CN111840586A - Biodegradable radioactive particles, particle composition and preparation method - Google Patents
Biodegradable radioactive particles, particle composition and preparation method Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
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- A—HUMAN NECESSITIES
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0404—X-ray contrast preparations containing barium sulfate
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
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- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0476—Particles, beads, capsules, spheres
- A61K49/048—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1213—Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1262—Capsules
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
Abstract
The invention provides a biodegradable radioactive particle, a particle composition and a preparation method thereof, wherein the radioactive particle comprises a radioactive inner core and an outer shell; the radioactive inner core comprises a radionuclide and alginate hydrogel; the shell is polycaprolactone. The invention has the advantages of complete degradation in vivo, convenient clinical use, high preparation efficiency, continuous and large-scale full-automatic production, totally closed preparation process, capability of simultaneously realizing radioactive ray treatment and drug local treatment, capability of preparing radioactive particles meeting the clinical requirements of complex focus conditions and the like.
Description
Technical Field
The invention belongs to the technical field of short-distance radioactive therapeutic instruments, and particularly relates to biodegradable radioactive particles, a particle composition and a preparation method.
Background
Radiotherapy is always a common treatment means for malignant tumors, and the close treatment of tumors by using radioactive particles in tissue is a new technology developed in recent decades. Radioactive particles are small radioactive sources which contain radioisotopes in titanium or other biocompatible metal tubes, welded at both ends by laser or electron beam techniques to form a sealed source, typically of 0.8mm external diameter and 4.5mm length. Nuclides commonly used for radioactive particles are192Ir、198Au、169Y、131Cs、103Pd and125i, etc., especially103Pd and1and 25I. The radioactive particles are directly implanted into the focus for close range continuous irradiation to destroy the DNA double bond of the tumor cell nucleus, kill or sublethal tumor cells and lose the replication capacity, so that the treatment purpose is achieved.
However, since the currently clinically used radioactive seeds for brachytherapy are all non-biodegradable products, especially for permanently implanted radioactive seeds, the radioactive seeds will be permanently retained in the human tissue after the treatment process is completed, and although most of the remaining radioactive seeds will be solidified in the lesion tissue calcified after the treatment, a few radioactive seeds may migrate, thereby bringing health risks to other tissues of the human body. In addition, the metal shell staying in the tissue for a long time also has the risk of leakage and local tissue stimulation, and the metal shell can shield a certain proportion of radioactive ray intensity, so that the shielding coefficient of the shell must be considered when the dose of the radioactive particles is designed, and the cost of the radioactive particles is increased.
For the existing preparation method of the radioactive particles with the metal shell, the main process is to weld and seal the material absorbed with the radioactive nuclide in the metal shell, and the defects of high welding technical requirement, high automation realization difficulty, low production efficiency, easy radioactive pollution to the operation of the radioactive material and the like exist.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a biodegradable radioactive particle, a particle composition and a preparation method thereof, which have the advantages of complete degradation in vivo, convenient clinical use, simultaneous realization of radioactive ray treatment and drug local treatment and the like, and the invention also aims to provide a biodegradable radioactive particle, a particle composition and a preparation method thereof, which have the advantages of high preparation efficiency, continuous and large-scale full-automatic production, totally-enclosed preparation process, capability of preparing radioactive particles meeting the clinical requirements of complex focus conditions and the like.
In order to achieve the above purposes, the invention adopts a technical scheme that: a biodegradable radioactive particle comprising a radioactive inner core and an outer shell; the radioactive inner core comprises a radionuclide and alginate hydrogel; the shell is polycaprolactone.
Further, the radioactive inner core also comprises a radioactive marker and/or a pigment.
Further, the housing further comprises a therapeutic agent.
Further, the outer shell also comprises auxiliary filler, the auxiliary filler comprises the inorganic filler, polymer filler and plasticizer, the inorganic filler comprises calcium carbonate, calcium sulfate, hydroxyapatite, carbon black, silicon nitride and aluminum hydroxide, the polymer filler comprises polylactic acid, polyglycolic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, starch and cellulose, and the plasticizer is tributyl citrate, acetyl tributyl citrate, glycerol triacetate, castor oil and coconut oil.
Further, the radionuclide comprises192Ir、198Au、169Y、131Cs、103Pd or125I。
Further, when the radionuclide is a water-soluble component, the radionuclide is dissolved in the alginate hydrogel; when the radionuclide is a water-insoluble liquid or solid powder, the radionuclide is dispersed in the alginate hydrogel.
Further, the alginate hydrogel is a thermally irreversible hydrophilic gel formed by crosslinking water-soluble alginate and polyvalent metal ions;
the alginate comprises sodium alginate, potassium alginate or ammonium alginate;
the polyvalent metal ions include calcium ions, aluminum ions, iron ions, ferrous ions, copper ions, barium ions or zinc ions.
Further, the radiation marker comprises barium sulfate, sodium iodide, diatrizoate, iodotaltamide, iodixanoic acid, iohexol, iopromide, iopyram, iodotrexone, or iodophenyl ester.
Further, the pigment includes amaranth, brilliant blue, erythrosine, acid red, allura red, indigo, carmine, sunset yellow, lemon yellow, sodium copper chlorophyllin, caramel or beta-carotene.
Further, the therapeutic drug includes an anti-tumor drug, an anti-rejection drug or an anti-inflammatory drug.
Furthermore, the radioactive particles comprise 0.1-10 parts of radionuclide, 90-100 parts of alginate hydrogel, 0.1-10 parts of ray marker, 0.1-10 parts of pigment, 70-100 parts of polycaprolactone and 0.1-30 parts of therapeutic drug.
Furthermore, the diameter of the radioactive inner core is 0.5mm, the length of each radioactive inner core is 2-5mm, the diameter of the outer shell is 0.8mm, and the length of the radioactive particles is 4-6 mm.
In order to achieve the above objects, one technical solution adopted by the present invention is to provide a particle composition having a certain shape formed by connecting at least two radioactive cores through an outer shell wrapped around the plurality of radioactive cores.
Further, the shape of the particle composition comprises: straight, curved, circular, spiral, or cruciform and web shapes formed by the concatenation of multiple straight tubular radioactive particle compositions.
Furthermore, the distance between the radioactive inner cores is 8-30mm, and the activity of each radioactive inner core is 0.1-10 mCi.
In order to achieve the above purposes, the invention adopts a technical scheme that: a method of making biodegradable radioactive particles and particle compositions, the method comprising:
(1) preparing a shell raw material and a radioactive inner core raw material;
(2) preparing the raw material of the shell into a tube, and injecting a radioactive inner core in a fluid state into the tube when the tube is cooled slightly to form a continuous tubular material with a polycaprolactone shell as an outer layer and the radioactive inner core as an inner layer;
(3) when the continuous tubular material is not completely cooled and shaped, pressing the continuous tubular material at a preset distance by using preset pressure and preset pressing length to obtain a continuous linear tubular radioactive particle composition;
(4) cutting and/or reshaping the continuous linear tubular radioactive particle composition into a desired quantity and shape as desired.
Further, the step (1) specifically comprises: uniformly mixing polycaprolactone serving as a main raw material of the shell in a molten state, wherein the melting temperature range is more than or equal to 80 ℃; alginate hydrogel in fluid state and radionuclide are uniformly mixed at 60-100 ℃ to form the radioactive inner core raw material.
Further, the melting temperature range in the step (1) is 100-120 ℃.
Further, the step (2) specifically comprises: the raw material of the shell is extruded to form a pipe through a plastic extrusion molding process, a radioactive inner core injection outlet is additionally arranged in the center of an outlet of a pipe extruder head, and the radioactive inner core in a fluid state is injected into the pipe when the pipe is cooled slightly.
Further, the step (4) of reshaping means that the linear tubular radioactive particle composition is softened at 60 ℃ and then placed in a certain mold to be cooled, and the linear tubular radioactive particle composition is reshaped into a curve shape, a circle shape, a circular arc shape, a spiral shape, and a cross shape and a net shape formed by splicing a plurality of linear tubular radioactive particle compositions.
The preparation method of the biodegradable radioactive particles has the advantages of high preparation efficiency, capability of realizing continuous large-scale full-automatic production, totally-enclosed preparation process, capability of preparing the radioactive particles meeting the clinical requirements of complex focus conditions and the like.
Drawings
FIG. 1 is a schematic view of a biodegradable radioactive particle according to the present invention;
FIG. 2 is a schematic structural view of a biodegradable radioactive particle composition according to the present invention;
FIG. 3 is a schematic view of the preparation process of a biodegradable radioactive particle and a particle composition thereof according to the present invention;
FIG. 4 is a schematic view of the tubing extruder head outlet of the present invention including a radioactive core injection outlet.
In the figure: 1-a radioactive inner core; 2-a housing; 21-a radioactive inner core; 22-a housing; 41-pipe extrusion channel; 42-radioactive core injection channel.
Detailed Description
In order to make the technical problems solved, the technical solutions adopted, and the technical effects achieved by the present invention clearer, the technical solutions of the embodiments of the present invention will be further described in detail with reference to the accompanying drawings. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Referring to fig. 1, the present invention provides a biodegradable radioactive particle, including a radioactive inner core 1 and an outer shell 2; the radioactive inner core 1 comprises radionuclide and alginate hydrogel, and the radioactive inner core 1 can also comprise a radioactive marker and/or pigment; the shell 2 is polycaprolactone, and the shell 2 can also comprise a therapeutic drug.
The therapeutic drug comprises an anti-tumor drug, an anti-rejection drug or an anti-inflammatory drug.
The radionuclide comprises192Ir、198Au、169Y、131Cs、103Pd or125I, preferably103Pd and125I。
when the radionuclide is a water-soluble component, the radionuclide is dissolved in the alginate hydrogel; when the radionuclide is a water-insoluble liquid or solid powder, the radionuclide is dispersed in the alginate hydrogel. The use mass of the radionuclide is 0.1-10 parts.
The alginate hydrogel is a thermally irreversible hydrophilic gel formed by crosslinking water-soluble alginate (mainly sodium alginate, potassium alginate and ammonium alginate) and polyvalent metal ions (mainly calcium ions, aluminum ions, iron ions, ferrous ions, copper ions, barium ions and zinc ions), and comprises calcium alginate hydrogel, aluminum alginate hydrogel, ferric alginate hydrogel, ferrous alginate hydrogel, copper alginate hydrogel, barium alginate hydrogel and zinc alginate hydrogel, preferably calcium alginate hydrogel. The use mass of the alginate hydrogel is 90-100 parts.
The ray marker is a material which is opaque to X rays, namely a contrast medium used clinically, so that the radioactive particles have good visibility under X rays or CT scanning and assist in positioning the radioactive particles clinically. The using mass of the ray marker is 0.1-10 parts.
The pigment is a chromogenic material which can visually observe the position of the radioactive inner core through the outer shell, and comprises non-toxic natural or synthetic edible pigments, including amaranth, brilliant blue, erythrosine, acid red, allura red, indigo blue, carmine, sunset yellow, lemon yellow, sodium copper chlorophyllin, caramel or beta-carotene, and the using mass is 0.1-10 parts.
The shell 2 is composed of polycaprolactone, and the using mass of the polycaprolactone is 70-100 parts. The housing 2 may also include a therapeutic drug therein. The therapeutic drugs comprise anti-tumor drugs, anti-rejection drugs, anti-inflammatory drugs and the like, and the using mass is 0.1-30 parts.
In a particular embodiment, the radioactive core 1 of the radioactive particle has a diameter of 0.5 mm; the length of each radioactive inner core 1 is 2-5mm, preferably 3 mm; the diameter of the shell 2 is 0.8 mm; the length of the radioactive particles is 4-6mm, preferably 4.5 mm.
Referring to fig. 2, the present invention also provides a particle composition having a certain shape formed by at least two radioactive cores as described above connected by a sheath 22 covering the plurality of radioactive cores. In this embodiment, the particle composition has a linear shape. The shape of the particle composition further comprises: straight, curved, circular, spiral, or cruciform and web shapes formed by the concatenation of multiple straight tubular radioactive particle compositions.
In a specific embodiment, the distance between the radioactive cores is 8-30mm, and the activity of each radioactive core is 0.1-10 mCi.
The following description is given with reference to specific examples:
specific example 1:
the biodegradable radioactive particles and the composition are composed of the following components:
the shell comprises the following components:
polycaprolactone 100 parts
The radioactive inner core comprises the following components:
iodine [ 2 ]125I]Sodium chloride 10 parts
100 portions of calcium alginate hydrogel
Specific example 2:
the biodegradable radioactive particles and the composition are composed of the following components:
the shell comprises the following components:
polycaprolactone 90 parts
5-Fluorouracil 10 parts
The radioactive inner core comprises the following components:
different from the characteristics of the prior art, the biodegradable radioactive particles and the composition thereof provided by the invention have the following advantages:
1. the radioactive particles provided by the invention have biodegradability, namely after the radioactive particles are implanted into focal tissues and complete all treatment functions, the outer shell and the inner core of the radioactive particles are degraded into small molecular components which can be metabolized by a human body or directly discharged out of the body through multiple mechanisms such as hydrolysis, enzymolysis and the like, so that the functions of the treated tissues of a patient cannot be influenced.
2. The shape and the size of the biodegradable radioactive particles and the particle composition provided by the invention are suitable for various implantation means such as the conventional radioactive particle puncture implantation, the implantation in an operation and the like, and the clinical use is convenient.
3. The biodegradable radioactive particles and particle compositions provided by the invention have small shielding of the radioactive nuclide by the materials used in the shell and the inner core, so that the treatment efficiency of the radioactive nuclide in the inner core can be greatly improved.
4. The shell of the biodegradable radioactive particles and the particle composition provided by the invention can be added with therapeutic drugs, so that dual treatment effects of radiotherapy and drug treatment are realized.
5. The radioactive inner core of the biodegradable radioactive particles and the particle composition uses the alginate hydrogel, and due to the good molecular immobilization capacity and the strong mechanical stability of the alginate hydrogel, the radionuclide is not easy to aggregate and precipitate in the gel, and the uniform dispersion of the radionuclide in the inner core and the uniform distribution of the radioactive dose are ensured.
6. The main biodegradable material used by the shell of the biodegradable radioactive particles and the particle composition provided by the invention is polycaprolactone, so that the biodegradable radioactive particles and the particle composition have the following characteristics: 1) polycaprolactone can stably exist in tissues for about 2 years, and has a half-life equivalent to ten half-lives of the currently commonly used radionuclide for radioactive particles, so that the radionuclide is prevented from leaking before most of therapeutic rays decay; 2) the melting point of polycaprolactone is 59-64 ℃, and the polycaprolactone has good shape memory property, so that the shape and the layout of the radioactive particles and the particle composition can be conveniently adjusted in clinical use; 3) the melted polycaprolactone has good adhesion performance, so the radioactive particles and the particle composition provided by the invention can be conveniently adhered to other human implants, and the human implants can perform local brachytherapy besides normal functions.
Referring to fig. 3, the present invention also provides a method for preparing biodegradable radioactive particles and a particle composition thereof, comprising the steps of:
(1) preparing a shell raw material and a radioactive inner core raw material;
the method specifically comprises the following steps: the main raw material polycaprolactone of the shell is uniformly mixed in a molten state, wherein the molten state refers to the condition that a uniform shell raw material is formed at the temperature above the melting point of the polycaprolactone, namely the temperature above 60 ℃, and the higher the melting temperature is, the lower the viscosity of the shell raw material is, and the easier the shell raw material is to be extruded. In this example, the melting temperature range is 80 ℃ or higher. Preferably, the melting temperature range is 100-.
The shell material can also comprise a therapeutic drug, so that the shell can locally release the therapeutic drug after being implanted into tissues, and the dual effects of radiotherapy and drug therapy are achieved. The therapeutic drugs include antitumor drugs, anti-rejection drugs, anti-inflammatory drugs, and the like.
The shell raw material can also comprise auxiliary filler, including the components for adjusting the biodegradation period of polycaprolactone, adjusting the mechanical property of polycaprolactone and reducing cost, the auxiliary filler comprises inorganic filler, polymer filler and plasticizer, the inorganic filler comprises calcium carbonate, calcium sulfate, hydroxyapatite, carbon black, silicon nitride and aluminum hydroxide, the polymer filler comprises polylactic acid, polyglycolic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, starch and cellulose, and the plasticizer comprises tributyl citrate, acetyl tributyl citrate, triacetin, castor oil and coconut oil. The use mass of the auxiliary filler is 1-30 parts.
Alginate hydrogel in fluid state and radionuclide are uniformly mixed at 60-100 ℃ to form the radioactive inner core raw material. The radionuclide comprises192Ir、198Au、169Y、131Cs、103Pd and125i, preferably103Pd or125I; the radionuclide can be a water-soluble component, is dissolved in the alginate hydrogel, and can also be water-insoluble liquid or solid powder, and is dispersed in the alginate hydrogel. The use mass of the radionuclide is 0.1-10 parts. The alginate hydrogel in the fluid state is water-soluble alginate (mainly sodium alginate, potassium alginate and ammonium alginate), and is mixed with slightly-soluble polyvalent metal ions (mainly calcium ions, aluminum ions, iron ions, ferrous ions, copper ions, barium ions and zinc ions) at a higher temperature under the weak acid condition, at the moment, because the temperature is higher, the alginate cannot generate ion crosslinking reaction with the polyvalent metal ions, the alginate hydrogel at the moment is in the fluid state, and only when the temperature is reduced to about 40 ℃, the alginate hydrogel can generate ion crosslinking to form a gel state with stronger mechanical property and thermal irreversible performance. Preferably, the mixing temperature is 80 ℃.
The radioactive inner core raw material also comprises a ray marker and/or a pigment. In other embodiments, the radiolabel and/or pigment is mixed with the alginate hydrogel and the radionuclide.
(2) Shell extrusion and filling of the radioactive core: preparing the raw material of the shell into a tube, and injecting a radioactive inner core in a fluid state into the tube when the tube is cooled slightly to form a continuous tubular material with a polycaprolactone shell as an outer layer and the radioactive inner core as an inner layer;
referring to fig. 4, the method specifically includes: the raw material of the shell is extruded to form a pipe through a plastic extrusion molding process, a radioactive inner core injection outlet is additionally arranged in the center of an outlet of a pipe extruder head, and the radioactive inner core in a fluid state is injected into the pipe when the pipe is cooled slightly.
(3) Compression molding of the radioactive particles: when the continuous tubular material is not completely cooled and shaped, pressing the continuous tubular material at a preset distance by using preset pressure and preset pressing length to obtain a continuous linear tubular radioactive particle composition;
the method specifically comprises the following steps: and (3) when the continuous tubular material in the step (2) is not completely cooled and shaped, pressing the tubular shell at a certain distance with a certain pressure and a certain pressing length, wherein the radioactive inner core in a fluid state is a water-based material and is incompatible with a polycaprolactone shell material, so that the continuous radioactive inner core is divided into discontinuous small sections after being pressed at a certain pressure, the distance between the radioactive inner cores can be adjusted by adjusting the pressing length of the tubular material, and finally, the shell and the radioactive inner core are both solidified and shaped by cooling.
(4) Pretreatment of radioactive particles for clinical use: cutting and/or reshaping the continuous linear tubular radioactive particle composition into a desired quantity and shape as desired.
The method specifically comprises the following steps: the continuous linear tubular radioactive particle composition prepared in the step (3) is cut and/or reshaped into a required number and shape according to the volume and shape of lesion tissues and the dose distribution situation planned by a treatment plan, wherein the reshaping means that the linear tubular radioactive particle composition is softened at 60 ℃ and then is put into a certain mold for cooling, and the linear tubular radioactive particle composition can be reshaped into a curve shape, a circle shape, a circular arc shape, a spiral shape and a cross shape and a net shape formed by splicing a plurality of linear tubular radioactive particle compositions.
The following description is given with reference to specific examples:
example 1.
1. Preparation of shell raw material and radioactive inner core raw material
The shell comprises the following components:
polycaprolactone 100 parts
The radioactive inner core comprises the following components:
melting and mixing the raw material of the shell at 100 ℃, mixing the components of the radioactive inner core at 80 ℃, and adjusting the pH value of the raw material of the radioactive inner core to 5.5 by using a 5% citric acid solution.
2. Shell extrusion and filling of radioactive core
Extruding and forming the raw material of the shell by a plastic pipe extruder to form a pipe, injecting the raw material of the radioactive inner core into the pipe when the pipe is cooled slightly to form a continuous tubular material with the outer layer being the polycaprolactone shell and the inner layer being the radioactive inner core.
3. Press molding of radioactive particles
And (3) pressing the tubular shell at intervals of 20mm at the time when the continuous tubular material in the step 2 is not completely cooled and shaped, wherein the pressing length is 16 mm.
4. Pretreatment for clinical use of radioactive particles
Cutting the radioactive particle composition obtained after the pressing in the step 3 along the pressing position into a linear radioactive particle composition which contains 10 radioactive cores and is separated by 10mm, sterilizing by using ethylene oxide, and pre-loading into an 18G puncture needle, thus being used for implanting radioactive particles in clinical puncture.
Example 2.
1. Preparation of shell raw material and radioactive inner core raw material
The shell comprises the following components:
polycaprolactone 90 parts
5-Fluorouracil 10 parts
The radioactive inner core comprises the following components:
melting and mixing the raw materials of the shell at 100 ℃, mixing the components of the radioactive inner core at 80 ℃, and adjusting the pH value of the raw materials of the radioactive inner core to 5.0 by using a 5% acetic acid solution.
2. Shell extrusion and filling of radioactive core
Extruding and forming the raw material of the shell by a plastic pipe extruder to form a pipe, injecting the raw material of the radioactive inner core into the pipe when the pipe is cooled slightly to form a continuous tubular material with the outer layer being the polycaprolactone shell and the inner layer being the radioactive inner core.
3. Press molding of radioactive particles
And (3) pressing the tubular shell at intervals of 10mm when the continuous tubular material in the step (2) is not completely cooled and shaped, wherein the pressing length is 6 mm.
4. Pretreatment for clinical use of radioactive particles
Cutting the radioactive particle composition obtained after the pressing in the step 3 along the pressing part into radioactive particles only containing single radioactive cores, and sterilizing the radioactive particles by using ethylene oxide, wherein the same is used as the radioactive particles sealed by common metal welding.
Different from the prior art, the preparation method of the biodegradable radioactive particles and the particle composition provided by the invention has the following advantages:
1. the preparation method of the biodegradable radioactive particles and the particle composition provided by the invention uses a mature industrial polymer extrusion molding production process, is simple and feasible, has high preparation efficiency, and can realize continuous large-scale full-automatic production.
2. The preparation method of the biodegradable radioactive particles and the particle composition provided by the invention can realize closed production in the whole process, no leftover materials are generated, and radioactive pollution is avoided to the maximum extent.
3. The preparation method of the biodegradable radioactive particles and the particle composition provided by the invention can be used for preparing the radioactive particle product meeting the clinical requirement of complex focus conditions, and is convenient for clinical use.
It will be understood by those skilled in the art that the radioactive particles, and the particle compositions and methods of making the same, of the present invention are not limited to the examples described in the detailed description, which is intended to be illustrative of the invention and not limiting. Other embodiments will be apparent to those skilled in the art from the following detailed description, which is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
Claims (20)
1. A biodegradable radioactive particle comprising a radioactive inner core and an outer shell;
the radioactive inner core comprises a radionuclide and alginate hydrogel; the shell is polycaprolactone.
2. The radioactive particle of claim 1, wherein said radioactive core further comprises a radio-label and/or a pigment.
3. The radioactive particle of claim 1, wherein said housing further comprises a therapeutic drug.
4. Radioactive particles according to claim 1, wherein the outer shell further comprises an auxiliary filler comprising the inorganic filler comprising calcium carbonate, calcium sulphate, hydroxyapatite, carbon black, silicon nitride, aluminium hydroxide, a polymeric filler comprising polylactic acid, polyglycolic acid, polyvinyl alkanone, polyvinyl alcohol, polyethylene glycol, starch, cellulose, and a plasticizer being tributyl citrate, tributyl acetyl citrate, glycerol triacetate, castor oil, coconut oil.
5. The radioactive particle of claim 1, wherein said radionuclide comprises192Ir、198Au、169Y、131Cs、103Pd or125I。
6. The radioactive particle according to claim 1, wherein when said radionuclide is a water-soluble component, the radionuclide is dissolved in the alginate hydrogel; when the radionuclide is a water-insoluble liquid or solid powder, the radionuclide is dispersed in the alginate hydrogel.
7. The radioactive particle according to claim 1, wherein the alginate hydrogel is a thermally irreversible hydrophilic gel formed by crosslinking water-soluble alginate with polyvalent metal ions;
the alginate comprises sodium alginate, potassium alginate or ammonium alginate;
the polyvalent metal ions include calcium ions, aluminum ions, iron ions, ferrous ions, copper ions, barium ions or zinc ions.
8. The radioactive particle of claim 2, wherein the radiation marker comprises barium sulfate, sodium iodide, diatrizoate, iothalamate, iodixanate, iohexol, iopromide, iobitrex, idoxuridine, or iodophenyl ester.
9. The radioactive particle according to claim 2, wherein the pigment comprises amaranth, brilliant blue, erythrosine, acid red, allura red, indigo, carmine, sunset yellow, lemon yellow, sodium copper chlorophyllin, caramel, or β -carotene.
10. The radioactive particle according to claim 3, wherein the therapeutic drug comprises an anti-tumor drug, an anti-rejection drug or an anti-inflammatory drug.
11. The radioactive particle according to any of claims 1 to 10, wherein the radioactive nuclide is used in an amount of 0.1 to 10 parts by mass, the alginate hydrogel is used in an amount of 90 to 100 parts by mass, the radiation marker is used in an amount of 0.1 to 10 parts by mass, the coloring matter is used in an amount of 0.1 to 10 parts by mass, the polycaprolactone is used in an amount of 70 to 100 parts by mass, the therapeutic drug is used in an amount of 0.1 to 30 parts by mass, and the auxiliary filler is used in an amount of 1 to 30 parts by mass.
12. The radioactive particle of claim 1, wherein the radioactive core has a diameter of 0.5mm, each radioactive core has a length of 2-5mm, the outer shell has a diameter of 0.8mm, and the radioactive particle has a length of 4-6 mm.
13. The particulate composition of any of claims 1-12 wherein at least two radioactive cores are joined by an outer shell surrounding a plurality of radioactive cores to form a shaped particulate composition.
14. The radioactive particle composition according to claim 13, wherein the shape of the particle composition comprises: straight, curved, circular, spiral, or cruciform and web shapes formed by the concatenation of multiple straight tubular radioactive particle compositions.
15. The radioactive particle composition according to claim 14, wherein the distance between the radioactive cores is 8 to 30mm and the activity of each radioactive core is 0.1 to 10 mCi.
16. A method for preparing biodegradable radioactive particles and particle compositions, comprising:
(1) preparing a shell raw material and a radioactive inner core raw material;
(2) preparing the raw material of the shell into a tube, and injecting a radioactive inner core in a fluid state into the tube when the tube is cooled slightly to form a continuous tubular material with a polycaprolactone shell as an outer layer and the radioactive inner core as an inner layer;
(3) when the continuous tubular material is not completely cooled and shaped, pressing the continuous tubular material at a preset distance by using preset pressure and preset pressing length to obtain a continuous linear tubular radioactive particle composition;
(4) cutting and/or reshaping the continuous linear tubular radioactive particle composition into a desired quantity and shape as desired.
17. The method according to claim 16, wherein the step (1) specifically comprises: uniformly mixing polycaprolactone serving as a main raw material of the shell in a molten state, wherein the melting temperature range is more than or equal to 80 ℃; alginate hydrogel in fluid state and radionuclide are uniformly mixed at 60-100 ℃ to form the radioactive inner core raw material.
18. The method as claimed in claim 16, wherein the melting temperature in step (1) is in the range of 100-120 ℃.
19. The method according to claim 16, wherein the step (2) specifically comprises: the raw material of the shell is extruded to form a pipe through a plastic extrusion molding process, a radioactive inner core injection outlet is additionally arranged in the center of an outlet of a pipe extruder head, and the radioactive inner core in a fluid state is injected into the pipe when the pipe is cooled slightly.
20. The method of claim 16, wherein the step (4) of reshaping comprises softening the linear tubular radioactive particle composition at 60 ℃ and cooling the softened composition in a mold, and reshaping the linear tubular radioactive particle composition into a curved shape, a circular arc shape, a spiral shape, and a cross shape and a net shape formed by splicing a plurality of linear tubular radioactive particle compositions.
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