JP2005287728A - Radiotherapy assisting implant - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an implant capable of being injected unopened-operationally and separating other tissues from a tissue to be treated in the radiotherapy without increasing burdens on a patient. <P>SOLUTION: The implant is injected for separating tissues other than the tissue to be treated from the tissue to be treated in the radiotherapy. The implant comprises a biocompatible material whose viscosity before injection at 37°C is 20-3,000 mPa s. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an implant used to assist in radiation therapy.

  Currently, radiotherapy using X-rays, electron beams, and the like has become one of the main treatments for malignant tumors. As is well known, this radiotherapy is intended to suppress the growth of malignant cells by irradiating the malignant tumor site, and the radiotherapy occurs in the prostate, uterus, lymph nodes, liver, pancreas, etc. It is used against a wide variety of malignant tumors.

  Efforts have been made to avoid irradiating non-tumor areas as much as possible in order to reduce side effects in radiation therapy.For example, as a method of avoidance, when irradiating malignant tumors with radiation, positioning with respect to the target is very accurate. And high energy rays are concentrated three-dimensionally with high accuracy (three-dimensional irradiation method). The technological innovation of this method continues today.

  Further, there is a method of avoiding irradiation to a non-tumor part by fixing an irradiation site from the outside by various mechanical fixtures and a plastic shell, etc., and reducing the movement of the target. However, the movements of the internal organs of the human body include those necessary for vital activities such as respiratory motion and heartbeat, and it is not possible to completely control them. In addition, due to the inherent scattering of high energy rays that are irradiated no matter how externally irradiated and the limits of the accuracy of the current irradiation, the part adjacent to the tumor on the boundary of the organ or structure is irradiated in the same way as the target. I have to do it.

  In other words, the current technology so far cannot avoid the risk of damage to normal organs and tissues surrounding the tumor. Therefore, in order to protect the normal tissue adjacent to the tumor, it was necessary to change the structure in the body.

Thus, a spacer between organs that enables such isolation in the body has been proposed (for example, see Patent Document 1). In addition, for a composition in which the effective atomic number (Z), density, and relative electron density are adjusted to the physical values of water and human soft tissue by adding waxes and inorganic substances to the chewing gum base material. It has been proposed (see, for example, Patent Document 2).
Japanese National Patent Publication No. 8-503628 JP-A-60-199835

  However, when a spacer is used, a thick bladder (bag-like structure) made from a silicone / polyurethane composite elastomer is used, so that it can be placed and fixed at a desired position in the body. For example, if it is in the abdominal cavity, open surgical laparotomy, or laparoscopes that must be passed through the instrument and the large laparoscope must be created to allow the spacer to be observed from another site Lower surgery is necessary. This method further increases the burden and risk on the patient, such as requiring additional laparotomy or endoscopic surgery to remove the spacers from the body after radiation treatment is completed. It is a big loss. Moreover, since the physical friction is also a large technique, there is a high risk of increasing the tumor.

  Furthermore, the composition containing the chewing gum base material is mainly used while being in close contact with the patient's skin and mucous membrane attachment site (such as in the oral cavity), and is used as an implant material to be introduced into the body as a spacer. When used, the burden on installation and removal is large. In addition, implants such as paraffins, waxes, silicone resin, polyester, polystyrene, polyisoprene have been tried by doctors involved in radiation therapy, but all involve invasive work, so the same applies to patients as above. I have a problem of heavy load.

  Accordingly, it is an object of the present invention to allow non-open surgical injection and to isolate other tissues from the tissue to be treated without increasing the burden on the patient during radiotherapy. It is to provide an implant.

That is, the present invention
[1] An implant that is injected to isolate other tissues from the tissue to be treated in radiotherapy, and contains a biocompatible material having a viscosity of 20 to 3000 mPa · s at 37 ° C. before injection. Implants,
[2] The implant according to [1], wherein the biocompatible material is a biodegradable material,
[3] The implant according to [1] or [2], wherein the implant is thickened after injection compared to before injection;
[4] The implant according to any one of [1] to [3], further comprising a crosslinking agent,
[5] The implant according to the above [4] comprising a composition containing a biocompatible material and a composition containing a cross-linking agent, and [6] a composition containing the biocompatible material before mixing. Use of a cross-linking agent to produce an implant having a viscosity at 37 ° C. of 20 to 3000 mPa · s, which thickens after injection,
About.

  The implant of the present invention allows non-open surgical injection, thereby isolating other tissues from the tissue to be treated during radiation therapy while minimizing the burden on the patient. The effect that it can be done is produced.

  The implant of the present invention has one major characteristic in that it contains a biocompatible material and has a viscosity at 37 ° C. before injection of 20 to 3000 mPa · s.

  Because the implant has such a viscosity, it is not only necessary to perform a large-scale surgical operation to insert the implant, but also used in surgery using a laparoscope that reduces the burden on the patient. The implant can be easily injected into a desired site using a tube, a hose, an injection needle or the like having a diameter smaller than that of the tube or hose-like injection tool. Furthermore, if the implant has a viscosity in such a range, normal tissue can be sufficiently isolated from the tissue to be treated, so that an effect of preventing damage to normal cells equal to or higher than that of the prior art can be obtained. It is done. Therefore, the present invention can reduce the burden on the patient that has occurred when the implant is inserted into the body by a surgical operation. Also, the physical friction when injecting the implant of the present invention is greatly reduced compared to the prior art, so the risk of tumor growth is very small.

  The radiotherapy in which the implant of the present invention is used is a treatment aimed at irradiating the malignant tumor site to suppress the growth of malignant cells, and the radiation used for the treatment includes X-rays. And electron beam. The tissues to be treated are a wide variety of malignant tumors that develop in the prostate, uterus, lymph nodes, liver, pancreas, and the like. The implant of the present invention can isolate other tissues from the tissue to be treated. In this specification, “isolation” means physically separating tissues, and the separation distance is not particularly limited as long as the effect of the present invention is exhibited.

  Examples of the biocompatible material used in the implant of the present invention include silicone, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, insoluble cellulose derivative, poloxamer 407, crosslinked polyhydroxyethyl methacrylate, crosslinked polyethylene oxide, crosslinked Poloxamer, lactic acid-glycolic acid copolymer, water-soluble cellulose derivative, polyvinyl alcohol, collagen, gelatin, casein, agar, starch, crosslinked starch, dextran, alginic acid, crosslinked alginic acid, hyaluronic acid, crosslinked hyaluronic acid, chitin , Chitosan, polyamino acid, polylactic acid, polyglycolic acid, polycaprolactone, poly-β-hydroxybutyric acid, polymalic acid, polyanhydride, acrylic acid polyglycolic acid copolymer (for example, mebi Lumpur Ltd .; Mebiol Gel, etc.), fumaric acid / polyethylene glycol / polyvinylpyrrolidone, polyorthoesters, polyalkyl cyanoacrylate, polycarbonate, peanut oil, and the like sunflower oil. These may be used alone or in combination of two or more.

  Among these, a biocompatible material that is biodegradable (in this specification, sometimes referred to as a biodegradable material) is preferable because it can reduce a burden on the patient due to removal of the implant. Among the above, biodegradable materials include water-soluble cellulose derivatives, polyvinyl alcohol, collagen, gelatin, casein, agar, starches, crosslinked starches, dextran, alginic acids, crosslinked alginic acids, hyaluronic acids, crosslinked hyaluronic acids, chitin , Chitosan, polyamino acid, polylactic acid, polyglycolic acid, polycaprolactone, poly-β-hydroxybutyric acid, polymalic acid, polyanhydride, acrylic acid polyglycolic acid copolymer (for example, manufactured by Meviol Co .; Meviol Gel, etc.) ), Fumaric acid / polyethylene glycol / vinyl pyrrolidone, polyorthoester, polyalkylcyanoacrylic acid, polycarbonate, peanut oil, sunflower oil, and the like. In addition, when a biodegradable material is used for the implant of the present invention, the biodegradable material may be a switch that starts decomposing by a light beam having a specific frequency or energy amount in order to prevent degradation during radiotherapy. It is also possible to use a biodegradable material that can be preliminarily added with a reactive site and can be processed to start decomposition from outside the body after treatment.

  The content of the biocompatible material is not particularly limited as long as the viscosity at 37 ° C. before injection of the obtained implant is within a range of 20 to 3000 mPa · s, and the viscosity obtained varies depending on the material. Is preferably 0.5 to 25% by weight.

  A thickener may be further added to the implant of the present invention. It does not specifically limit as a thickener, A well-known thickener can be used in the said field | area. The content may be an amount such that the viscosity at 37 ° C. before injection of the prepared implant is in the range of 20 to 3000 mPa · s.

  The implant of the present invention is preferably thickened after injection as compared to before injection from the viewpoint of more reliably isolating normal tissue from the tissue to be treated. From this point of view, it is preferable that the implant of the present invention contains a cross-linking agent to gradually form a cross-link between the biocompatible materials to increase the viscosity of the implant.

  Examples of the crosslinking agent used in the present invention include organic compounds having a reactive functional group such as ethylenediamine, and polyvalent metal salts such as calcium chloride. The content of the crosslinking agent is not particularly limited as long as a desired increase in viscosity is obtained, but is preferably 0.05 to 10 parts by weight per 100 parts by weight of the biocompatible material.

  The viscosity after injection at 37 ° C. is preferably increased to 100 to 5000 mPa · s from the viewpoint of more reliably isolating normal tissue from the tissue to be treated. More preferably, it is gelled after injection. The time required for thickening is not particularly limited, but it is preferably 1 to 60 minutes, more preferably 3 to 15 minutes, and the above viscosity range is preferable.

  The implant of the present invention can easily monitor the position and shape of the implant in the living body by X-ray fluoroscopy, X-ray CT, MRI, ultrasonic echo, radioisotope image, etc. It is preferable. Examples of the contrast agent include an iodine contrast agent and a barium-containing contrast agent.

  For the implant of the present invention, for example, the biocompatible material may be used as it is, or the biocompatible material may be dissolved or dispersed in water and used as an aqueous solution, or the biocompatible material or an aqueous solution thereof may be used. You may add and use a crosslinking agent.

  Alternatively, if the implant of the present invention contains a cross-linking agent, the composition containing the biocompatible material and the composition containing the cross-linking agent are separated so that the cross-linking reaction does not proceed during storage or preparation. It may be prepared as a two-component implant that is used immediately before injection.

  The viscosity at 37 ° C. before injection of the implant of the present invention obtained as described above is 20 to 3000 mPa · s, preferably 20 to 1000 mPa · s, more preferably 20 to 100 mPa · s. If the viscosity is 20 mPa · s or more, the retention property at the desired site after injection into the desired site is sufficient, and if it is 3000 mPa · s or less, the injection property to the desired site is good. The viscosity can be measured by the method described in Example 1 described later.

  Here, “before injection” in this specification means immediately before being injected into a living body. That is, even if the viscosity immediately after preparation deviates from the above range, the implant is included in the present invention as long as the viscosity of the implant immediately before being injected into the living body falls within the above range. Further, in the case of a two-component implant, the viscosity of each composition may deviate from the above range, but the implant is prepared immediately by mixing the composition to prepare the implant of the present invention and injecting it into the living body. If the viscosity is within the above range, the implant is also included in the present invention.

  In consideration of being injected into a living body, the implant of the present invention is preferably prepared in a sterile room or sterilized after preparation. Examples of the sterilization method include conventional sterilization methods such as autoclave sterilization, filtration sterilization, EOG sterilization, γ-ray sterilization, electron beam sterilization, and plasma sterilization. In consideration of convenience in use, the implant is preferably filled in a known container such as a vial, tube, or prefilled syringe, and more preferably in a container for each dose. In the case of a two-component implant, the composition containing the biocompatible material and the composition containing the cross-linking agent are processed in a separate container or one container, but not in contact with each other. The container is filled.

  The injection into the living body is preferably performed from the container filled with the implant through an injection needle, a puncture needle, a guide needle, a catheter, an elastor tube, a sheath, a sheath introducer, and the like. In the case of a two-component implant, it is necessary to mix immediately before injection. As the mixing method, a method of mixing the other into a container filled with one, a method of mixing each composition in a new container If the container is processed so that it does not come into contact with each other, an external load is applied to destroy the process and mix each other, while extruding two components such as a static mixer The method of using the tool to mix from.

  The dose to be injected is set in consideration of various factors such as the distance to be isolated, the tissue to be isolated, the residence time, the age, weight, and sex of the subject.

  The residence time at the desired site after the injection may be retained during the radiotherapy.

  When a biodegradable material is used for an implant after the end of radiotherapy, it is naturally degraded in vivo, so the necessity for removal is extremely low unless the subject desires. On the other hand, when a material other than the biodegradable material is used, it needs to be removed. Examples of the method for removing the implant of the present invention include a method in which the burden on the subject is suppressed as much as possible, for example, a puncture drainage method under X-ray fluoroscopy or ultrasonic echo guide. However, even if the subject does not want to remove, since the biocompatible material is used in the implant of the present invention, there is almost no adverse effect caused by not removing it.

  The present invention will be described with reference to the following examples, but the present invention is not limited to the following examples.

  10 g of 2.0% calcium chloride aqueous solution is added to 100 g of ethylenediamine-crosslinked sodium alginate aqueous solution of 1.0% concentration (Kimitsu Chemical Industry Co., Ltd .; Kimitsu Argin: viscosity at 37 ° C .: 170 mPa · s). The contrast medium iopamidol (manufactured by Schering; Iopamiron: iodine concentration: 370 mg / ml) was added so as to be 10% in the implant to prepare the implant of the present invention. It was 120 mPa * s when the viscosity at 37 degrees C of the obtained implant was measured with the E-type viscosity meter (made by Tokyo Keiki Co., Ltd.).

  X-ray fluoroscopy was performed so that the sacral surface of the beagle dog was separated from the intestinal tract using a syringe with a long injection needle with a diameter of 18 gauge in the abdominal cavity of a laboratory beagle dog weighing approximately 9.8 kg. The injection was made while confirming the internal position below. Thereafter, the injected implant lost its fluidity and gelled. Although the practice was performed by a skilled physician, the time required for a series of operations from preparation of the implant to confirmation of loss of fluidity after injection was 12 minutes. Visual observation under fluoroscopy 30 minutes after treatment confirmed that the surface of the sacrum and the intestinal tract were sufficiently separated, and the target site and other sites that were not desired to be exposed during radiotherapy could be isolated.

  The implant of the present invention can be used as an aid for radiotherapy of medical sites, particularly cancer patients.

Claims (6)

  Implant that is injected to isolate other tissues from the tissue to be treated in radiation therapy, and contains a biocompatible material having a viscosity of 20 to 3000 mPa · s at 37 ° C. before injection .   The implant of claim 1, wherein the biocompatible material is a biodegradable material.   The implant according to claim 1 or 2, wherein the implant is thickened after injection as compared to before injection.   The implant according to any one of claims 1 to 3, further comprising a crosslinking agent.   The implant according to claim 4, comprising a composition containing a biocompatible material and a composition containing a crosslinking agent.   Use of a cross-linking agent to produce an implant which is mixed with a composition comprising a biocompatible material and has a viscosity at 37 ° C. before injection of 20 to 3000 mPa · s and thickens after injection.