CN1083714C - Microcapsule containing chemotherapeutic medicine and capsule-forming method - Google Patents
Microcapsule containing chemotherapeutic medicine and capsule-forming method Download PDFInfo
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- CN1083714C CN1083714C CN99114035A CN99114035A CN1083714C CN 1083714 C CN1083714 C CN 1083714C CN 99114035 A CN99114035 A CN 99114035A CN 99114035 A CN99114035 A CN 99114035A CN 1083714 C CN1083714 C CN 1083714C
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- microcapsule
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- chemotherapeutic
- ethyl cellulose
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Abstract
The present invention relates to a medicinal preparation characterized in a special physical shape, particularly to a method for preparing a release-type microcapsule. The present invention has the technical scheme that a chemotherapeutic medicine is used as a capsule core object, ethyl cellulose is used as a capsule wall, and the microcapsule contains the chemotherapeutic medicine. The method mainly comprises the following steps: preparing an organic solution of the capsule wall; cooling and condensing the organic solution into a capsule; sealing the microcapsule in a waxing mode; drying the microcapsule; finally, irradiating the microcapsule by cobalt 60 for disinfection. A dispersant is added to the reaction process for preparing the microcapsule, so the ethyl cellulose can form the capsule successfully without condensation or conglobation. Moreover, the capsule preparing method is improved, so the grain size of the microcapsule produced by the method conforms to requirements, and gas the advantages of good dispersivity and good releasing performance.
Description
The invention relates to the pharmaceutical product that is shaped as feature with specific physical, especially belong to the encystation method of the microencapsulation of sustained releasing type.
Microcapsule is a kind of slow release formulation, can be used as the artery embolization for treatment malignant tumor, in order to the extended treatment time, improves the drug level of target organ on pharmaceutics, improves curative effect, and lowers whole body blood drug level, effectiveness such as reduced toxicity.Microcapsule is to be cyst wall with macromolecular compound or natural materials, in the capsule core material of required parcel is wrapped in, becomes small capsule (particle diameter from several microns to the hundreds of micron).
The method of making microcapsule has a variety of, the single coacervation of the present invention, single coacervation symbolic animal of the birth year is separated coacervation, macromolecular solution is subjected to the influence of flocculating agent, temperature, pH value or other factors, the dissolubility of macromolecular solution is by being dissolved into limited dissolving fully or when not dissolving, originally the solution of homogeneous is layered as biphase.One is condensed phase mutually, and a lot of polymer drops are arranged in the solvent, and another is the phase that steadily weighs mutually, has only polymer seldom in the solvent.Condensed phase is separated out around granule, microcapsule.
The mitomycin microcapsule is succeeded in developing by Japanese Tetsuro Kato etc. at first.Relevant article has 1980kato, and T. etc. are " cancer " 46 phase P14-21 " is that cyst wall ametycin microcapsule pours into to the arteriorenal lasting releasing properties of dog with the ethyl cellulose "; " ametycin--the carrier microcapsule is in the treatment of rectal cancer hepatic metastases " that 1991 " cancers ", 67 phase P952-955Goldberg, J.A. etc. write.Mentioning the encystation method that contains the mitomycin microcapsule in these articles is: " mix ethyl cellulose 0.5g, polyethylene 0.5g and thiacyclohexane 50ml and be heated to 80 ℃ of dissolvings in vierics, be scattered in this solution with 2 gram mitomycins.With this mixture cool to room temperature gradually, stir at a slow speed simultaneously, in this process, dissolved ethyl cellulose bag mitomycin granule and encystation.Capsule is washed 5 times with the n-hexane that contains 1% castor oil hydrogenated, and 45 ℃ of dryings 6 hours, with the volatilization n-hexane, capsule was collected by 45 mesh sieves, through 140 ℃ of autoclave sterilizations 1 hour, contains 80% mitomycin in the microcapsule, 20% ethyl cellulose.”。Above encystation method except that adding the cyst material ethyl cellulose, also is added with second polymer--polyethylene in thiacyclohexane, it can reduce and condenses, it also may be a kind of cohesion derivant, but because it belongs to non-medicinal raw material, do not enter pharmacopeia, can not be directly used in pharmacy.
The objective of the invention is to avoid adopting non-medicinal raw material pharmacy, select a kind of medicinal raw material as dispersant, short flocculating agent and improve pharmaceutical methods, produce a kind of particle diameter and close the symbol needs, dispersibility, slow-releasing are good contains the chemotherapeutic microcapsule.
The said microcapsule that contains chemotherapeutic of the present invention, capsule core material is a chemotherapeutic, and cyst wall is an ethyl cellulose, and its encystation method is:
1. the preparation of cyst material organic solution: in retort, add thiacyclohexane, and add and to account for the dispersant of thiacyclohexane 1-10% and the ethyl cellulose of 0.5--1.5%, thiacyclohexane is an organic solvent, is again carrier, its boiling point is 81 ℃, when thiacyclohexane was not heated, ethyl cellulose did not wherein dissolve, when the heating ring hexane reaches boiling point, 81 ℃, the ethyl cellulose dissolving, stir at a slow speed simultaneously, speed is 40--160 rev/min, makes it become the ethyl cellulose organic solution of homogeneous.Dispersant is the HLB value less than the mixing of 8 water in oil surfactant (as sorbester p18--85, propylene glycolmonostearate or lanoline) or more than one surfactants, it can form thin film on oil, water termination, parcel disperses the unlikely merging of mutual-assistance spherolite, plays in course of reaction and disperses and the poly-effect of coagulant.If do not add surfactant, when the temperature of thiacyclohexane raises, ethyl cellulose begins to soften, at this moment the group of sticking into easily is difficult for redispersion and also is difficult for dissolving, can reduce this bond state if add polyethylene (Japan's prescription), but can't eliminate fully, after adding certain surfactant, this state can not take place, and the ethyl cellulose dissolving is very fast.
2. condense encystation: above solution limit is stirred the limit at a slow speed and is lowered the temperature naturally, during to 55-65 ℃ best 60 ℃, adds other chemotherapeutics such as mitomycin or cisplatin, continue to lower the temperature when reaching room temperature, put some ice cubes and make 10 ℃ of jar Nei Wenduda around retort, continue to stir at a slow speed 2 hours, capsule forms.The ratio of capsule core material chemotherapeutic and ethyl cellulose is 1: 1-1: 4, and wall thickness computing formula: h=r
1{ [(w
2d
2)/w
1d
1)+1]
1/3-1} formula center material radius is r
1, the proportion of nuclear material and wall material is respectively d
1And d
2, w
1For the nuclear material is heavy, W
2For the wall material is heavy, h is a wall thickness, and constant when the proportion and the nuclear material footpath of nuclear material and wall material, the thickness of cyst wall is the cube root function of wall material, nuclear material weight ratio, therefore can adjust wall thickness according to the needs of chemotherapeutic rate of release.The temperature that general chemotherapeutic adds is 55--65 ℃, too high active influential to chemotherapeutic of temperature, and the aggregation of too low macromolecular solution begins generation.Mixing speed is controlled at 40--160 rev/min, and according to the volume of production size, the size of microcapsule is directly proportional with rotating speed, and the fast microcapsule of rotating speed is little.The particle diameter that we need is at 140 μ m, so as long as microcapsule can be floated in solution, slowly rotation gets final product.In this step program, surfactant has played critical effect, if do not add surfactant, can bond gradually between the microcapsule, forms one at last and rotates in thiacyclohexane, makes the entire reaction failure.The amount of surfactant that adds can not be excessive, otherwise microcapsule diameter is too little, and is undesirable.
After reaction is finished, microcapsule suspension is poured in the glass container, make the microcapsule sedimentation after, abandon liquid, (go up liquid be thiacyclohexane, dispersant, the little microcapsule of only a few) gives a baby a bath on the third day after its birth time with n-hexane or the eleventh of the twelve Earthly Branches alkane, heptane etc., abandons liquid, gets microcapsule and starches.
3. microcapsule is sealed with wax and solidified: preparation contains the n-hexane of 1% wax, and after the dissolving of heating wax, being cooled to wax noncondensing is degree, be generally 60 ℃, constant temperature is washed microcapsule 5 times, abandons liquid, the microcapsule slurry is layered on exsiccant glass or the enamel flat board, stirs gently, make the thiacyclohexane volatilization and the microcapsule that scatter.Wax is some liquid state more than uniform temperature, is solid-state material below uniform temperature, does not participate in reaction, generally uses paraffin, castor oil hydrogenated, spermaceti, Cera Flava.
4. microcapsule drying: microcapsule was placed 37 ℃ of vacuum drying ovens 12 hours,, big microcapsule is removed, little microcapsule is removed by 200 mesh sieves by 60 mesh sieves with the volatilization organic solvent;
5. sterilization: use the width of cloth according to sterilization, as cobalt 60 width of cloth photographs, exposure dose is 5KGY.Autoclave sterilization method commonly used can make the wax fusing because temperature is too high, influences the slow-releasing of microcapsule and the part bonding takes place.
More than each step all under aseptic condition, carry out, used equipment all need be sterilized, used chemical raw material is medicinal specification.
The invention has the advantages that: in the prescription of microcapsule wall, add a certain amount of pharmaceutically useful dispersant, make ethyl cellulose can form microcapsule smoothly, pass through control reaction temperature, mixing speed, seal with wax, to make the microcapsule mean diameter of making be 140 ± 40 μ m to the width of cloth according to the sterilization several steps, chemotherapeutic content is more than 25%, and the dispersibility slow-releasing is good.
Be specific embodiments of the invention below.
1. taking by weighing ethyl cellulose 1000mg puts in the reaction bulb, add the thiacyclohexane solution 100ml that contains 1% sorbester p37, heat while stirring, mixing speed is at 40--100 rev/min, how much regulate the speed (the output multiple speed hurry up) by output, be heated to the dissolving of thiacyclohexane boiling ethyl cellulose, stop heating, naturally cooling continues slowly to stir;
2. take by weighing refining mitomycin 500mg, question response jar temperature drops to about 60 ℃, and mitomycin is added, and continues stirring at a slow speed under the cooling naturally, about 30 ℃, capsule obviously forms, when being cooled to room temperature, add ice-cooledly at reaction bulb, reach about 10 ℃, constant temperature continues to stir at a slow speed 2 hours.The reaction bulb content is inclined to glass container, make microcapsule natural subsidence (also available centrifuging sedimentation), abandon upper strata liquid; It is inferior to give a baby a bath on the third day after its birth with n-hexane, abandons liquid;
3. will make 1% castor oil hydrogenated n-hexane, and heat to more than 80 ℃, the castor oil hydrogenated dissolving is cooled to 60 ℃ naturally, and constant temperature is washed microcapsule 5 times, abandons liquid,
4. microcapsule is layered on the exsiccant glass plate, stirs gently, make the n-hexane volatilization and the microcapsule that scatter, the microcapsule of substantially dry is placed on crosses liquid in 37 ℃ of vacuum drying ovens, big microcapsule is removed, little microcapsule is removed with 200 mesh sieves with 60 mesh sieves.
5. shine sterilization with cobalt 60 width of cloth, exposure dose is 5KGY.
Claims (10)
1. encystation method that contains the microcapsule of chemotherapeutic, the capsule core material of microcapsule is a chemotherapeutic, cyst wall is an ethyl cellulose, it is characterized in that:
1.1 preparation cyst wall organic solution: add thiacyclohexane and add the dispersant that accounts for thiacyclohexane 1--10% in advance and the ethyl cellulose of 0.5--1.5% in retort, be heated to the thiacyclohexane boiling, the ethyl cellulose dissolving becomes the ethyl cellulose organic solution of homogeneous;
1.2 cohesion saccilar process: the limit is stirred on ethyl cellulose organic solution limit at a slow speed lower the temperature naturally when reaching 55--65 ℃, add chemotherapeutic, stir at a slow speed, be cooled to room temperature naturally, on the rocks outside retort, make organic liquor reduce to 10 ℃, continue to stir 2 hours, and abandoned liquid, wash microcapsule three times with n-hexane or the eleventh of the twelve Earthly Branches alkane, heptane, abandon liquid, get the microcapsule slurry;
1.3 microcapsule is sealed with wax; Preparation contains the n-hexane solution of 1% wax, heats to the wax dissolving, keeps constant temperature, washes microcapsule 5 times, abandons liquid;
1.4 it is dry: that the microcapsule slurry is layered on exsiccant glass or enamel plate surface, stir gently, make the n-hexane volatilization and the microcapsule that scatter, with the microcapsule of substantially dry in 37 ℃ of vacuum drying ovens dry 12 hours, with 60 mesh sieves big microcapsule is removed, 200 mesh sieves remove little microcapsule;
1.5 sterilization: the width of cloth is according to sterilization.
2. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1 is characterized in that dispersant is HLB less than the surfactant of 8 Water-In-Oil character or the mixing of more than one surfactants.
3. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1 and 2 is characterized in that dispersant is a sorbester p18--85.
4. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1 is characterized in that mixing speed is 40--160 rev/min at a slow speed.
5. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1, the used wax when it is characterized in that sealing with wax is paraffin.
6. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1, used wax is castor oil hydrogenated when it is characterized in that sealing with wax.
7. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1, used wax is spermaceti when it is characterized in that sealing with wax.
8. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1, used wax is Cera Flava when it is characterized in that sealing with wax.
9. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1 is characterized in that the constant temperature that is kept when microcapsule is sealed with wax is 60 ℃.
10. the encystation method that contains the microcapsule of chemotherapeutic according to claim 1, the width of cloth when it is characterized in that the width of cloth according to sterilization is 5KGY according to dosage.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99114035A CN1083714C (en) | 1999-01-22 | 1999-01-22 | Microcapsule containing chemotherapeutic medicine and capsule-forming method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99114035A CN1083714C (en) | 1999-01-22 | 1999-01-22 | Microcapsule containing chemotherapeutic medicine and capsule-forming method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1237414A CN1237414A (en) | 1999-12-08 |
| CN1083714C true CN1083714C (en) | 2002-05-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99114035A Expired - Fee Related CN1083714C (en) | 1999-01-22 | 1999-01-22 | Microcapsule containing chemotherapeutic medicine and capsule-forming method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103852180B (en) * | 2012-12-05 | 2018-01-12 | 海尔集团公司 | Temperature sensor clamping device and water heater |
| CN110331138A (en) * | 2019-06-29 | 2019-10-15 | 南京永正生物科技有限公司 | A kind of production technology of biological complex enzyme microcapsules |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57209223A (en) * | 1981-06-19 | 1982-12-22 | Tanabe Seiyaku Co Ltd | Microcapsule for intracranial anti hypotension and its production |
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1999
- 1999-01-22 CN CN99114035A patent/CN1083714C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57209223A (en) * | 1981-06-19 | 1982-12-22 | Tanabe Seiyaku Co Ltd | Microcapsule for intracranial anti hypotension and its production |
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| CN1237414A (en) | 1999-12-08 |
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