WO2018028643A1

WO2018028643A1 - Medical phosphorus-32 carbon microsphere and preparation method therefor

Info

Publication number: WO2018028643A1
Application number: PCT/CN2017/096891
Authority: WO
Inventors: 李茂良; 蔡继鸣; 胡学正; 郭强
Original assignee: 成都纽瑞特医疗科技有限公司
Priority date: 2016-08-11
Filing date: 2017-08-10
Publication date: 2018-02-15
Also published as: CN107715123B; CN107715123A

Abstract

A medical phosphorus-32 carbon microsphere for use in cancer treatment and a preparation method therefor. The medical phosphorus-32 carbon microsphere is prepared as follows: using carbon microspheres to absorb an yttrium tartrate complex generated from a reaction between YCl₃ and a tartaric acid solution, and then treating by using a solution of Na₃ ³²PO₄ to generate Y³²Po₄, next performing precipitation curing and purification, and thus obtaining the microsphere.

Description

Medical phosphorus-32 carbon microsphere and preparation method thereof

Technical field

The invention relates to a tumor radiotherapy medicine and a preparation method thereof, in particular to a medical phosphorus-32 carbon microsphere and a preparation method thereof.

Background technique

Radiation therapy is an important method for cancer treatment. Although various tumors have different sensitivities to radiation therapy, they are sensitive to radiation therapy at therapeutic doses. Current radiotherapy forms include external radiation therapy, inter-tissue implantation, and radiological embolization. Taking liver cancer as an example, since the tolerance of liver tissue to radiation is about 30 Gy, which is much lower than the therapeutic dose of liver cancer (at least 60 Gy), conventional external radiotherapy is not suitable for the treatment of liver cancer because it is easy to cause radiation hepatitis [Cheng Baoxing, Wu Haorong, Wu Jinchang. Experimental study on the treatment of metastatic liver cancer in rats by iodine-125 interstitial implantation. Journal of Suzhou University (Medical Science Edition), 2002, 22: 13-16], when the radiation dose of normal liver tissue is >35Gy Causes obvious hepatotoxicity, symptoms such as ascites, hepatomegaly, and elevated transaminases [Lewandowski RJ, Geschwind, Liapi E, et al. Transcatheter intraarterial therapies: rationale and overview. Radiology, 2011, 259(3): 641-657] Therefore, external irradiation therapy is not limited by the tolerated dose of cancer tissues, and can only achieve the palliative treatment effect of inhibiting tumor growth. Interstitial implant therapy mainly uses ¹²⁵ I sealed seed source [Luo Kaiyuan, Yang Guokai, et al. Peripheral implantation of 125I particles for the treatment of malignant tumors. Chinese Journal of Surgery, 2003, 41 (2): 122-124], Inter-tissue implantation requires multiple points and multiple site punctures, which increases the patient's pain. At the same time, the particles are unevenly distributed in actual operation, and the distribution is too dense or too sparse, which affects the therapeutic effect. Radioactive embolization treatment mainly uses ⁹⁰ Y glass microspheres and ⁹⁰ Y resin microspheres. The ⁹⁰ Y glass microspheres under the trade name Therasphere and the resin microspheres under the trade name Sir-sphere have been approved by the US Food and Drug Administration (FDA). US listing.

Phosphorus-32 ( ³² P) is the most commonly used therapeutic nuclides in nuclear medicine. Phosphorus-32 ( ³² P) glass microspheres have been developed in China for many years, and many studies have been reported in clinical research [Zheng Guangyong, Wang Dazhang. A new kind of Anticancer therapy - radiotherapy glass microspheres through intra-arterial infusion irradiation therapy. Journal of Oral and Maxillofacial Surgery 1991;1 (1): 52-55] [Wang Dazhang, Sun Wenhao, et al. Phosphate-32 glass microsphere regional perfusion resistance Experimental and clinical application of cancer effect. West China Journal of Stomatology 1991;9(1):7-10][Wang Dazhang, Li Maoliang, et al. Evaluation of initial application of arterial infusion of phosphorus-32 glass microspheres for oral cancer. West China Oral Medical Journal 1991; 9 (2): 138-141], has a remarkable effect on tumors such as liver cancer, and has received great attention from the international medical community, but timely production of high specific activity of phosphorus-32 ( ³² P) glass micro The ball is limited and affects the promotion and application.

Summary of the invention

In view of the above insufficiency, the object of the present invention is to provide a simple process, high nuclide adsorption rate, and release rate. Low medical phosphorus-32 carbon microspheres and a preparation method thereof.

In order to achieve the above object, the present invention adopts the following technical solutions:

The invention utilizes carbon microspheres as a carrier, adsorbs a complex formed by a non-radioactive YCl ₃ solution and a tartaric acid solution (Y-tartaric acid), and then reacts with a solution of radioactive sodium phosphate (Na ₃ ³² PO ₄ ) in carbon microspheres. A radioactive phosphonium phosphate (Y ³² PO ₄ ) precipitate is formed in the sphere to solidify the phosphorus-32 ( ³² P) nuclide, and then further purified to prepare medical phosphorus-32 carbon microspheres. The medical phosphorus-32 carbon microsphere prepared by the invention has higher adsorption efficiency to phosphorus-32( ^32P ) nuclide than 99%, and the release rate of phosphorus-32 ( ^32P ) is less than 0.01%, which is suitable for tumor radiotherapy.

The carbon microsphere adsorption of the present invention is physical adsorption, since the phosphorus-32 ( ^32P ) nuclides are in the form of Na ₃ ³² PO ₄ compounds and cannot be directly adsorbed by carbon microspheres, but ³² PO ₄ ^3- ions and non-radioactive Y ³⁺ ions can form insoluble phosphate of yttrium (Y ³² PO ₄₎ precipitation, can be (Y ³² PO ₄₎ precipitation of phosphorous -32 ⁽³² P) curing the carbon microspheres species generated by the yttrium phosphate in the carbon microspheres The desired phosphorus-32 ( ³² P) carbon microspheres were prepared. However, the non-radioactive Y ³⁺ (present in YCl ₃ solution) ions are positive trivalent cations (Y ³⁺ ). When the acidity of the solution is high, the amount of direct physical adsorption by carbon microspheres is small (<30mgY/g microspheres). When the pH of the solution is greater than 1, the Y ³⁺ ion is easily hydrolyzed to form a precipitate, so in order to increase the adsorption of the carbon microspheres to cure the phosphorus-32 ( ³² P) nuclides (by immobilizing the yttrium phosphate (Y ³² PO ₄ )) Appropriate measures must be taken to prevent the hydrolysis of Y ³⁺ ions and to increase the amount of Y ³⁺ ions adsorbed by carbon microspheres. The specific method is to select a complexing agent and Y ³⁺ ions to form a stable complex, which not only prevents Y. ³⁺ ion hydrolysis and more ruthenium-containing complexes are adsorbed by carbon microspheres, and the Y ³⁺ ions complexed and adsorbed in the carbon microspheres can form insoluble yttrium phosphate with ³² PO ₄ ^3- ions ( Y ³² PO ₄ ) precipitates, so that more phosphorus-32 ( ³² P) nuclide precipitates and solidifies in the carbon microspheres, and the phosphorus-32 ( ³² P) nuclide precipitation solidification rate is higher than 99%, and the precipitate solidifies. The release rate of phosphorus-32( ^32P ) nuclide in carbon microspheres is extremely low (<0.1%), achieving the goal of developing phosphorus-32( ^32P ) carbon microspheres that function as tumors. The present inventors have found that the complexing agent tartrate tartrate may generate non-radioactive yttrium complexes with Y ³⁺ ion adsorption and carbon microspheres, non-radioactive Y ³⁺ ions are adsorbed in the carbon microspheres before and Na ₃ ³² PO ₄ Compound A poorly soluble precipitate of yttrium phosphate (Y ³² PO ₄ ) is formed to produce medical phosphorus-32 carbon microspheres that can be used for tumors. The specific preparation method is as follows: A medical phosphorus-32 carbon microsphere is mainly composed of carbon microspheres and a radionuclide phosphorus-32 which is precipitated and solidified in carbon microspheres.

Further, the medical phosphorus-32 carbon microspheres are prepared by the following methods: adsorption with carbon microspheres Y- tartaric acid complexes, and then radioactive Na ₃ ³² PO ₄ solution reacts with Y ³² PO ₄ precipitate was cured It is prepared by further purification treatment.

A method for preparing medical phosphorus-32 carbon microspheres comprises the following steps:

(1) Preparation of carbon microspheres adsorbing Y-tartaric acid complex: the carbon microspheres are thoroughly mixed with the Y-tartaric acid complex solution, shaken at a constant temperature of 40-50 ° C for 40-60 minutes, and removed by solid-liquid separation. After the reaction solution is repeatedly washed with purified water, the un-adsorbed Y-tartaric acid complex is washed away, that is, the carbon microspheres to which the Y-tartaric acid complex is adsorbed are obtained;

(2) Preparation of medical phosphorus-32 carbon microspheres: carbon microspheres having adsorbed Y-tartaric acid complexes were soaked in a radioactive Na ₃ ³² PO ₄ solution containing ³² P greater than 7.4 GBq (200 mCi), and at 40 ° C - The mixture was shaken at a constant temperature of 50 ° C for 20-30 minutes to form Y ³² PO ₄ precipitated solidified phosphorus-32, and the reaction liquid was removed by solid-liquid separation, and then repeatedly washed with purified water to obtain medical phosphorus-32 carbon microspheres.

The preparation method of the radioactive Na ₃ ³² PO ₄ solution is:

Sealing the magnesium hydrogen phosphate or aluminum phosphate in a quartz glass tube and irradiating it with a nuclear reactor with a thermal neutron flux higher than 5×10 ¹³ n/cm ² .s, generating radioactivity through ³¹ P(n,r) ³² P MgH ³² PO ₄ or radioactive Al ³² PO ₄ , ³² P has a nuclear purity of not less than 99.9%, a specific activity greater than 148G Bq(4Ci)/gP, dissolved with hydrochloric acid, and precipitated Mg ²⁺ ions and Al with NaOH solution. ³⁺ ion, conversion of MgH ³² PO ₄ or Al ³² PO ₄ to radioactive Na ₃ ³² PO ₄ , the radiochemical purity of Na ₃ ³² PO ₄ solution is not less than 95%, and the activity per ml of Na ₃ ³² PO ₄ solution The concentration is not less than 14.8 GBq (400 mCi) / mL, and is diluted to the required concentration according to the use requirements.

The method for preparing tartaric acid Y- complex is: YCl ₃ solution and the solution of tartaric acid of 1: 2-2.5 molar ratio of tartaric acid to generate complex Y-, pH 1.0 to 2.0 which solution.

The YCl ₃ solution is prepared by dissolving Y ₂ O ₃ with a HCl solution, wherein the Y ^{3 +} ion concentration of the YCl ₃ solution is 40 mg/mL-60 mg/mL, and the pH of the solution is <1.0 (preventing Y ³⁺ Ionic hydrolysis precipitation).

The tartaric acid solution is prepared by dissolving tartaric acid in purified water at a concentration of 0.1 g/mL.

Further, the method for preparing the medical phosphorus-32 carbon microsphere further comprises the purification treatment of the carbon microspheres, specifically: soaking the carbon microspheres with ethyl acetate, acetone or ethanol to remove the fat, and soaking with the sodium hydroxide solution. The alkali-soluble impurities are repeatedly washed with purified water to a weakly alkaline state, and then the acid-soluble impurities are soaked with nitric acid, and washed with purified water until the pH is 1-2.

The carbon microsphere refers to a microsphere prepared by carbon-rich organic material, which is carbonized at a high temperature, and then degreased, alkali washed, acid washed, etc. to remove various impurities, thereby preparing a spherical body which is non-toxic and biocompatible to the human body. particle.

The carbon microspheres have a diameter of 20-30 μm.

The carbon microspheres have a diameter of 30 to 100 μm.

The carbon microspheres have a diameter of more than 100 μm and can be used for in vivo implantation to treat tumors.

The carbon microspheres have a diameter of 10 to 100 nm.

The carbon microspheres have a diameter of 100 to 150 nm.

The adsorption rate of the carbon microspheres to the ³² P nuclide in the medical phosphorus-32 carbon microspheres is higher than 99%.

The release rate of ³² P nuclides in the medical phosphorus-32 carbon microspheres is less than 0.01%.

A preparation for use in in vivo tumor radiation therapy prepared from medical phosphorus-32 carbon microspheres.

The activity of phosphorus-32 in the preparation for tumor treatment is 1.85 GBq-3.70 GBq (50 mCi-300 mCi), The size of carbon microspheres depends on the application: medical phosphorus-32 carbon microspheres with a particle size of 20μm-30μm are mainly used for arterial perfusion embolization for liver cancer, and the diameter of 30μm-100μm can be used for lung cancer, kidney cancer and tongue cancer. VEGF-rich tumors such as breast cancer and cervical cancer can also be used for direct dispersion injection into other tumors; radioactive implantation therapy for tumors with a particle size of 100 μm or more; medical phosphorus-32 with a particle diameter of 100 nm to 150 nm Carbon microspheres are mainly used for the treatment of lymphoma. Medical phosphorus-32 carbon microspheres with a particle size of 10 nm-100 nm have tumor-like properties and can be used for tumor diagnosis and targeted therapy.

Use of the medical phosphorus-32 carbon microspheres for the treatment of a medicament for a mammal having a medical condition, wherein the medical phosphorus-32 carbon microsphere is administered with an interventional catheter, a syringe or an in vivo implant .

The beneficial effects of the invention are:

1. The method is simple, the introduction of impurities is small, and the product purity is high.

2. Phosphorus-32 has high utilization rate and produces less radioactive waste, which is conducive to environmental protection.

3. Phosphorus-32 release rate is low and safety is good.

4. The radioactivity of medical phosphorus-32 carbon microspheres can be adjusted according to individual needs, and can meet the individualized precise treatment requirements at any time.

5. Phosphorus-32 is easily obtained from multiple sources. The normal production of medical phosphorus-32 carbon microspheres is not affected by the supply of raw materials, and can meet the annual production and supply requirements.

6. The medical phosphorus-32 carbon microspheres have low production cost and good curative effect, and are convenient for popularization and application.

detailed description

Example

(1) Purification of carbon microspheres: soaking the fat with an organic solvent such as ethyl acetate, acetone or ethanol; soaking the alkali-soluble impurities with a dilute sodium hydroxide solution (0.1-0.5 mol/L), and then repeatedly washing to a weak base (pH 8-10); then dilute the acid-soluble impurities with dilute nitric acid (0.1mol/L-0.5mol/L) and wash to a pH of 1-2.

(2) Preparation of sodium phosphate (Na ₃ ³² PO ₄ ) solution: sealing commercially available pure grade 30 g of magnesium hydrogen phosphate (MgHPO ₄ ) or aluminum phosphate (AlPO ₄ ) in a quartz glass tube to have a high thermal neutron flux Irradiation of 5×10 ¹³ n/cm ² .s nuclear reactor, generation of radioactive magnesium hydrogen phosphate (MgH ³² PO ₄ ) or radioactive aluminum phosphate (Al ³² PO ₄ ) via ³¹ P(n,r) ³² P, The nuclear purity of ³² P is not less than 99.9%, and the specific activity is greater than 148G Bq(4Ci)/gP, using hydrochloric acid [where the hydrochloric acid is treated with 36-38% HCl solution and water by 1:1 (mL/mL) Diluted into a solution, and precipitated Mg ²⁺ ions and Al ³⁺ ions with NaOH solution, and converted into Mg ³ ³² PO ₄ or Al ³² PO ₄ to prepare radioactive Na ₃ ³² PO ₄ , radiochemistry of Na ₃ ³² PO ₄ solution. The purity is not less than 95%. The concentration of the activity of the Na ₃ ³² PO ₄ solution per ml is not less than 14.8 GBq (400 mCi) / mL, and is diluted to the desired concentration according to the use requirements.

(3) Preparation of YCl ₃ solution: The commercially available excellent grade pure Y ₂ O ₃ is dissolved in HCl solution to prepare YCl ₃ solution, and the Y ³⁺ ion concentration of the YCl ₃ solution is 40 mg/mL-60 mg/mL, the pH of the solution A value below 1.0 prevents the Y ³⁺ ion from hydrolyzing the precipitate.

(4) Preparation of tartaric acid solution: The analytical pure tartaric acid was dissolved in purified water to prepare a tartaric acid solution having a concentration of 0.1 g/mL for preparing a Y-tartaric acid complex.

(5) Preparation of tartaric acid complex: the YCl ₃ solution prepared in the step (3) and the tartaric acid solution prepared in the step (4) are mixed at a molar ratio of 1:2-2.5 to form a Y-tartaric acid complex, and the pH of the solution The value is 1.0-2.0.

(6) Preparation of carbon microspheres for adsorbing Y-tartaric acid complex: Mix 1-3g carbon microspheres with 5-10mLY-tartaric acid complex solution (Y content greater than 150mg), at a constant temperature of 40-50 °C After shaking for 40-60 minutes, the reaction solution is removed by solid-liquid separation (centrifugation or filtration), and then repeatedly washed with purified water to wash away the unadsorbed Y-tartaric acid complex, that is, the Y-tartaric acid complex is adsorbed. Carbon microspheres, carbon microspheres adsorbed yttrium (Y) content greater than 100mg, can be used to prepare medical phosphorus-32 carbon microspheres.

(7) Preparation of medical phosphorus-32 carbon microspheres: soaking 5-10 mL of Na ₃ ³² PO ₄ solution containing ³² P greater than 7.4 GBq (200 mCi) (containing 50-60 mg of total phosphorus) prepared according to step (2) The 1-3 g carbon microspheres which have been adsorbed by the Y-tartaric acid complex are prepared and shaken at a constant temperature of 40 ° C to 50 ° C for 20-30 minutes to form a Y ³² PO ₄ precipitated solidified phosphorus-32 ( ³² P). After the reaction solution was removed by solid-liquid separation (centrifugation or filtration), it was repeatedly washed with purified water to obtain medical phosphorus-32 carbon microspheres.

The adsorption rate of phosphorus-32 ( ^32P ) by the medical phosphorus-32 carbon microsphere prepared in this example is higher than 99%, and the release rate of phosphorus-32 ( ^32P ) is less than 0.01%, and the biocompatibility is good. Can be used for tumor radiation therapy.

Claims

A medical phosphorus-32 carbon microsphere, characterized in that the medical phosphorus-32 carbon microsphere is mainly composed of carbon microspheres and a radionuclide phosphorus-32 precipitated and solidified in carbon microspheres.
The medical phosphorus-32 carbon microsphere according to claim 1, wherein the medical phosphorus-32 carbon microsphere is obtained by the following method: adsorbing Y-tartaric acid complex by carbon microspheres, and then radioactive The Na 3 32 PO 4 solution is reacted to form a Y 32 PO 4 precipitate and solidified, and then further purified by a treatment.
A method for preparing medical phosphorus-32 carbon microspheres, characterized in that the preparation method comprises the following steps:

(1) Preparation of carbon microspheres adsorbing Y-tartaric acid complex: the carbon microspheres are thoroughly mixed with the Y-tartaric acid complex solution, shaken at a constant temperature of 40-50 ° C for 40-60 minutes, and removed by solid-liquid separation. After the reaction solution is repeatedly washed with purified water, the un-adsorbed Y-tartaric acid complex is washed away, that is, the carbon microspheres to which the Y-tartaric acid complex is adsorbed are obtained;

(2) Preparation of medical phosphorus-32 carbon microspheres: carbon microspheres having adsorbed Y-tartaric acid complexes were soaked in a radioactive Na 3 32 PO 4 solution containing 32 P greater than 7.4 GBq (200 mCi), and at 40 ° C - The mixture was shaken at a constant temperature of 50 ° C for 20-30 minutes to form Y 32 PO 4 precipitated solidified phosphorus-32, and the reaction liquid was removed by solid-liquid separation, and then repeatedly washed with purified water to obtain medical phosphorus-32 carbon microspheres.
The medical phosphorus-32 or 2 carbon microspheres according to claim 3, characterized in that: the method of preparing a radioactive Na 3 32 PO 4 solution was:

Sealing the magnesium hydrogen phosphate or aluminum phosphate in a quartz glass tube and irradiating it with a nuclear reactor with a thermal neutron flux higher than 5×10 13 n/cm 2 .s, generating radioactivity through 31 P(n,r) 32 P MgH 32 PO 4 or radioactive Al 32 PO 4 , 32 P has a nuclear purity of not less than 99.9%, a specific activity greater than 148G Bq(4Ci)/gP, dissolved with hydrochloric acid, and precipitated Mg 2+ ions and Al with NaOH solution. 3+ ion, conversion of MgH 32 PO 4 or Al 32 PO 4 to radioactive Na 3 32 PO 4 , the radiochemical purity of Na 3 32 PO 4 solution is not less than 95%, and the activity per ml of Na 3 32 PO 4 solution The concentration is not less than 14.8 GBq (400 mCi) / mL, and is diluted to the required concentration according to the use requirements.
The medical phosphorus-32 carbon microsphere according to claim 2 or 3, wherein the Y-tartaric acid complex is prepared by adding a solution of YCl 3 and tartaric acid to 1 (YCl 3 ): 2 The molar ratio of 2.5 (tartaric acid) is mixed to form a Y-tartaric acid complex, and the pH of the solution is 1.0-2.0.
The medical phosphorus-32 carbon microsphere according to claim 5, wherein the YCl 3 solution is obtained by dissolving Y 2 O 3 in a HCl solution, wherein the Y 3 + ion concentration of the YCl 3 solution is 40mg/mL-60mg/mL, the pH value of the solution is <1.0.
The medical phosphorus-32 carbon microsphere according to claim 5, wherein the tartaric acid solution is prepared by dissolving tartaric acid and purified water at a concentration of 0.1 g/mL.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the medical phosphorus-32 carbon microsphere The preparation method of the ball further comprises the purification treatment of the carbon microspheres, specifically: soaking the carbon microspheres with ethyl acetate, acetone or ethanol to remove the fat, soaking the alkali-soluble impurities with the sodium hydroxide solution, and repeatedly washing with the purified water to weak Alkaline, then soak the acid-soluble impurities with nitric acid, and rinse with purified water until the pH is 1-2.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microsphere refers to a carbon ball prepared by carbon-rich organic material, which is carbonized at a high temperature, and then degreased and alkali. Washing, pickling, etc. to remove various impurities, to prepare spherical particles that are non-toxic and biocompatible to the human body.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microspheres have a diameter of 20 to 30 μm.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microspheres have a diameter of 30 to 100 μm.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microspheres have a diameter of more than 100 μm.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microspheres have a diameter of 10 to 100 nm.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microspheres have a diameter of 100 to 150 nm.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, wherein the carbon microspheres in the medical phosphorus-32 carbon microspheres have an adsorption rate of 32 P nuclide higher than 99%.
The medical phosphorus-32 carbon microsphere according to any one of claims 1 to 7, characterized in that the release rate of 32 P nuclide in the medical phosphorus-32 carbon microsphere is less than 0.01%.
A preparation for use in in vivo tumor radiation therapy prepared from the medical phosphorus-32 carbon microspheres of any of claims 1-7.
The preparation for use in in vivo tumor radiation therapy according to claim 17, wherein the activity of phosphorus-32 in the preparation for in vivo tumor radiotherapy is 1.85 GBq - 3.70 GBq (50 mCi - 300 mCi), carbon The particle size of the microspheres depends on the application.
Use of the medical phospho-32 carbon microspheres of any of claims 1-7 for the treatment of a medicament for a mammal having a medical condition.
The use of claim 19, wherein said medical phosphorus-32 carbon microspheres are administered using an interventional catheter, a syringe or an in vivo implant.