CN104027313A - Preparation method of octocalcium phosphate double-layer composite particle containing ibuprofen - Google Patents
Preparation method of octocalcium phosphate double-layer composite particle containing ibuprofen Download PDFInfo
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- CN104027313A CN104027313A CN201410286785.3A CN201410286785A CN104027313A CN 104027313 A CN104027313 A CN 104027313A CN 201410286785 A CN201410286785 A CN 201410286785A CN 104027313 A CN104027313 A CN 104027313A
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Abstract
The invention provides a preparation method of an octocalcium phosphate double-layer composite particle containing ibuprofen, and belongs to the technical field of novel materials and pharmaceutic preparations. The preparation method comprises the following steps of adding glutamic acid, disodium hydrogen phosphate, sodium hydroxide, urea, calcium nitrate and trisodium citrate into water in sequence, and then transferring the liquor to a stainless steel high-pressure kettle containing ibuprofen andpolyvinyl alcohol, filtering, washing and drying to prepare the octocalcium phosphate particle containing ibuprofen after reacting for 24 hours at 100 DEG C; adding citric acid, calcium nitrate and diammonium hydrogen phosphate into the liquor containing water and alcohol, adding polyethylene glycol and stirring for one hour after regulating a pH value of the liquor to 9, adding the prepared octocalcium phosphate particle liquor containing ibuprofen, and centrifuging, washing and drying to obtain the octocalcium phosphate double-layer composite particle containing ibuprofen after three hours. The method disclosed by the invention is simple in process, low in material price and easy for industrial production. The ibuprofen is slowly released from the particle, and the particle is good in biocompatibility and easy to degrade.
Description
Technical field
The preparation method that the invention provides a kind of OCP double-layer compound particles containing ibuprofen, belongs to new material and technical field of medicine.
Background technology
Ibuprofen has antiinflammatory, analgesia and refrigeration function, as one of three Class A products of benzenpropanoic acid non_steroidal anti_inflammatory drug, is put into China's list of OTC medicines.But the molecular structure feature of ibuprofen causes its taste bitterness when oral, in water, dissolubility is very low, be about 0.1 gram every liter, the half-life is in vivo only 1.8 ~ 2 hours, causes and takes medicine frequently, often take day by day 3 ~ 4 times, adult's consumption is approximately 150 milligrams.Ibuprofen discharges too fast in human body, cause blood concentration fluctuation larger, bring comparatively serious dyspepsia, stomach burn feeling, stomachache, feel sick, the side effect such as vomiting, limited to a certain extent its application, therefore people around the dissolubility of ibuprofen, hide the aspects such as taste and sustained release performance and launch deep research.Patent CN102423490B reported ibuprofen and houghite nano hybrid preparation method and for medicine carrying, conveying and the release control of ibuprofen, but the regulation and control aspect of rate of release is still not ideal enough.Patent CN102258791B has reported and has utilized cyclodextrin/Fe
3o
4the clathrate of magnetic Nano complex and ibuprofen, for the preparation of ibuprofen targeted drug, is positioned at diseased region and discharges under outside magnetic field effect, packaging medicine amount is only 5.66 ~ 10.25 milligrams every gram.Up to the present, utilize pharmaceutical carrier absorption or parcel ibuprofen in the quantity of medicine carrying and still not ideal enough aspect the Modulatory character of rate of release in granule.
Calcium phosphate is the main inorganic component of human teeth and bone, has good biocompatibility, and catabolite is friendly ion in body.Patent CN102552913B discloses calcium phosphate carrying hydrophobic drug and the hydrophilic protein matter medicine of nanostructured, realize medicine (ibuprofen and bovine serum albumin) and discharge lentamente from granule interior, shortcoming is that the degradation speed of preparation-obtained hydroxyapatite pharmaceutical carrier is excessively slow.Comparatively speaking, in calcium phosphate, the degradation speed of unformed calcium phosphate, calcium hydrogen phosphate and OCP is faster.When medicine carrying granule has drug release function, the degradation problem of pharmaceutical carrier in human body environment is more and more subject to the attention of research worker, and people expect that prepared medicine carrying granule can integrate the carrying of drug molecule, performance of control and the degradation property of release behavior.The degraded of the carrier chemical analysis to material, structure and residing solution environmental has dependence, about there is not yet report in the relevant research of the lower ibuprofen carrier to having readily degradable energy of pH neutral condition (as pH=7.2 ~ 7.4 of phosphorus buffer).
Summary of the invention
The preparation method that the object of this invention is to provide a kind of OCP double-layer compound particles containing ibuprofen, for achieving the above object, the technical solution adopted in the present invention step is as follows:
(1) preparation is containing the aqueous solution of Pidolidone, sodium hydrogen phosphate and sodium hydroxide, after stirring at room temperature is dissolved it completely, add successively again carbamide, lime nitrate and trisodium citrate, after solution stirring is even, transfer in the stainless steel autoclave containing ibuprofen and polyvinyl alcohol, under 100oC, hydro-thermal reaction is after 24 hours, filter, wash, under 60oC, be dried 12 hours, obtain the OCP granule containing ibuprofen;
(2) in the mixed solution of moisture and ethanol, add successively the pH value to 9 with ammonia regulator solution after citric acid, lime nitrate and diammonium phosphate, add subsequently Polyethylene Glycol, stirring reaction adds the alcoholic solution of the OCP granule containing ibuprofen obtaining containing ibuprofen and step (1) after 1 hour, then stirring reaction 3 hours;
(3) reaction solution step (2) being obtained is centrifugal, and with being dried 12 hours after washing with alcohol precipitum under 60oC, obtains the OCP double-layer compound particles containing ibuprofen.
Wherein, in step (1), the concentration of Pidolidone, sodium hydroxide and sodium hydrogen phosphate is respectively 0.091 mole every liter, 0.039 mole every liter and 0.024 mole every liter, the concentration of carbamide is 0.056 mole every liter, the concentration of lime nitrate is 0.026 mole every liter, the concentration of trisodium citrate is 0.013 mole every liter, polyvinyl alcohol is selected the polyvinyl alcohol 124 that molecular weight is 105000, and the addition of ibuprofen and polyvinyl alcohol and the mol ratio of lime nitrate are respectively: 1.65:1 and 1.22 × 10
-3: 1.After 24 hours, prepare the OCP granule containing ibuprofen through 100oC hydro-thermal reaction.
In step (2), the volume ratio of water and ethanol is 3:1, and the concentration of citric acid is 0.058 ~ 0.174 mM every liter, and best is 0.116 mM every liter.In solution, the concentration of lime nitrate and diammonium phosphate is respectively 0.0567 mM every liter and 0.0349 mM every liter.The molecular weight of Polyethylene Glycol is 400 ~ 6000, and concentration is every liter of 0.833 ~ 10 micromole, and the molecular weight of best Polyethylene Glycol is 2000, and its best concentration is every liter of 2.5 micromole.Adding the concentration of ibuprofen in the alcoholic solution of the OCP granule containing ibuprofen obtaining containing ibuprofen and step (1) is 20 grams every liter, and the concentration of granule is 10 grams every liter.Lime nitrate in step (2) is 4.31:1 with the mass ratio of the OCP granule containing ibuprofen.In the time regulating the pH value to 9 of reaction solution, calcium ion in solution and phosphoric acid hydrogen radical ion can generate OCP, under the synergism of citrate ion and Polyethylene Glycol, be deposited into the OCP particle surface containing ibuprofen, and then prepare the OCP double-layer compound particles containing ibuprofen.
Beneficial effect of the present invention is:
(1) this method technique is simple, cost of material is low and be easy to suitability for industrialized production;
(2) surface of the preparation-obtained OCP double-layer compound particles containing ibuprofen is Polyethylene Glycol, citric acid and calcium phosphate layer, good biocompatibility, and in human body fluid environment, easily degraded, can use safely;
(3) due to the special construction of the OCP double-layer compound particles containing ibuprofen, the time that ibuprofen molecule discharges from granule interior extends greatly, extends the ibuprofen time of staying in vivo, and then can increase substantially the systemic efficiency of body by being conducive to.
Brief description of the drawings
Fig. 1 is the X-ray diffraction spectrogram of granule.(a) the JCPDS standard card (being numbered 26-1056) of OCP; (b) the OCP granule containing ibuprofen that the step of the embodiment of the present invention 1 (1) prepares; (c) the OCP double-layer compound particles containing ibuprofen that the embodiment of the present invention 1 prepares.
Fig. 2 is the SEM electron scanning micrograph containing the OCP double-layer compound particles of ibuprofen that the embodiment of the present invention 1 prepares.
Fig. 3 is the behavior discharging in the OCP double-layer compound particles of ibuprofen that contains that ibuprofen prepares from the embodiment of the present invention 1 in different solutions.(a) phosphorus buffer (pH=7.2 ~ 7.4); (b) simulation lysosome buffer (pH=4.7).
Fig. 4 is the behavior discharging in the OCP granule of ibuprofen that contains that ibuprofen prepares from the step (1) of the embodiment of the present invention 1 in different solutions.(a) phosphorus buffer (pH=7.2 ~ 7.4); (b) simulation lysosome buffer (pH=4.7).
Detailed description of the invention
Further illustrate the present invention below in conjunction with embodiment.
Embodiment 1:
(1) preparation is containing the aqueous solution of 0.091 mole of every liter of Pidolidone, 0.024 mole of every liter of sodium hydrogen phosphate and 0.039 mole of every liter of sodium hydroxide, after stirring at room temperature is dissolved it completely, add successively again carbamide, lime nitrate and trisodium citrate, make its concentration be respectively 0.056,0.026 and 0.013 mole every liter, after stirring, transfer to containing ibuprofen and polyvinyl alcohol (polyvinyl alcohol 124, molecular weight is 105000) stainless steel autoclave in, the addition of ibuprofen and polyvinyl alcohol and the mol ratio of lime nitrate are respectively 1.65:1 and 1.22 × 10
-3: 1, under 100oC, process after 24 hours and be cooled to room temperature, after filtration, washing the dry OCP granule obtaining after 12 hours containing ibuprofen under 60oC;
(2) in the solution containing 138.3 ml waters and 46.1 milliliters of ethanol, add successively citric acid, lime nitrate and diammonium phosphate, make its concentration be respectively 0.116 mM every liter, 0.0567 mM every liter and 0.0349 mM every liter, use until completely dissolved the pH value to 9 of ammonia regulator solution, adding molecular weight is 2000 Polyethylene Glycol again, making its concentration is every liter of 2.5 micromole, stirring reaction adds the alcoholic solution of 40 milliliters of OCP granules containing ibuprofen that obtain containing ibuprofen and step (1) after 1 hour, wherein ibuprofen and the concentration containing the OCP granule of ibuprofen are respectively 20 grams every liter and 10 grams every liter, stirring reaction 3 hours again,
(3) reaction solution step (2) being obtained is centrifugal, and with obtain the OCP double-layer compound particles containing ibuprofen after washing with alcohol precipitum after dry 12 hours under 60oC.
Product is accredited as OCP (see figure 1) through X-ray powder diffraction.SEM scanning electron microscope testing product pattern (see figure 2).
0.02 gram of granule is put into the phosphorus buffer (pH=7.2 ~ 7.4) of 25 milliliters and the color comparison tube of the lysosomal buffer of simulation (pH=4.7) are housed, speed with 120 rpms under 37oC is shaken, the behavior (seeing Fig. 3 and Fig. 4) of measuring the OCP double-layer compound particles of the self-contained ibuprofen of ibuprofen and discharging containing the OCP granule interior of ibuprofen with UV-spectrophotometry.In addition, through UV-spectrophotometry test, be respectively 346 milligrams every gram and 177 milligrams every gram containing the OCP of ibuprofen with containing the parcel amount of the inner ibuprofen of OCP double-layer compound particles of ibuprofen.
By 0.10 gram of beaker that contains the OCP double-layer compound particles of ibuprofen and put into respectively the phosphorus buffer (pH=7.2 ~ 7.4) that is equipped with 125 milliliters containing the OCP granule of ibuprofen, under 37oC, with the speed shake of 120 rpms, measure the quality (m of granule after different time
t), with the initial mass (m of granule
0) obtain the degradation rate ((m of granule after comparing
0-m
t)/m
0).Up to 83.5%, and be only that after 20.8%, 48 hour, degradation rate also no longer changes containing OCP granule degradation rate after 6 hours of ibuprofen containing the OCP double-layer compound particles of ibuprofen degradation rate after 6 hours.
By 0.10 gram of beaker that contains the OCP double-layer compound particles of ibuprofen and put into respectively the lysosomal buffer of simulation (pH=4.7) that is equipped with 125 milliliters containing the OCP granule of ibuprofen, under 37oC, with the speed shake of 120 rpms, find to degrade completely through 1 hour and 24 hours respectively containing the OCP double-layer compound particles of ibuprofen with containing the OCP granule of ibuprofen.
The result of measuring shows, slowly, easily degrades in solution containing the OCP double-layer compound particles of ibuprofen containing OCP granule degraded in phosphorus buffer and the lysosomal buffer of simulation of ibuprofen.
Claims (8)
1. a preparation method that contains the OCP double-layer compound particles of ibuprofen, is characterized in that comprising the following steps:
1) preparation is containing the aqueous solution of Pidolidone, sodium hydrogen phosphate and sodium hydroxide, after stirring at room temperature is dissolved it completely, add successively again carbamide, lime nitrate and trisodium citrate, after solution stirring is even, transfer in the stainless steel autoclave containing ibuprofen and polyvinyl alcohol, under 100oC, hydro-thermal reaction is after 24 hours, filter, wash, under 60oC, be dried 12 hours, obtain the OCP granule containing ibuprofen;
(2) in the mixed solution of moisture and ethanol, add successively the pH value to 9 with ammonia regulator solution after citric acid, lime nitrate and diammonium phosphate, add subsequently Polyethylene Glycol, stirring reaction adds the alcoholic solution of the OCP granule containing ibuprofen obtaining containing ibuprofen and step (1) after 1 hour, then stirring reaction 3 hours;
(3) reaction solution step (2) being obtained is centrifugal, and with being dried 12 hours after washing with alcohol precipitum under 60oC, obtains the OCP double-layer compound particles containing ibuprofen.
2. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, it is characterized in that: in step (1), the concentration of Pidolidone, sodium hydrogen phosphate, sodium hydroxide, carbamide, lime nitrate and trisodium citrate is respectively 0.091,0.024,0.039,0.056,0.026 and 0.013 mole every liter, and the addition of ibuprofen and polyvinyl alcohol and the mol ratio of lime nitrate are respectively 1.65:1 and 1.22 × 10
-3: 1.
3. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, it is characterized in that: in step (2), the volume ratio of water and ethanol is 3:1, and the concentration of lime nitrate and diammonium phosphate is respectively 0.0567 mM every liter and 0.0349 mM every liter.
4. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, is characterized in that: in step (2), the concentration of citric acid is 0.058 ~ 0.174 mM every liter.
5. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, is characterized in that: in step (2), the concentration of Polyethylene Glycol is every liter of 0.083 ~ 10 micromole.
6. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, is characterized in that: in step (2), the molecular weight of Polyethylene Glycol is 400 ~ 6000 grams every mole.
7. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, it is characterized in that: when the solution of the OCP granule that contains ibuprofen preparing with ethanol preparation steps (1) in step (2), the mass concentration of granule is 10 grams every liter, and the concentration that adds ibuprofen is 20 grams every liter.
8. the preparation method of a kind of OCP double-layer compound particles containing ibuprofen according to claim 1, is characterized in that: in step (2), lime nitrate is 4.31:1 with the mass ratio of the OCP granule containing ibuprofen.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919948A (en) * | 2016-06-30 | 2016-09-07 | 山东理工大学 | Method for preparing ibuprofen microspheres by calcium phosphate precipitation assistance and normal pressure filtration |
| CN106110328A (en) * | 2016-06-30 | 2016-11-16 | 山东理工大学 | A kind of utilize calcium phosphate precipitation auxiliary improve ibuprofen method of dissolubility in water |
| CN106397181A (en) * | 2016-09-08 | 2017-02-15 | 山东理工大学 | Method for preparing long needle-like ibuprofen crystals from aqueous solution by adding sodium dodecyl sulfate |
| CN106420661A (en) * | 2016-09-20 | 2017-02-22 | 山东理工大学 | Preparation method of hydroxyapatite/tannic acid composite particles capable of rapidly releasing ibuprofen in acidic solution |
| CN106518655A (en) * | 2016-09-08 | 2017-03-22 | 山东理工大学 | Method for preparing flaky ibuprofen crystal by adding crystal-growing controlling agent into aqueous solution |
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| CN101979091A (en) * | 2010-11-04 | 2011-02-23 | 中国科学院上海硅酸盐研究所 | Preparation method of calcium phosphate nano medicament-carrying systems |
| WO2012089276A1 (en) * | 2010-12-31 | 2012-07-05 | Ahmet Cuneyt Tas | Preparation method of brushite and octacalcium phosphate granules |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919948A (en) * | 2016-06-30 | 2016-09-07 | 山东理工大学 | Method for preparing ibuprofen microspheres by calcium phosphate precipitation assistance and normal pressure filtration |
| CN106110328A (en) * | 2016-06-30 | 2016-11-16 | 山东理工大学 | A kind of utilize calcium phosphate precipitation auxiliary improve ibuprofen method of dissolubility in water |
| CN106397181A (en) * | 2016-09-08 | 2017-02-15 | 山东理工大学 | Method for preparing long needle-like ibuprofen crystals from aqueous solution by adding sodium dodecyl sulfate |
| CN106518655A (en) * | 2016-09-08 | 2017-03-22 | 山东理工大学 | Method for preparing flaky ibuprofen crystal by adding crystal-growing controlling agent into aqueous solution |
| CN106397181B (en) * | 2016-09-08 | 2019-01-01 | 山东理工大学 | A method of long needle-shaped ibuprofen crystal being prepared from aqueous solution by adding lauryl sodium sulfate |
| CN106518655B (en) * | 2016-09-08 | 2019-01-04 | 山东理工大学 | A method of sheet ibuprofen crystal being prepared from aqueous solution by adding crystal control agent |
| CN106420661A (en) * | 2016-09-20 | 2017-02-22 | 山东理工大学 | Preparation method of hydroxyapatite/tannic acid composite particles capable of rapidly releasing ibuprofen in acidic solution |
| CN106420661B (en) * | 2016-09-20 | 2019-04-16 | 山东理工大学 | A kind of hydroxyapatite/tannic acid composite particles preparation method of the brufen of quick release in an acidic solution |
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