Radiopharmaceutical composition


(57) Abstract:

The invention relates to medicine, namely to radiopharmaceutical drugs containing a radionuclide samarium-153, and may be used for the treatment of metastases of malignant tumors in the bones and rheumatoid arthritis. The invention lies in the fact that the claimed tool is a radiopharmaceutical composition comprising samarium-153, samarium in the form of a complex with oxa-bis(ethylenedithio)tetramethylphosphonium acid or its physiologically acceptable salt, sodium chloride, water for injection at a specific ratio of ingredients, this volume activity of samarium-153 is 240-740 MBq/ml, and the pH of the composition 5-7. The invention provides ease of cooking, increase therapeutic effect, the elimination of toxic reactions when introduced into the patient's body. table 2.

The invention relates to medicine, namely to radiopharmaceutical drugs containing a radionuclide153Sm, and can be used for the treatment of metastases of malignant tumors in the bones and rheumatoid arthritis.

Radionuclide samarium-153 emits gamma-quanta with energy 69,7 and 106 Kev and outputs the Aria-153 is 46,2 PM

Complexes153Sm with polimetilenovye acids have the ability to selective accumulation in metastatic and inflammatory destructive lesions of bone. Due to the presence of gamma radiation153Sm drugs on the basis of these complexes affect cells metstaticescoe or inflammatory lesion and the surrounding nerves, causing simultaneously analgesic and anti-proliferative effect. The presence of gamma radiation logs the distribution of accumulation of the drug in the body using a gamma camera.

Currently, there are several preparations containing153Sm, for the treatment of metastases of malignant tumors in the bones.

Thus, the known complexes of organic aminophosphonic acids for the treatment of calcified tumors [1]. To create compositions using radionuclides 153Sm166Ho,175Yb,177Lu,159Gd and organic aminophosphonate acid in which the amine nitrogen and phosphorus are linked through alkylene group

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where X and Y independently of one another is hydrogen, hydroxyl, carboxyl, phosphonic group, a hydrocarbon radical having 1 to 8 carbon ATO is to ichatusa number of carbon atoms.

Structural formulas of the compounds can be depicted as follows:

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where the substituents A, B, C, D, E and F independently of one another is hydrogen and acid radicals physiologically acceptable salts;

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where X, Y and n, and X' and Y' are independent hydrogen, methyl or ethyl radical, n' is 2 or 3; m and m' each independently may be 0 to 10, with at least one nitrogen atom may be replaced by a predominantly fosforsoderzhashchie group;

where R is a hydrocarbon radical, which may be linear, branched, cyclic, heterocyclic or to have a closed ring structure, provided that if m or m'>1, then substitute E and F are the same or different from other substitutes the number of nitrogen atoms, and R may be the same or different.

Specifically described, the composition comprising 25 to 35 mg EDTMP (ethylenediaminetetramethylene acid) and 10 MCI153Sm and having pH 7 to 8, and a similar composition to other acids.

The disadvantage of the described compositions is set to the present time, the fact of formation of products of radiation decomposition of organic acids in the case of high activity radionuclide and probably is more closely analogous to the claimed technical solution is frozen radiopharmaceutical composition, representing a set of at least one radionuclide with ligand or its physiologically acceptable salt, especially153Sm-EDTMP (ethylenediaminetetramethylene acid), which may contain metal ions (Ca2+and that frozen, thawed and then used for injection [2]. In this case, ions of Ca2+are introduced into the composition to prevent binding of calcium blood EDTMP, and freezing is to slow radiolysis reactions in solution and consequently reducing the amount of radiolysis products in the drug. Thus ions of divalent metal (Ca2+) enter before freezing of the composition in a molar ratio of Me:ligand 0,25:1; 0,5:1; 0,75: 1; 0,9: 1. You can also use Fe2+, Mn2+or ions of alkaline-earth elements Be2+, Mg2+, Sr2+, Ba2+. After thawing the drug is administered parenterally, intravenously, intramuscularly or subcutaneously.

Disadvantages of analogue:

the level of calcium in the patient's blood is enough individual indicator, and its introduction in the composition of the drug is not always necessary and desirable; the mechanism of action of drugs on the basis of polimetilenove is if a significant part of the coordinating groups in the ligand molecule is bound with metal ions; in addition, the use of the base for the preparation of large quantities of metals such as Fe, Mn, Be, Sr, Ba, can cause toxic reactions in the patient; and salts of divalent metals with EDTMP have limited solubility in the field of pH above 5, so in some cases, the formation of colloids or suspensions in solution, which leads to increased accumulation in the liver; it should be noted that in the examples of the text of the prototype there are indications on the facts of the increased accumulation of the drug in the liver, which the authors attributed to uninterpreted results;

the procedure of freezing and thawing of a radioactive drug is a serious complication of technology; at the same time to ensure the safety of the drug in frozen during transportation from production to the clinic almost impossible, and the need for defrosting in the clinic due to the additional time and radial loads on the medical staff.

These circumstances put before the authors to develop the drug, which is a physiologically acceptable solution 153Sm, with the ability to increased accumulation in inflammatory lesions of bone radionuclide was selected in 4 days.

This object is achieved in that, as a drug for the treatment of bone metastasis and rheumatoid arthritis proposed composition, representing a solution containing samarium-153, samarium in the form of a complex with oxa-bis(ethylenedithio)tetramethylphosphonium acid (oxabiphor) or its sodium salt, and sodium chloride

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The drug is prepared as follows. Samarium-153 get irradiating in a nuclear reactor 1-2 mg enriched samarium-152 in the form of chloride. After irradiation the latter is dissolved in 0.1 M hydrochloric acid solution and gradually mixed with a pre-prepared auxiliary solution containing 15,0-25,0 mg/ml sodium oxabiphor and 4.0-6.0 mg/ml sodium chloride. Volume activity of the drug received at the time of manufacture ranges from 240 to 740 MBq/ml of the resulting preparation is Packed in bottles for medicines portions from 925 to 3700 MBq and sterilized.

Limit values of concentrations of the components installed on the basis of experimental data obtained by analyzing a number of samples of the drug, and below, mg:

Sodium oxa-bis(ethylenedithio)tetramethylphosphonium acid - 15 - 25

Samarium in the form of a complex of Samara is Nyenzi, ml - Up to 1

This volume activity of samarium-153 is 240-740 MBq/ml

The preparation is sterile and apyrogenic and has a pH of 5-7.

Clinical tests conducted [in accordance with the decision of the Pharmacological state Committee No. 1 from 12.01.95 g] in the Medical radiological research center of RAMS during 1996-1999

The purpose of persistent reduction in pain intensity caused by the presence of metastatic tissue in the bone lesions, the drug is administered in the amount of 55.5 MBq/kg body weight of the patient intravenously. In rheumatologic practice to use the activity from the calculation of 18.5 MBq/kg body weight. With the aim of reducing radiation exposure to personnel and safety during the procedure (decalcomania blood, which may occur with rapid administration of the drug and which can cause seizures patient) use the technique of intravenous drip with pre-breeding portions of the drug in 50-100 ml of saline. For this purpose establish a system for intravenous infusion and start a drip of saline. Then, temporarily blocking clamp tube system, is injected into the vial with fiziologicheskii trials studied the behavior of the drug in 50 patients with metastases of malignant tumors in bone and 20 rheumatologic patients. After intravenous drug153Sm-oxabiphor during the first 2 h accumulates in the kidneys, bladder, small inclusion (up to 5% of the injected dose) may occur in the liver, the projection of the nasal sinuses. After 2 h, the drug begins to actively fixed in the bones, mostly in the affected areas (metastatic foci, areas of inflammation). During the first day of the urine excreted from 28 to 42% of the injected activity. The maximum removal occurs within the first 8-12 hours the Level of excretion depends on renal function, volume lesions of bone and fixation activity of the drug in the pathological foci. The level of accumulation of the drug in metastatic lesions compared with symmetrical areas of healthy bones - coefficient differential accumulation (DVS) is usually 2.0 to 3.0, reaching in some cases the value 5.0. The most active accumulation was observed in patients with cancer of the prostate, breast, lung. In patients with rheumatoid arthritis due to multiple character articular lesions was difficult to accurately determine the percentage accumulation of sick/healthy joint. In cases where this was possible, the ratio reached the older patients more than 6 months after a single injection).

If there is evidence the drug can be executed again after 3 months. Radionuclide therapy proposed by the drug can be combined with chemo - and hormone therapy, other therapies, monitoring the General condition of the patient and the peripheral blood.

The technical essence of the invention consists in the following. Oxa-bis(ethylenedithio)tetramethylphosphonium forms a strong complex with samarium-153, compared with EDTMP by implementing additional corrdination ties with the bridge oxygen atom in the molecule of oxabiphor. However, the specified connection forms a less strong in comparison with EDTMP complexes with calcium.

Therefore, the drug-based complex153Sm-oxabiphor has a higher chemical and radiation stability at relatively lower ability to bind calcium to the blood.

The proposed use of the composition in combination with the method drip of the drug eliminates the possibility of negative effects of the introduction of the drug to patients with a positive clinical effect of the treatment.

Igumenova on samarium-152 to 99%, placed in the container, sealed and irradiated with thermal neutrons in a nuclear reactor in the flow (5-6)1013neutrons/cm2with a duration of 80-72 h, respectively. The specific activity of samarium-153 at the end of the irradiation is 22-37 GBq/mg

Irradiated samarium chloride dissolved in 0.1 M HCl. To the resulting solution was added a reagent containing 6455 mg oxabiphor-acid, 9 ml of distilled water, 650,1 ml of 1 M NaOH solution and 601 mg NaCl. Stir the mixture for 5 min by bubbling air, poured the finished drug153Sm-oxabiphor in a container for packaging and packaged in bottles for medicines portions at 925, 1850, 2775, 3700 MBq. Vials of the drug is sealed by rolling and sterilized in an autoclave at a temperature of 119 - 121oC (1,0 - 1,1) MPa for 8 min, the Concentration of ligand in the preparation of 0.05 mol/l, the molar ratio of Sm:L 310-2.

Example 2.

To obtain comparative data on the biological distribution were cooked preparations based on oxabiphor, EDTMP control and NTF (nitrilotriacetate acid) according to the method described in example 1. The drugs were injected intravenously to rats - females weighing 160-180 g into the tail vein in an amount of 0.2 ml.

by composition; 3 - NTF.

From the data table. 1 shows that the use of compositions based on NTF (also described in [1 and 2]) practically unacceptable because of the high accumulation of the drug in the liver. The distribution of complexes153Sm-EDTMP and153Sm-oxabiphor almost the same; the ratio of bone/blood and bone/liver slightly higher for oxabiphor.

Example 3.

Radiochemical purity of the preparation prepared according to the procedure described in example 1, was controlled by chromatography paper Whatman No. 1 using as solvent a mixture of ethanol-pyridine-water (1:2: 4). In this system the value of Rfcomplex153Sm-oxabiphor 0.75.

As follows from the data presented in table. 2, the content of the complex in the preparation of at least 95% within 4 days (the expiry date, established by the draft Interim monograph in preparation), which is a Testament to the radiation stability of the composition.

Example 4.

The drug in the amount of 37 MBq/kg (1 MCI/kg) weights were introduced drip method patient K. (41, breast cancer). There is a high accumulation of153Sm in metastatic foci (DVS over 2). The product provided is but the re-introduction of the drug in the amount of 55.5 MBq/kg (1.5 MCI/kg) in weight; one month after the second treatment, there was a further decrease in pain.

Example 5.

Patient M. (63, thyroid cancer, prostate cancer) received the drug in the amount of 45 MBq/kg (1.2 MCI/kg) of weight. The pain stopped completely, the improvement of the functions of the musculoskeletal system. Clinical effect within 6 months.

Example 6.

Patient I. (34, rheumatoid arthritis, arthritis, aseptic necrosis of the femoral head on the right). After drip injection of 18.5 MBq/kg (0.5 MCI/kg) weight marked accumulation of activity in the affected joints with DVS to 5.6. The clinical effect was observed after 10 days and was maintained for 5 months.

Thus, the technical effect of the invention is the simplicity of preparation, in enhancing therapeutic effect in the elimination of toxic reactions when introduced into the patient's body.


1. The US patent N 4898724, IPC A 61 K 43/00 U. S. CI. 424/1.1, 1987, publ. 1990.

2. The US patent N 5762907, IPC A 61 K 51/04 U. S. CI. 424/1.77, 1993, publ. 1998.

Radiopharmaceutical composition, characterized in that it contains samarium-153, samarium in the form of a complex with oxa-bio for injection in the following ratio of ingredients, mg/ml:

Samarium in the form of a complex with oxa-bis(ethylenedithio)-tetramethylphosphonium acid or its sodium salt - 0,025 - 0,100

Sodium chloride - 4 - 6

Water for injection To 1

this volume activity of samarium - 153 is 240 - 740 MBq/ml, and the pH of the composition is 5 to 7.


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