Pharmaceutical composition containing poloxamer 188 for use as a radiomitigator

Abstract

The invention relates to the field of human and veterinary medicine, and more particularly to a pharmaceutical composition for use as an agent for enhancing the ability to tolerate radiotherapy and also for providing a therapeutic effect after radiation exposure. The claimed pharmaceutical composition for use as an agent for enhancing a cancer patient's ability to tolerate radiotherapy and also for providing a therapeutic effect for humans or animals after radiation exposure comprises poloxamer 188 as a pharmacologically active agent, and at least one excipient. Proposed are variants of the pharmaceutical composition for use as a radiomitigator, the qualitative composition of which provides for a beneficial effect on bone marrow by preventing fatty infiltration and supporting de novo platelet production.

Description

[0001] A PHARMACEUTICAL COMPOSITION CONTAINING POLOXAMER 188 FOR USE AS A RADIOMITIGATOR

[0002] The invention can be used as a medicinal product when administered to the body in the early stages (hours, days) after damaging radiation exposure to the cells of the body's hematoimmune system.

[0003] Radiomitigators are radiation-protective drugs that exert their effect at the systemic level by accelerating post-radiation recovery of radiosensitive tissues. This is achieved through the activation of several pro-inflammatory signaling pathways and increased secretion of hematopoietic growth factors.

[0004] State of the art.

[0005] It is known that when Perftoran PFO emulsion was administered to cancer patients at a dose of 400-600 ml (approximately 5-12 ml / kg) prior to chemotherapy or radiation therapy, no significant changes in peripheral blood or biochemical parameters were observed compared to the control group. Clinical data showed a more significant tumor regression (Krylov N.L., Moroz V.V., 1994).

[0006] It is known that the use of the PFOS emulsion "Perftoran" at a dose of 6 ml / kg has a beneficial effect on peripheral blood parameters, has an organoprotective effect, improves the tolerability of radiation therapy in cancer patients, and also increases its effectiveness. (Vasilieva T.P., Use of PFOS emulsion in oncology. / Physiologically active substances based on perfluorocarbons in experimental and clinical medicine. Abstracts of the All-Army Scientific Conference, September 23-24, 1999. / St. Petersburg, 1999. pp. 10-12).

[0007] It is known that the use of Perftoran during chemoradiation therapy eliminates its adverse effects. In the complex chemoradiation treatment of cancer patients, the use of Perftoran at a dose of 200 ml (approximately 2.5 - 4 ml / kg) for 5 days led to a significant improvement in well-being, a decrease in severe asthenic syndrome and a smaller amplitude of the increase in creatinine and transaminases compared to the control group, which indicates improved tolerability of chemoradiation therapy. (M.V. Petrova, D.L. Biryukov, T.V. Krasnova. Experience of using Perftoran in the complex treatment of cancer patients. And Physiologically active substances based on perfluorocarbons in experimental and clinical medicine, St. Petersburg, 1999. pp. 64-65.

[0008] Perftoran, administered intravenously to rats at a single dose of 5 ml / kg body weight 5 minutes after exposure to 8 Gy of whole-body X-ray irradiation, is known to affect oxidative stress parameters and the severity of radiation-induced apoptosis. Studies were conducted 6 hours after irradiation, during the development of early post-radiation apoptosis. A moderate decrease in lactate levels was observed in the animals' blood, resulting in a decreased lactate / pyruvate ratio. This shift in the balance of the lactate dehydrogenase reaction indicates the preferential formation of reduced forms of pyridine nucleotides, which occurs due to improved tissue respiration. The increase in tissue respiration was accompanied by activation of oxidative stress processes, as evidenced by a significant increase in SOD activity in animals of this group.The level of endogenous nitrates in the blood can also be assessed as a result of activation of nitroxide-producing processes. Thus, the introduction of perfluorane immediately after irradiation led to the intensification of cellular metabolism and oxidative processes in experimental animals. The noted biochemical changes were observed against the background of increased apoptosis of thymus cells compared to the control group of irradiated animals that were not administered perfluorane. (Pshenkina H.N., Veselova O.M., Murzina E.V., Andreeva N.B. The effect of perfluorane on oxidative stress indices and the severity of radiation apoptosis in rats. Perfluorocarbon compounds in experimental and clinical medicine. Coll. of materials of the conf. St. Petersburg; 2004. P. 104.).

[0009] Document RU2341306, when treating cancer patients, including perfluorane infusion and radiation therapy, recommends conducting laser diagnostics during an occlusion test to determine microcirculation in the fingertips before the occlusion test and the maximum microcirculation index after the occlusion test. Oxygen saturation should be determined before and immediately before the completion of the occlusion test, followed by administration of 25-30 mg of prednisolone solution, followed by perfluorane at a rate of 2.5-3.5 ml / kg of body weight. Microcirculation and saturation should be re-evaluated after 1-1.5 hours, and once these parameters reach the required values, radiation therapy should be administered. Increasing saturation in the tumor and surrounding tissues enhances the damaging effects of radiation therapy on the tumor and improves short-term cure rates.

[0010] The composition of Perftoran emulsion is known to be: 13 g of PFD (polyphosphate compound), 6.5 g of PMCP (perfluorocarbonyl group), 4 g of Proxanol 268 (Emuxol 268) emulsifier, a saline composition, and up to 100 ml of water for injection (data from the official reference book). The emulsifier Emuxol 268 is a block copolymer of ethylene oxide and propylene oxide, and according to its physical properties (molecular weight, ratio of oxypropyl to oxyethylene groups), it belongs to the polyoxamer 188.

[0011] The authors suggested that the properties of the PFO emulsion Perftoran as a radiomitigator depend mainly on poloxamer 188, which is part of its composition.

[0012] It is known that the technology for producing emulsions based on PFO compounds involves the use of expensive high-pressure homogenizers (working pressure 40-80 MPa) and work in aseptic conditions with sterile components, due to the impossibility of final thermal sterilization (various patents).

[0013] It should be remembered that up to 7% of cases of Perftoran administration experience moderate-intensity anaphylactoid reactions, such as tachycardia, decreased blood pressure, difficulty breathing, fever, chest pain, dizziness, headache, cold sweat, and kidney pain (Maevsky on reactogenicity). (Our article on Oxyftem and the toxicity of PFD should be mentioned.) To prevent such reactions, document RU2341306 recommends administering the corticosteroid prednisolone before Perftoran administration.

[0014] The authors previously demonstrated that solutions of poloxamer 188 of various brands, Emuksol 268 brand A (NIOPIK, Russia) and Kolliphor P68 (BASF, Germany), showed themselves to be non-toxic substances when tested for acute toxicity at doses of 800 and 1330 mg / kg and chronic toxicity at doses of 400 and 665 mg / kg / day. (E.V. Arshintseva, S.Yu. Pushkin. Comparative study of acute toxicity of poloxamers upon intravenous administration in outbred rats / / Internauka. - 2022. - No. 13-1 (236). - P. 50-55. - DOI 10.32743 / 26870142.2022.13.236.336593. Arshintseva, E.V., Pushkin, S.Yu.

[0015] INCLUDED BY REFERENCE (RULE 20.6)Comparison of the chronic toxicity of poloxamers administered intravenously to outbred rats / / Scientific Almanac of the Central Black Earth Region. - 2022. - No. 2-5. - P.

[0016] 404-419.)

[0017] The aim of this invention is to create an effective pharmaceutical product with radiomitigator properties that does not require expensive equipment and raw materials, and that does not exhibit reactogenicity or toxicity.

[0018] The essence of the invention.

[0019] Based on the composition of Perftoran PFO emulsion and known cases of its use as a radiomitigate agent, it can be assumed that a single administration of a 4% poloxamer 188 solution will be effective at doses of 2.5-12 ml / kg, which corresponds to an administered amount of poloxamer 188 of 5 to 38.4 g. Calculations were made taking into account that the average woman's weight is 50-70 kg, and the average man's weight is 70-80 kg. However, for a patient weighing, for example, 100 kg, the amount of poloxamer 188 administered could range from 10 to 48 g, and for a patient weighing 40 kg, from 4 to 19.2 g.

[0020] The clinical preparation P188 (composition P188) can be formulated as a clear, colourless, sterile, apyrogenic solution intended for administration with or without dilution. The preferred concentration of the solution is approximately 16%. In the 16% solution, each 100 ml contains 16 g of P 188 (160 mg / ml), 0.6 g of sodium chloride and water for injection up to 100 ml. The clinical formulation of composition P188 may have a different salt composition, for example, 0.6 g of sodium chloride, 0.039 g of potassium chloride, 0.019 g of magnesium chloride, 0.065 g of sodium hydrogen carbonate, 0.02 g of sodium dihydrogen phosphate, and may also contain dextrose, for example, in an amount of 0.2 g.

[0021] Methods for achieving a therapeutic effect following exposure to ionizing radiation on cells of critical body systems, including the hematoimmune system, as a radiomitigator, including for improving tolerance, peripheral blood parameters, for providing an organoprotective effect, and for increasing the effectiveness of radiation therapy in cancer patients, are implemented by administering to the patient an effective amount of a pharmaceutically acceptable composition containing P188 described herein. The effective amount of the composition is administered directly to the patient according to methods well known to those skilled in the art. The pharmaceutical composition is preferably administered by intravenous infusion.

[0022] The patient to whom the P188 described herein is administered is a human or non-human subject who has a condition following exposure to ionizing radiation.

[0023] The effective amount is preferably delivered by administration as an infusion, such as a single bolus infusion or a continuous infusion administered once or repeatedly. The effective amount will preferably achieve a concentration in the patient's circulation of about 0.05 mg / ml to 10 mg / ml, depending on the duration of the infusion and the needs of individual patients. In a preferred embodiment of intermittent bolus infusions at weekly, biweekly, or triweekly intervals, the target range is about 0.5 to 5.0 mg / ml. In a preferred embodiment for continuous infusions, the target range is about 0.1 to 1 mg / ml, preferably about 0.5 mg / ml. These ranges are not limiting and will vary depending on the needs and response of the individual patient.The amount of P188 dosage sufficient to achieve the target concentration can be easily determined by one skilled in the art following standard procedures.

[0024] INCORPORATE BY REFERENCE (RULE 20.6) The pharmaceutical composition is typically administered at a concentration of approximately 0.5% to 16%. The composition may also be delivered in a more dilute or more concentrated dosage, depending on the needs of the individual patient. The actual amount or dose of the composition required to achieve the desired effect will vary for each individual patient based on the individual's response. Therefore, the specific amount administered to an individual will be determined through routine experimentation and based on the training and experience of a specialist in the field.

[0025] The effective amount of P188 will depend on the degree of radiation exposure, the disease state, and other clinical factors, including, but not limited to, factors such as patient weight, as known in the art. The methods described herein involve a single continuous infusion, multiple continuous infusions, or bolus administrations administered one or more times over an extended period of time for as long as necessary to achieve the desired effect.

[0026] It should be understood that the methods presented in this document have application to both humans and veterinary medicine.

[0027] The pharmaceutical compositions provided herein are suitable for various routes of administration, including, but not limited to, subcutaneous, intraperitoneal, intramuscular, intrapulmonary, and intravenous. The formulations may be presented in single or multiple dose form and may be prepared by conventional pharmaceutical methods. Such methods include the step of combining the active ingredient with the pharmaceutical carrier(s) or excipient(s).

[0028] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that optimally contain antioxidants, buffers, bacteriostats, and solutes that make the formulation compatible with the intended route of administration. Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, prefilled syringes, or other delivery devices, and may be stored in aqueous solution, dried, or lyophilized, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use.

[0029] The method proposed herein is further illustrated by reference to the following examples, which should in no way be construed as limiting its scope. On the contrary, it should be clearly understood that other embodiments, modifications, and equivalents thereof may appear to those skilled in the art upon reading the description provided without departing from the spirit and / or scope of the present invention and the appended claims.

[0030] Any suitable amount of P188 can be used in the compositions and methods of the invention. Typically, the pharmaceutical composition will contain from about 0.005% to about 25% P188 by weight. The pharmaceutical composition can contain, for example, 0.005%, or 0.025%, or 0.05%, or 0.1%, or 0.25%, or 0.5%, or 1%, or 2.5%, or 5%, or 10%, or 12.5%, or 15%, or 20%, or 25% or more P188 by weight. In some embodiments, the composition comprises P188 in an amount of from about 0.5% to about 20%, such as 0.5, 1, 2, 3, 4.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% by weight.

[0031] INCORPORATE BY REFERENCE (RULE 20.6) The compositions may be administered to a patient by any suitable route in accordance with the methods of the invention. In some embodiments, the composition is administered by intravenous infusion. In some embodiments, the formulation is administered as a single continuous infusion, multiple continuous infusions, a single bolus administration, or multiple bolus administrations.

[0032] Example.

[0033] Three groups of outbred rats were taken, with 6 animals in each.

[0034] Control group - rats from this group were not exposed to irradiation; they were injected once into the tail vein with a 0.9% sodium chloride solution at a dose of 5 ml / kg of animal body weight.

[0035] Irradiation group - rats from this group were exposed to irradiation, 1 hour after irradiation they were injected once into the tail vein with a 0.9% sodium chloride solution at a dose of 5 ml / kg of animal body weight.

[0036] Experimental group - rats from this group were exposed to irradiation, 1 hour after irradiation they were injected once into the tail vein with a 4% solution of poloxamer 188 containing 0.6% sodium chloride at a dose of 5 ml / kg of animal body weight.

[0037] Rats from the irradiated and experimental groups were exposed to gamma rays using a ROKUS-M cobalt source, with a radiation dose of 7 Gy, which causes grade 4 bone marrow acute radiation sickness (ARS).

[0038] Two weeks after euthanasia of the animals, bone marrow was collected from the femur of each animal for subsequent histology.

[0039] Pictures with explanations.

[0040] Result.

[0041] Administration of a 4% poloxamer 188 solution one hour after irradiation has a positive effect on bone marrow, preventing fatty infiltration of the organ. Despite a decrease in megakaryocytes, it is clearly evident that promegakaryocytes are the primary platelet precursors. This suggests that the use of a 4% poloxamer 188 solution does not reduce the bone marrow's ability to form platelets de novo.

[0042] Therefore, according to the results of histological analysis, a 4% solution of poloxamer 188 has radiomitigatory properties in the model of bone marrow acute radiation sickness.

[0043] INCORPORATE BY REFERENCE (RULE 20.6)

Claims

Invention formula 1. A pharmaceutical composition for use as a means for improving the tolerability of radiotherapy, as well as for providing a therapeutic effect after radiation exposure, containing poloxamer 188 as a pharmacologically active substance in a therapeutically effective amount.

2. The agent according to claim 1, characterized in that it contains a therapeutically effective amount of poloxamer 188 from 0.05 to 25%.

3. The agent according to paragraphs 1-2, characterized in that it is an aqueous-salt solution of poloxamer 188.

4. The method of using the agent for the treatment of kidney disease is the intravenous administration of the pharmaceutical composition.

5. The method of using the agent according to paragraphs 1-4, characterized in that the intravenous administration is carried out repeatedly.

6. The method of using the agent according to paragraphs 4-5, characterized in that with a single administration the pharmaceutical composition contains from 4 to 48 g of poloxamer 188.

7. The method of using the agent according to paragraph 6, characterized in that the pharmaceutical composition is administered to the patient daily for at least 5 days. INCORPORATE BY REFERENCE (RULE 20.6)