CN102188724A - Novel ultrasonic quick-release preparation for radiotherapy of tumor in vivo, and preparation method thereof - Google Patents
Novel ultrasonic quick-release preparation for radiotherapy of tumor in vivo, and preparation method thereof Download PDFInfo
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- CN102188724A CN102188724A CN2010101175791A CN201010117579A CN102188724A CN 102188724 A CN102188724 A CN 102188724A CN 2010101175791 A CN2010101175791 A CN 2010101175791A CN 201010117579 A CN201010117579 A CN 201010117579A CN 102188724 A CN102188724 A CN 102188724A
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Abstract
The invention discloses a novel ultrasonic quick-release preparation for radiotherapy of tumor, a preparation method thereof and application thereof. The ultrasonic quick-release preparation comprises sorbitol, medical high molecular polymer and radionuclide, wherein the weight of the medical high molecular polymer and the weight of the radionuclide respectively account for 1-10% of the weight of the sorbitol. Proven by ultrasonic imaging results, the ultrasonic quick-release preparation can notably increase the drug release speed and degree of the preparation in tumor tissues. The method disclosed by the invention is simple, easy and convenient for production, and has good application prospects in the aspect of radiotherapy of tumor disease.
Description
Technical field:
The present invention relates to supersonic speed release formulation, Its Preparation Method And Use in a kind of novel body, belong to field of medicaments.
Background technology:
Malignant tumor has become serious threat and one of disease of human health, and radiation therapy technology and surgical excision, internal medicine chemotherapy and interventional therapy are four big treatment systems of tumor.In recent years, close-range treatment becomes noticeable Therapeutic Method in field of radiation therapy, obtains more surprising clinical efficacy.Plesioradiotherapy between tissue is near a kind of method of the enclosed type radioactive source being planted tumor tissues or being subjected to interstitial therapy's tumor of cancer cell infiltration it.Radioactive particle close-range treatment malignant tumor is a new technique of carrying out in recent years, and is easy and simple to handle, wound is little, therapeutic effect is relatively good, has a good application prospect clinically.But exist the lonizing radiation medicine in vivo the holdup time long, to various normal structure organs bring the irradiation side effect shortcoming.
At the problem that above-mentioned closely radiation exists, numerous researcheres have been carried out extensive studies, but up to now, research does not still propose any rational suggestion or way.
Therefore, this area exist a kind of can preparation method simple, little to the human body wound, can discharge rapidly in vivo or in the tissue, the needs of supersonic speed release formulation in therapeutic effect is good, the holdup time is short, toxic and side effects is low in the body the body, to satisfy radiotherapy tumor disease development need.
The inventor is by studying for a long period of time, find that the preparation sorbitol is a carrier material, coat medical high polymer polymer particulates (granule) on its surface, and then it is mixed with radionuclide can prepare supersonic speed release formulation in a kind of body that can be used in the radiotherapy tumor
After Rotary Evaporators reaches the certain vacuum degree, the mixed liquor that sucks is the surface of atomized spray to carrier granular, by rotation constantly, make mixed liquor be coated on the carrier medicament surface, form the rapid release microgranule through rotary evaporation, again this rapid release microgranule and radiation material are mixed and made in a kind of novel body supersonic speed and discharge and penetrate treatment tumor preparation, solved a plurality of shortcomings that exist in the prior art, thereby finished the present invention.
Summary of the invention:
The invention provides a kind of supersonic speed release formulation that is used for the treatment of tumor, it comprises sorbitol, medical high polymer polymer and radionuclide, wherein in the weight of sorbitol, the weight of medical high polymer polymer and radionuclide is respectively the 1-10% of sorbitol weight.
In this article, described medical high polymer polymer is selected from one or more in the following material: polylactic acid (PLA, MW 30,000-200,000 dalton), polycaprolactone (PCL, MW2000-200,000 dalton), polylactic acid (PLA, MW 30,000-200,000 dalton) and polycaprolactone (PCL, MW 2000-200,000 dalton) polymer (PLA-PCL), EudragitRL 100, Eudragit RS 100, preferred molecular weight range is 30,000-200,000 daltonian PLA.
In this article, radionuclide has identical implication with radiosiotope, and it can be selected from
125I,
103Pd,
90Y,
60Co,
226Ra,
198Au,
137Cs,
182Ta or
191Ir etc., preferred
125I,
103Pd or
90Y; Described sorbitol is preferably 60-1000 purpose sorbitol microgranule.
The supersonic speed release formulation that is used for the treatment of tumor of the present invention is the column type granule, and diameter is for about about 0.5-1mm, and length is about 2-5mm.
In one embodiment, supersonic speed release formulation of the present invention can be prepared into tablet form, be 5.5mm such as diameter, and thickness is the tablet of 3mm.These dosage forms can adopt conventional method preparation known in the art.
The present invention also provides the preparation method of supersonic speed release formulation of the present invention, and it comprises the steps:
(1) randomly under room temperature or room temperature, the medical high polymer polymer is dissolved in the organic solvent, stir it is dissolved evenly fully;
(2) sorbitol is placed Rotary Evaporators, at 30-70 ℃, preferred 60 ℃ of rotation preheatings down, the mixture that adds step (1) acquisition every gradation in 1-10 minute carries out coating, continues rotary evaporation, drying after adding is finished;
(3) product with step (2) is cooled to room temperature, promptly gets the rapid release microgranule of sorbitol and polymer, randomly sieves, such as the 60-100 order that sieves;
(4) sorbitol that step (3) is obtained and the rapid release microgranule of polymer with lonizing radiation nucleic mix homogeneously, are pressed into the cylindrical particle of corresponding size afterwards with tablet machine in radioactive environment, are supersonic speed release formulation in the body.
In above-mentioned preparation method, wherein the organic solvent in the step (1) is selected from ether, chloroform, ethyl acetate, isopropyl alcohol, preferred chloroform; Wherein the consumption of medical high polymer polymer is the 10-100% (w/v) of organic solvent.
In above-mentioned preparation method, wherein step (1) is for to be dissolved in organic solvent with the medical high polymer polymer, and stirring is dissolved evenly it fully, and room temperature left standstill 18-36 hour afterwards; Gradation was incorporated as every 1-10 minute in the step (2), added once in preferred 2 minutes, and each not requirement especially of amount that adds, those skilled in the art can determine according to routine techniques.
In a preferred scheme, in step (2), sorbitol is placed Rotary Evaporators, 60 ℃ of rotation preheatings 5-30 minute, preferred 10 minutes; After adding was finished, wherein, in preparation process, Rotary Evaporators should keep vacuum or near vacuum state, rise near 0.1MPa such as vacuum pump pressure.
In a preferred scheme, in step (2), the time of continuing rotary evaporation after adding is finished can be for 10 minutes-20 minutes, such as about 10 minutes; Afterwards, the microgranule behind the coating is taken out, placed baking oven (such as 60 ℃) dry a period of time 10-30 minute, such as about 20 minutes.
The present invention also provides the purposes of supersonic speed release formulation as herein described in preparation treatment tumor preparation, and wherein said tumor can be selected from the cerebral tumor, nasopharyngeal carcinoma, pulmonary carcinoma, hepatocarcinoma, bladder cancer, carcinoma of prostate etc.
Ultimate principle of the present invention: with the sorbitol is carrier material, in Rotary Evaporators, make its surface coat medical high polymer polymer mixed liquid, form the rapid release microgranule through rotary evaporation, again this rapid release microgranule and radiation material are mixed and made in a kind of novel body supersonic speed and discharge to penetrate and treat the tumor preparation under radioactive environment.After being implanted to supersonic speed release formulation of the present invention in the tissue, smash through the ultrasound wave of 1-MHz, medicine is discharged in the tumor tissues rapidly.
The preparation method of supersonic speed release formulation adopts simple method to prepare supersonic speed release formulation in the novel body first in the novel body provided by the invention, make multiple radionuclide be easy to be prepared into solid preparation, compare with traditional radio nuclide therapy tumor disease, this quick releasing formulation can discharge rapidly in tissue, interference to normal surrounding tissue is littler than the radio nuclide therapy of using clinically at present, toxic and side effects is little, can reduce whole body radiation material concentration.When with preparation of the present invention under guiding such as B ultrasonic or CT, the guiding of direct-view or endoscope down in the art, implant with puncture needle, be expelled to tumor locus, the use in conjunction ultrasound wave, the radiation material targeting is discharged, not only can improve curative effect (the ultrasonic picked-up that can increase tumor cell to radiation material) and can reduce toxic and side effects, therefore technology of the present invention has excellent application value and application prospect in fields such as treatment tumor diseases.
Explanation and embodiment further elaborate the present invention below with reference to accompanying drawings, still it will be appreciated by those skilled in the art that but the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can carry out it is equal to replacement, combination, improvement or modification according to description of the invention to the present invention, but these all will comprise within the scope of the invention.
Description of drawings:
Fig. 1 is the stereoscan photograph of the sorbitol that do not coat, and it be an acicular texture, does not see other material coating.
Fig. 2 is the stereoscan photograph of the immediate-release granules of embodiment 1, wherein can not see sorbitol granule acicular texture more, and its surface is covered by thin film, shows to be coated by the mixture of radioactive substance and PLA (MW:30,000 dalton).
(A is for putting into tissue 0 minute for the digital photograph of the disintegrate situation of tablet in the beef tissue of embodiment 1 for Fig. 3; B is for putting into tissue 30 minutes; C is for putting into tissue 60 minutes; D is for putting into tissue 90 minutes; E is for putting into tissue 120 minutes; F is for putting into tissue 180 minutes), tablet disintegrate in the beef tissue at leisure as can be seen.
(A organizes the back 0 minute ultransonic observed result of 14-MHz for putting into to Fig. 4 for the B ultrasonic image of the disintegrate situation of tablet in the beef tissue of embodiment 1; B uses the ultransonic observed result of 14-MHz for putting into tissue after 120 minutes), wherein putting into the tablet that clearly to see tissue when organizing back 0 minute, do not see the tablet image after 120 minutes and place, illustrate that tablet is discharging after 2 hours in the beef tissue.
Fig. 5 is the disintegrate situation photo of tablet in the beef tissue with embodiment 1 behind the 1-MHz ultrasonic echography, and we have compared different ultrasound conditions, and (A is for putting into the beef tissue 0 minute for the comparison of radioactivity rapid release microgranule releasing effect; B is the figure as a result that observes homologue after 2 minutes once more; C uses 1 minute observed figure as a result of 1-MHz ultrasonic echography after the observation in 2 minutes immediately; D is for the second time with 1 minute figure as a result afterwards of 1-MHz ultrasonic echography homologue; E is for using 1 minute figure as a result afterwards of 1-MHz ultrasonic echography homologue for the third time), it is not very fast just having begun drug releasing rate as can be seen, but with the obviously rapid disintegrate of medicine as can be seen behind the 1-MHz ultrasonic echography 1min, and number of times increases the disintegrate degree also along with increase.
Fig. 6 is that (A is for putting into the ultransonic observed result of tissue back 14-MHz with the B ultrasonic image of the disintegrate situation of tablet in the beef tissue of embodiment behind the ultrasonic echography 1; B is the figure as a result that used the 14-MHz ultrasound observation for the first time with the tissue of the above-mentioned A of 1-MHz ultrasonic echography in 1 minute afterwards; C used the ultransonic observed result of 14-MHz in 1 minute afterwards with 1-MHz ultrasonic echography homologue for the second time; D is for using the ultransonic observed result of 14-MHz in 1 minute afterwards with 1-MHz ultrasonic echography homologue for the third time), when just putting into the beef tissue, can clearly see the tablet of tissue as can be seen, and begin to blur with image behind the 1-MHz ultrasonic echography 1min, do not seen the tablet image when ultrasonic for the third time, illustrated that tablet is through discharging rapidly after the 1-MHz ultrasonic echography in tissue.
The specific embodiment:
Embodiment 1
Under the room temperature, 0.4g PLA (MW:30,000 dalton) is dissolved in the 12ml acetonitrile, mixes, standby.The sorbitol microgranule is crossed 100 mesh sieves, take by weighing 20g and place Rotary Evaporators, 60 ℃ of water-bath rotation preheating 10min, vacuum pump pressure rises near 0.1MPa simultaneously.Draw above-mentioned mixed solution every 2min sorbitol is carried out coating, all sucked, and continue rotary evaporation 10min until mixed liquor.Microgranule behind the coating is taken out, take out after placing 60 ℃ of dry 20min of baking oven, be cooled to room temperature, cross 60 mesh sieves.Under airtight radiation environment with the 2g radioactive substance (
90Y) with the rapid release microgranule mix homogeneously of above-mentioned sorbitol and polymer, obtain the radioactivity immediate-release granules, be pressed into diameter 5.5mm with tablet machine, thickness is the tablet of 3mm.
Embodiment 2
Under the room temperature, 1.6g PLA (MW:30,000 dalton) is dissolved in the 12ml chloroform, mixes, standby.The sorbitol microgranule is crossed 100 mesh sieves, take by weighing 20g and place Rotary Evaporators, 60 ℃ of water-bath rotation preheating 5min, vacuum pump pressure rises near 0.1MPa simultaneously.Draw above-mentioned mixed solution every 2min sorbitol is carried out coating, all sucked, and continue rotary evaporation 10min until mixed liquor.Microgranule behind the coating is taken out, take out after placing 60 ℃ of dry 10min of baking oven, be cooled to room temperature, cross 80 mesh sieves.Under airtight radiation environment with the 1g radioactive substance (
125I) with the rapid release microgranule mix homogeneously of above-mentioned sorbitol and polymer, obtain the radioactivity immediate-release granules, suppress, obtain tablet with tablet machine.Scanning electron microscope, B ultrasonic image analysing computer show that the mixed thing of sorbitol coats, and the surface is more even, and be smooth.
Embodiment 3
Under the room temperature, 0.1g PLA (MW:30,000 dalton) and 0.1g PCL (MW:2,000 dalton) are dissolved in the 12ml ethyl acetate, mix, standby.The sorbitol microgranule is crossed 100 mesh sieves, take by weighing 20g and place Rotary Evaporators, 60 ℃ of water-bath rotation preheating 20min, vacuum pump pressure rises near 0.1MPa simultaneously.Draw above-mentioned mixed solution every 2min sorbitol is carried out coating, all sucked, and continue rotary evaporation 20min until mixed liquor.Microgranule behind the coating is taken out, take out after placing 60 ℃ of dry 30min of baking oven, be cooled to room temperature, cross 60 mesh sieves.Under airtight radiation environment with the 0.2g radioactive substance (
90Y) with the rapid release microgranule mix homogeneously of above-mentioned sorbitol and polymer, obtain the radioactivity immediate-release granules, suppress, obtain tablet with tablet machine.Scanning electron microscope analysis shows that the mixed thing of sorbitol coats, but rough surface has many holes.
Embodiment 4
Under the room temperature, 1.0g PLA (MW:200,000 dalton) is dissolved in the 12ml chloroform, mixes, standby.The sorbitol microgranule is crossed 100 mesh sieves, take by weighing 20g and place Rotary Evaporators, 60 ℃ of water-bath rotation preheating 30min, vacuum pump pressure rises near 0.1MPa simultaneously.Draw above-mentioned mixed solution every 2min sorbitol is carried out coating, all sucked, and continue rotary evaporation 10min until mixed liquor.Microgranule behind the coating is taken out, take out after placing 60 ℃ of dry 25min of baking oven, be cooled to room temperature, cross 100 mesh sieves.Under airtight radiation environment with the 1.6g radioactive substance (
103Pd) with the rapid release microgranule mix homogeneously of above-mentioned sorbitol and polymer, obtain the radioactivity immediate-release granules, suppress, obtain tablet with tablet machine.Scanning electron microscope, B ultrasonic image analysing computer show that the mixed thing of sorbitol coats, and the surface is more even.
Embodiment 5. polymer carrier materials orthogonal experiment examples
Under the room temperature, with variable concentrations, different molecular weight size, different types of medical high polymer polymer dissolution in the 12ml chloroform, stirring and evenly mixing, standby.Used medical high polymer polymer has: Eudragit RL 100, Eudragit RS 100, PCL, PLA (MW:200,000), PLA (MW:30,000) etc., it is also all different that the medical high polymer polymer accounts for the concentration of total rapid release microgranule, identical medical high polymer polymer is all done 4 parts, is used to average.The sorbitol microgranule is crossed 100 mesh sieves, take by weighing 20g and place Rotary Evaporators, 60 ℃ of water-bath rotation preheating 10min, vacuum pump pressure rises near 0.1MPa simultaneously.Draw above-mentioned mixed solution every 2min sorbitol is carried out coating, all sucked, and continue rotary evaporation 10min until mixed liquor.Microgranule behind the coating is taken out, take out after placing 60 ℃ of dry 20min of baking oven, be cooled to room temperature, cross 60 mesh sieves, be pressed into tablet with tablet machine.
Table 1: polymer carrier materials Orthogonal experiment results table
The result of table 1 shows, the medical high polymer polymer of different materials, and its disintegration is also all inequality, and wherein, the disintegration of PLA (MW:30,000) and other medical high polymer polymer phases are very fast frequently, especially 2% PLA (MW:30,000).
Claims (10)
1. supersonic speed release formulation that is used for the treatment of tumor, it comprises sorbitol, medical high polymer polymer and radionuclide, wherein in the weight of sorbitol, the weight of medical high polymer polymer and radionuclide is respectively the 1-10% of sorbitol weight.
2. the supersonic speed release formulation of claim 1, wherein said medical high polymer polymer is selected from one or more in the following material: MW 30,000-200,000 daltonian polylactic acid (PLA), MW 2000-200,000 daltonian polycaprolactone (PCL), MW 30,000-200,000 daltonian polylactic acid and MW 2000-200, the polymer of 000 daltonian polycaprolactone (PLA-PCL), Eudragit RL 100, Eudragit RS 100, preferred MW 30,000-200,000 daltonian polylactic acid (PLA).
3. claim 1 or 2 supersonic speed release formulation, wherein said medical high polymer polymer is a molecular weight ranges 30,000-200,000 daltonian PLA.
4. each supersonic speed release formulation in the claim 1 to 3, wherein said radionuclide is selected from
125I,
103Pd,
90Y,
60Co,
226Ra,
198Au,
137Cs,
182Ta or
191Ir, preferred
125I,
103Pd or
90Y.
5. each supersonic speed release formulation in the claim 1 to 4, wherein said sorbitol is a 60-1000 purpose sorbitol microgranule, and described supersonic speed release formulation is the column type granule, and diameter is about 0.5-1mm, and length is about 2-5mm.
6. the preparation method of each supersonic speed release formulation among the claim 1-5, it comprises the steps:
(1) the medical high polymer polymer is dissolved in the organic solvent, stirring is dissolved evenly it fully;
(2) sorbitol is placed Rotary Evaporators, at 30-70 ℃, preferred 60 ℃ of rotation preheatings down, the mixture that adds step (1) acquisition every the 1-10min gradation carries out coating, continues rotary evaporation, drying after adding is finished;
(3) product with step (2) is cooled to room temperature, promptly gets the rapid release microgranule of sorbitol and medical high polymer polymer, randomly sieves;
(4) sorbitol that step (3) is obtained and the rapid release microgranule of medical high polymer polymer mix with the lonizing radiation nucleic in radioactive environment, are pressed into supersonic speed release formulation in the columniform body of corresponding particle size range with tablet machine.
7. the preparation method of claim 6, wherein the organic solvent in the step (1) is selected from ether, chloroform, ethyl acetate, acetonitrile, acetone or isopropyl alcohol, preferred chloroform.
8. claim 6 or 7 preparation method, wherein the consumption of high molecular polymer is the 0.5-100% (w/v) of organic solvent.
9. each preparation method among the claim 6-8, wherein step (1) is for to be dissolved in organic solvent with the medical high polymer polymer, stirs it is dissolved evenly fully, and room temperature left standstill 18-36 hour afterwards; Gradation is incorporated as every 2 minutes and adds once in the step (2).
10. each supersonic speed release formulation is preparing the purposes for the treatment of in the tumor preparation among the claim 1-5, and wherein said tumor is selected from the cerebral tumor, nasopharyngeal carcinoma, pulmonary carcinoma, hepatocarcinoma, bladder cancer or carcinoma of prostate.
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Application publication date: 20110921 |