropriate volume of saline to the weighed portion of the polysaccharide at room temperature. The amount of polysaccharide taken to prepare the polymer solution depends on the type of polysaccharide. For methylcellulose (dynamic viscosity of 4000 mPa s), the concentration is 5-7 wt.%, for hydroxyethyl starch (M w = 130-200 kDa, s.z. 0.4) - from 3 to 20 mass%, for hyaluronic acid (M w= 800-1000 kDa) - 0.5-2 wt%. Unlike hyaluronic acid and hydroxyethyl starch, methylcellulose is a heat-sensitive polymer, 5 and 7 wt% aqueous solution of methylcellulose has a phase transition at 39 and 36 °C, respectively, which makes it possible to easily prepare compositions according to the invention and administer it in the form of a viscous gel-like solution that turns into a gel at physiological body temperature. The resulting compositions are homogeneous for 7 days at room temperature and at 37 °C. During this period, no side processes in the form of precipitation or phase separation were observed.

[0060] The release of doxorubicin from the composition according to the invention was carried out using a gel-like solution based on 5% methylcellulose containing nanoparticles loaded with doxorubicin as an example. The release of doxorubicin was 5% after 7 days of incubation in a sodium phosphate buffered saline solution at a temperature of 37 °C. After 14 days of incubation under the same conditions, the release of doxorubicin was 22%. The release into blood plasma from the composition according to the invention was significantly more intense and reached 57% after 7 days of incubation at a temperature of 37 °C.

[0061] The above in vitro experiment was conducted for up to 14 days, so the degree of doxorubicin release is not complete. At the same time, under in vivo conditions, since the drug is not extracted from the brain, the drug is absorbed and degraded, providing a complete gradual release of doxorubicin, i.e. the final degree of release will inevitably reach 100%. The time to achieve this depends on the composition of the particles, the polysaccharide medium, and the dosage of DOX.

[0062] In vitro experiments demonstrate the potential drug release capacity of these carriers and the estimated release time.

[0063] Use of the composition according to the invention in the treatment of transplantable intracranial glioma C6 in rats

[0064] In the first stage, 1 million C6 glioma cells were implanted into five male rats under anesthesia in an animal operating room through a 1 mm hole in the skull under the dura mater. Ten days later, as neurological symptoms appeared in the animals, a second surgical treatment was performed, during which tumor growth at the implantation site was visualized in all cases (Fig. 2). During the second operation, the tumor was coagulated with an infrared laser in one case and in four cases, after coagulation, a composition according to the invention was introduced, consisting of nanoparticles based on a copolymer of L-glutamic acid with D-phenylalanine in a ratio of 2.9:1, loaded with doxorubicin and distributed in 5% methylcellulose in a physiological solution (0.9% sodium chloride in water). Characteristics of the copolymer in the nanoparticle: average molecular weight 6500, dispersion 1.28. Characteristics of nanoparticles: hydrodynamic diameter - 130 nm, polydispersity index - 0.30.The drug loading into the particles was 459 ± 15 μg doxorubicin / mg particles (encapsulation efficiency 92%). The content of loaded nanoparticles in the gel was 200 μg / mL gel.

[0065] The animals were observed for 1 month, during which no disability or death of the animals was observed. After the animals were withdrawn from the experiment, the animal's brain was extracted and the treatment results were assessed. In no case was tumor tissue observed when visualizing the operation site under magnification of 2.5-5.0 times. The cerebral cortex had an externally matte surface and some depletion of superficial vessels, which confirms their coagulation during laser hyperthermia (Fig. 3). Microscopic examination of hematoxylin-eosin-stained brain microsections in the operation area, conducted by pathologists, showed the absence of tumor cells on the brain surface and in the underlying cortex and white matter in four animals treated with both the laser and the composition according to the invention. And in the animal treated only with laser coagulation (control operation), infiltration of the animal's brain adjacent to the operation with tumor cells was observed.That is, the control animal, unlike the four animals with complex treatment, did not recover. Moreover, one can expect further progression of the disease in the control animal. Thus, the conducted studies confirm that the combination of laser hyperthermia of the tumor with local chemotherapy allowed achieving virtually complete recovery of animals with transplantable glioblastoma.

[0066] Although the invention has been described with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments described in detail are provided merely for the purpose of illustrating the present invention and should not be considered as limiting the scope of the invention in any way. It will be understood that various modifications can be made without departing from the spirit of the present invention.

Claims

Invention formulas 1. A pharmaceutical composition for postoperative local treatment of oncological disease of the brain, which is a gel-like solution of a polysaccharide in which nanoparticles with a diameter of 100-300 nm are distributed based on a copolymer of L-glutamic acid or L-aspartic acid and L-phenylalanine or D-phenylalanine, or 1_, D-phenylalanine, or L, D-leucine, or L, D-isoleucine, containing 200-500 μg of chemotherapeutic agent / mg of particles.

2. The pharmaceutical composition according to claim 1, wherein the chemotherapeutic agent is doxorubicin, docetaxel, paclitaxel, irinotecan.

3. The pharmaceutical composition according to claim 1, wherein the polysaccharide is methylcellulose, hydroxyethyl starch or hyaluronic acid.

4. The pharmaceutical composition according to claim 1, wherein the gel-like solution of the polysaccharide is a solution of 5 mass % methylcellulose or a gel-like solution of 3-20 mass % hydroxyethyl starch or a gel-like solution of 0.5-1 mass % hyaluronic acid.

5. The pharmaceutical composition according to claim 1, wherein the concentration of nanoparticles in the gel-like solution is 0.1-2.0 mg / ml.

6. The pharmaceutical composition according to claim 1, wherein the oncological disease of the brain is a glioblastoma, glioma, malignant glioma, malignant meningioma, or metastases of cancer in the brain.

7. The pharmaceutical composition according to claim 1, wherein the solvent in the gel-like solution of the polysaccharide is water or a physiological solution.

8. The pharmaceutical composition according to claim 1, wherein the copolymer is a copolymer of L-glutamic acid and L-phenylalanine or a copolymer of L-glutamic acid and D-phenylalanine or a copolymer of L-glutamic acid and L,D-phenylalanine.

9. The pharmaceutical composition according to claim 1, wherein the molar ratio of L-glutamic acid or L-aspartic acid units and L-phenylalanine or D-phenylalanine, or L, D-phenylalanine, or L, D-leucine, or L, D-isoleucine in the copolymer is in the range of 2: 1-3:

1.

10. A pharmaceutical composition according to item 1, which is intended for local injection into the brain.

11. A pharmaceutical composition according to item 10, which is intended for administration into the perifocal zone of the brain.

12. A pharmaceutical composition according to claim 10, which is intended for administration directly into a brain tumor.

13. Use of the pharmaceutical composition according to item 1 for postoperative local treatment of oncological disease of the brain.

14. The use according to claim 13, wherein the brain disease is glioblastoma, glioma, malignant glioma, malignant meningioma, metastasis of cancer in the brain.

15. The use according to claim 13, wherein the surgical treatment is laser hyperthermia.

16. A method for treating an oncological disease of the brain, comprising: a) laser hyperthermia of a brain tumor; b) local administration of the composition according to item 1 into the brain.

17. The method according to claim 16, wherein the local administration of the composition is carried out into the perifocal zone of the brain.

18. The method according to claim 16, wherein the local administration of the composition is carried out into a brain tumor.

19. The method according to claim 16, wherein the brain disease is a glioblastoma, glioma, malignant glioma, malignant meningioma, brain metastases.

20. The method according to claim 16, wherein the composition is administered using a syringe or injector.

21. The method according to claim 16, wherein the introduction of the composition is carried out at the border of the coagulated tumor after stage a) and the perifocal zone.

22. The method according to claim 16, wherein laser hyperthermia of the tumor is carried out using infrared laser radiation with a power of 2 W.

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