RU2209625C1 - Radiopharmaceutical composition for diagnosis of digestive tract disease - Google Patents

Abstract

FIELD: medicine, gastroenterology. SUBSTANCE: invention relates to radiopharmaceutical composition used for diagnosis of digestive tract diseases. Radiopharmaceutical preparation comprises an aqueous solution of urea labeled with radionuclide carbon-14 and anhydrous sodium pyrophosphate placed into solid gelatin capsule and using as diagnostic agent in ulcer disease of digestive tract. Invention provides the enhanced precision of distribution of radioactive urea solution and cold carrier and rapid delivery of the preparation-containing capsule into stomach mucosa layer. EFFECT: enhanced and valuable properties of composition. 4 cl

Description

 The invention relates to medicine, namely to radiopharmaceuticals, and can be used as a diagnostic tool for diseases of the gastrointestinal tract by analysis of exhaled air. The drug is intended for oral administration.

The essence of this diagnostic tool as a breath test is as follows. A capsule containing urea labeled with a carbon-14 radionuclide is swallowed by the patient. Helicobacter pylori (Hp) is present in the patient’s stomach in the presence of peptic ulcer, in the presence of which the urea is broken down into carbon dioxide, CO ₂ and ammonia, NH ₃ , which are absorbed into the blood and appear in the exhaled breath of the patient.

After 10 minutes after ingestion of the capsules, a portion of exhaled air is collected in a balloon, passed through a special liquid to absorb labeled CO ₂ . The solution with absorbed CO _{2 is} examined on a liquid scintillation counter.

By the quantitative indicators of the test, the presence of Hp in the patient’s stomach is determined for various diseases of the stomach and duodenum. Exceeding the level of ¹⁴ C over the control value indicates the presence of a pathological process.

Urea labeled with a ¹⁴ C radionuclide, which did not decompose under the influence of (Hp), enters the urine with a half-life of 12 hours. About 10% of the ¹⁴ C radionuclide remains in the human body and gradually decreases with a biological half-life of about 40 hours.

The radionuclide ¹⁴ C is a beta emitter with a half-life of T _1/2 = 5730 years with a beta particle energy of E _max - 157 keV, E _cf = 49 keV.

 As a prototype, the composition of the radiopharmaceutical (RP) was used, containing urea labeled with a carbon-14 radionuclide dispersed on the surface of an inert carrier (sugar) enclosed in a gelatin capsule described in [1].

 [1] Application WO 98/53808. Date of publication 03.12.1998 (priority 05.28.97).

The composition of the radiopharmaceutical described in [1] is as follows:
Carbon-14 - 1 μCi, 37 kBq
Sugar - 200 mg
Gelatin Capsule - Size 3
The essence of the method of obtaining this composition of the radiopharmaceutical is as follows: powdered or granular sugar is placed in one of the known rotating devices, for example, a rotating drum, this drum is launched and one of the known methods disperses an alcohol solution of urea labeled with carbon radionuclide onto the surface of an inert carrier (sugar) -14 in a predetermined ratio: the volume of the active solution of urea, the weight of sugar. As the drum rotates, the alcohol evaporates, and the urea labeled with the carbon-14 radionuclide disperses on the surface of the inert carrier, sugar. Then, urea dispersed on an inert carrier (sugar) is loaded using one of the known methods into a No. 3 hard gelatin capsule, which contains 200 mg of sugar with an activity of 1 μCi (37 kBq).

The disadvantages of the composition of the prototype are:
1. Based on the activity of the urea solution (alcohol solution), a large uneven distribution of the active urea solution on the surface of an inert carrier (sugar) during rotation of the drum.

 2. A significant deviation of the values of the activity of carbon-14 in each capsule from the nominal value (± 20%).

 3. The complexity of the technology for obtaining this composition of the radiopharmaceutical, requiring the capture and return to the working cycle of evaporated ethanol; risk of entrainment of radioactive urea with ethanol.

 4. Use of the number 3 capsule, which is not very convenient for the patient to swallow.

The objectives of the claimed invention are:
1. Simplification of the technology for obtaining the composition of the radiopharmaceutical using an inert carrier.

 2. Reducing the deviation of carbon-14 activity values in each capsule from the nominal value.

 3. Greater accuracy in the distribution of the active solution of urea and an inert carrier.

 4. The use of a heavier inert carrier, providing fast delivery of the capsule with the drug into the layer of gastric mucose.

 5. Use of a smaller capsule number 4 for ease of swallowing by the patient.

 The objectives of the claimed invention are achieved in that as an inert carrier of the radiopharmaceutical containing urea labeled with carbon-14 radionuclide in a hard gelatin capsule, anhydrous sodium phosphate pyro (196-204 mg) is used, the amount of phosphorus in the form of anhydrous sodium phosphate pyro is 42-52 mg , an aqueous urea solution was used in which the concentration of a urea solution with carbon-14 dispersed on the surface of a solid inert carrier was from 0.0334 to 0.2 μCi / μl, an inert carrier with a dispersed solution -urea contained within a gelatin capsule, size 4, the total activity of one capsule 1 Ci (37 kBq). From 5 to 30 μl of an aqueous urea solution labeled with a carbon-14 radionuclide is dispersed onto an anhydrous inert Carrier.

 The method of obtaining the composition of the radiopharmaceutical containing labeled urea with a carbon-14 radionuclide is as follows.

 In a nest cell of one of the devices, one of the known methods loads a predetermined number of hard gelatin capsules of size 4. The capsules are oriented with their caps up. One of the known methods removes caps closed from the transport “lock” from capsule bodies, opening access to the capsule body using one of the known devices, using one of the known methods, a predetermined amount of anhydrous sodium phosphate is loaded into the body of each capsule located in the nest cell pyro. One of the known methods is used to disperse an aqueous urea solution of a predetermined concentration labeled with carbon-14 radionuclide on the surface of anhydrous sodium pyrophosphate pyro. Anhydrous sodium pyrophosphate is used to absorb water when dispersed in a gelatin capsule of an aqueous solution of urea with carbon-14, thereby preventing the destruction of the gelatin capsule. One of the known methods is closing the capsules of gelatin capsules with caps and locking them with a “lock”. Ready RFP is packaged in bottles for medicines or blister packs.

 The limit values of component concentrations established on the basis of experimental data obtained by analyzing a number of samples of the drug are presented below.

Examples of the proposed method
Example 1
In one of the known devices containing 10 nests for capsules, one of the known methods is loaded 10 empty gelatin capsules of size 4 and removed from the capsule body caps, closed on a transport "lock". 200 mg ± 2% of an inert carrier of anhydrous sodium pyrophosphate pyro is weighed on an electronic balance and, using one of the known methods, is loaded into each hard gelatin capsule. One of the known methods, using an automatic pipette, dispenses (disperses) 5 μl of an aqueous solution of urea with carbon-14 with a concentration of 0.2 μCi / μl onto the surface of an inert carrier of each capsule. One of the known methods is closing capsule bodies with caps and locking with a “lock”. Using a scintillation counter, the activity of the capsules is determined, which should be at least 1 μCi (37 kBq).

 The deviation of the values of carbon-14 activity in the control capsule from the nominal value does not exceed ± 15%. Capsules with radiopharmaceuticals are sent for packaging in blisters.

Patient K., at the age of 80, took one capsule of the radiopharmaceutical "Ureacaps, ¹⁴ C" with an activity of 1 μCi. A breath test on a scintillation counter showed 1428 dec. / min, which indicates the presence of a patient K-va disease of the gastrointestinal tract. Peptic ulcer 12 p. Colon confirmed by gastroscopy.

Example 2
In one of the known devices containing 20 nests for capsules, one of the known methods is loaded 20 empty gelatin capsules of size 4 and removed from the capsule body caps, closed on a transport "lock". 200 mg ± 2% of an inert carrier of anhydrous sodium pyrophosphate pyro is weighed on an electronic balance and, using one of the known methods, is loaded into each hard gelatin capsule. One of the known methods using an automatic pipette, dose (disperse) on the surface of the inert carrier of each capsule 10 μl of an aqueous solution of urea with carbon-14 with a concentration of 0.1 μCi / μl. One of the known methods is closing capsule bodies with caps and locking with a “lock”. Using a scintillation counter, the activity of the capsules is determined, which should be at least 1 μCi (37 kBq).

 The deviation of the values of carbon-14 activity in the control capsule from the nominal value does not exceed ± 15%. Capsules with radiopharmaceuticals are sent for packaging in blisters.

Patient K-ko, aged 47, took 1 capsule of the radiopharmaceutical "Ureacaps, ¹⁴ C" with an activity of 1 μCi. A breath test on a scintillation counter showed 1882 dec. / min, which indicates that the patient has a number of diseases of the gastrointestinal tract. Gastric cancer confirmed by gastroscopy and histologically.

Example 3
In one of the known devices containing 50 slots for capsules, one of the known methods is loaded with 50 empty gelatin capsules of size 4 and the caps locked on the transport lock are removed from the capsule body. 200 mg ± 2% of an inert carrier of anhydrous sodium pyrophosphate pyro is weighed on an electronic balance and, using one of the known methods, is loaded into each hard gelatin capsule. One of the known methods, using an automatic pipette, dispenses (disperses) 20 μl of an aqueous solution of urea with carbon-14 at a concentration of 0.05 μCi / μl onto the surface of an inert carrier of each capsule. One of the known methods is closing capsule bodies with caps and locking with a “lock”. Using a scintillation counter, the activity of the capsules is determined, which should be at least 1 μCi (37 kBq).

The deviation of the values of carbon-14 activity in the control capsule from the nominal value does not exceed ± 15%. Capsules with radiopharmaceuticals are sent for packaging in vials for medicines. Patient M., aged 65, took 1 capsule of the radiopharmaceutical "Ureacaps, ¹⁴ C" with an activity of 1 μCi. A breath test on a scintillation counter showed 714 rpm / min, which indicates the presence of a disease of the gastrointestinal tract in patient M. Peptic ulcer 12 p. Colon confirmed by gastroscopy.

Example 4
In one of the known devices containing 100 nests for capsules, one of the known methods is loaded with 100 empty gelatin capsules of size 4 and the caps locked on the transport lock are removed from the capsule body. 200 mg ± 2% of an inert carrier of anhydrous sodium pyrophosphate pyro is weighed on an electronic balance and loaded into a hard gelatin capsule using one of the known methods. One of the known methods, using an automatic pipette, dispenses (disperses) 30 μl of an aqueous solution of urea with carbon-14 with a concentration of 0.0333 μCi / μl onto the surface of an inert carrier of each capsule. One of the known methods is closing capsule bodies with caps and locking with a “lock”. Using a scintillation counter, the activity of the capsules is determined, which should be at least 1 μCi (37 kBq). The deviation of the values of carbon-14 activity in the control capsule from the nominal value does not exceed ± 15%. Capsules with radiopharmaceuticals are sent for packaging in vials for medicines.

Patient C-co, at the age of 63 years, took 1 capsule of the radiopharmaceutical "Ureacaps, ¹⁴ C" with an activity of 1 μCi. A breath test on a scintillation counter showed 67 pacn. / min, which indicates that he does not have a disease of the gastrointestinal tract.

Example 5
In one of the known devices containing 25 slots for capsules, one of the known methods is loaded 25 empty gelatin capsules of size 4 and removed from the capsule body caps, closed on a transport "lock". 200 mg ± 2% of an inert carrier of anhydrous sodium pyrophosphate pyro is weighed on an electronic balance and, using one of the known methods, is loaded into each hard gelatin capsule. One of the known methods, using an automatic pipette, dispenses (disperses) 50 μl of an aqueous solution of urea with carbon-14 at a concentration of 0.02 μCi / μl onto the surface of an inert carrier of each capsule. It was experimentally established that when dosing an aqueous solution of urea labeled with carbon-14 radionuclide onto a solid inert carrier (pyroxate sodium) at a ratio of ≥ 0.25 μl per 1 mg, the urea aqueous solution does not have time to be absorbed by an inert carrier, the capsule is deformed.

 When dispersing 50 μl of an aqueous solution of urea per 200 mg of inert carrier, the neck of the gelatin capsule is destroyed, the capsule softens, does not lock, the capsule is deformed and defective.

Laboratory (preclinical) tests of the drug were carried out in the Cardiology Research and Production Complex. Eight batches of radiopharmaceuticals with urea labeled with a carbon-14 radionuclide in capsules on an inert carrier (sodium pyrophosphate), Ureacaps, ¹⁴ C, were tested.

Laboratory tests have shown the safety and functional suitability of the RFP "Ureakaps, ¹⁴ C".

The solubility of the capsule at 37 ^o C in distilled water is not more than 20 minutes

 This method of obtaining radiopharmaceuticals according to the proposed composition was tested in a laboratory setup, samples of radiopharmaceuticals for laboratory and clinical trials were developed, laboratory regulations were developed.

Claims (4)

 The composition of the radiopharmaceutical (RFP), for the diagnosis of diseases of the gastrointestinal tract, including urea labeled with radionuclide carbon-14, a solid inert carrier, enclosed in a hard gelatin capsule, characterized in that it contains an aqueous solution of urea labeled with radionuclide carbon-14, as a solid an inert carrier, anhydrous sodium phosphate pyro was used, enclosed in number 4 hard gelatin capsule, the hard inert carrier of each capsule containing 196-204 mg of anhydrous sodium phosphoric acid syllable pyro.  2. The composition according to p. 1, characterized in that it contains an aqueous solution of urea labeled with a carbon radionuclide - 14, with a concentration of 0.0333-0.20 μCi / μl.  3. The composition according to p. 1, characterized in that from 5 to 30 μl of an aqueous solution of urea labeled with a carbon radionuclide is dispersed on a solid inert carrier of each capsule - 14 predetermined concentration.  4. The composition according to p. 1, characterized in that it includes urea labeled with a radionuclide carbon - 14, with an activity of 0.85-1.15 μCi.