CN105997937A - Preparation method of 5-fluorouracil imprinted gel microspheres - Google Patents
Preparation method of 5-fluorouracil imprinted gel microspheres Download PDFInfo
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- CN105997937A CN105997937A CN201610516103.2A CN201610516103A CN105997937A CN 105997937 A CN105997937 A CN 105997937A CN 201610516103 A CN201610516103 A CN 201610516103A CN 105997937 A CN105997937 A CN 105997937A
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- fluorouracil
- styrene sulfonate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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Abstract
The invention belongs to the technical field of colon cancer positioning and treating medicines and macromolecule materials and in particular relates to a preparation method of 5-fluorouracil imprinted gel microspheres. The method comprises the following steps: adding aqueous phase formed by dissolving sodium p-styrenesulfonate used as a functional monomer, 5-fluorouracil used as a template molecule and N,N'-methylene bisacrylamide used as a cross-linking agent in distilled water into oil phase composed of ethyecellulose and methylbenzene, and reacting under a certain condition to generate the 5-fluorouracil imprinted gel microspheres. Targeting preparations prepared by the method are high in medicine loading capacity and can be positioned and released in the colon part; the curative effect is enhanced; the side effects of the medicine are reduced.
Description
Technical field
The invention belongs to colon cancer location medicine and the technical field of macromolecular material, be specifically related to 5-fluorouracil blot gel method for preparing microsphere.
Background technology
Along with the raising of people's living standard, the change of dietary structure, knot, the sickness rate of rectal cancer rise year by year, occupy the 4th～6 of tumor.And 5-fluorouracil is treatment knot, star's medicine of rectal cancer, can individually medication, it is also possible to drug combination.But it is low that 5-fluorouracil has bioavailability, toxic and side effects is big, and the most with injection administration, the compliance of patient is poor.In order to overcome the disadvantages mentioned above of 5-fluorouracil, improving knot, the therapeutic effect of rectal cancer, the colon-specific drug delivery system of 5-fluorouracil receives much concern (Rai G., Yadav A.K., Jain N. K., Agrawal G. P., Drug
Delivery, 2016,23:328).Medicine is positioned knot, the release of rectum position by this medicine-releasing system, can avoid the systemic Absorption of 5-fluorouracil, be greatly improved the drug level of diseased region local, reduce dosage, improve curative effect, reduce systemic side effects, reduce medical expense.
Gel micro-ball be have inside a class cross-linked structure, can the most swelling and undissolved micrograde polymer microsphere in aqueous medium.Gel micro-ball not only has the environment-responsive feature of large scale macroscopic view gel, when external environment (such as temperature, pH, solvent etc.) condition changes, gel micro-ball can quickly produce swelling-relieving distension respondent behavior, and there are the interfacial effect of uniqueness, skin effect, dimensional effect, bulk effect, seep effect etc., therefore gel micro-ball is at (Bekhit M., Sanchez-such as many field such as drug controlled release, material separation, environmental improvements
Gonzalez L.,
Ben Messaoud G., Desobry S. Journal of Food Engineering, 2016,180:1) field has important application.
At present report utilize gel to build 5-fluorouracil colon-specific drug delivery system mostly to be large scale hydrogel, water absorption and swelling is strong, but drug loading few (Xiao Yuliang, Duan Guiyun, Li Yuqin, the summer becomes a useful person, Zheng Lianying. advanced chemical engineering journal, 2011,25:123).The present invention uses the method for " via Inverse-Phase Suspension Polymerization with molecular engram synchronize carry out " to prepare one blot gel microsphere, and this microsphere had both had the water absorption and swelling of gel, and had again strong negative charge, can medicine carrying efficiently, it is also possible to realize colon positioning release.
Summary of the invention
The technical problem to be solved is: how to solve 5-fluorouracil colon positioning release process and there is water absorption and swelling by force, but the problem that drug loading is few.
The technical solution adopted in the present invention is: 5-fluorouracil blot gel method for preparing microsphere, and its step is as follows:
The first step, is placed in ethyl cellulose and toluene in container composition oil phase, is heated for a period of hours under uniform temperature.
Second step, by function monomer sodium p styrene sulfonate, template molecule 5-fluorouracil, cross-linking agent N, N '-methylene-bisacrylamide is dissolved in distilled water composition aqueous phase, under nitrogen protection, adds in the container to the first step；Add initiator, the lower stoichiometric number hour of constant temperature stirring, with the aqueous solution cyclic washing of the pH=11 containing 1mol/L NaCl, until ultraviolet detection does not go out in eluent to have template molecule 5-fluorouracil, again with ethanol, distilled water washs successively, is dried to constant weight, prepares 5-fluorouracil blot gel microsphere.
As a kind of optimal way: in the first step, the quality of toluene is 23～26 times of ethyl cellulose, and heating-up temperature is 60～70 DEG C, and heat time heating time is 0.5～2h.
As a kind of optimal way: in second step, oil phase with the volume ratio of aqueous phase is: 1.3/1～1.7/1, described monomer sodium p styrene sulfonate is strong anion electrolyte, the quality of distilled water is 6～7.5 times of described sodium p styrene sulfonate quality, N, the molal quantity of N '-methylene-bisacrylamide is the 1/14～1/12 of described sodium p styrene sulfonate, the molal quantity of 5-fluorouracil is the 1/9～1/5 of described sodium p styrene sulfonate, aqueous phase is added dropwise in oil phase, and time for adding is about 5 minutes.
As a kind of optimal way: in second step, initiator used is Ammonium persulfate., and the quality of Ammonium persulfate. is the 1.1%～1.3% of sodium p styrene sulfonate, and feed postition is for being added dropwise over, and time for adding is about 3 minutes.
As a kind of optimal way: mixing speed described in second step is 250～400 rpm, and reaction temperature is 60～70 DEG C, and the response time is 6～7h.
Advantages of the present invention and benefit are: (1), first with sodium p styrene sulfonate as function monomer, 5-fluorouracil is template molecule, N, N '-methylene-bisacrylamide is cross-linking agent, Ammonium persulfate. is initiator and distilled water constitutes aqueous phase；Toluene and ethyl cellulose constitute oil phase；Via Inverse-Phase Suspension Polymerization is used to prepare 5-fluorouracil blot gel microsphere；(2) 5-fluorouracil blot gel microsphere is along with pH increase, drug loading minimizing；(3) medicine carrying gel micro-ball have pH sensitivity and time stickiness, 5-fluorouracil can be avoided to discharge under one's belt, slightly discharge in small intestinal, colon site location release；(4) preparation technology of the present invention is simple, and raw material is cheap and easy to get, and the compliance of patient is high.
Detailed description of the invention
The invention provides a kind of novel, preparation technology simple oral colon cancer location preparation, (SSS) is received as function monomer with p styrene sulfonic acid, N, N'-methylene-bisacrylamide (MBA) is cross-linking agent, 5-fluorouracil is template molecule, Ammonium persulfate. is initiator, constitute aqueous phase, toluene be disperse medium, ethyl cellulose be that dispersant constitutes oil phase, the method using via Inverse-Phase Suspension Polymerization and molecular engram Tong Bu to carry out prepares gel micro-ball, eluted template molecule, it is thus achieved that 5-fluorouracil blot gel microsphere.By the swellability carrying medicament 5-fluorouracil of electrostatic interaction and gel micro-ball, medicine carrying blot gel microsphere does not the most discharge medicine, and in small intestinal, release amount is little, discharges in a large number at colon site.The method can reduce the dosage of 5-fluorouracil, improves the bioavailability of medicine, reduces the toxic and side effects of medicine.Preparation technology is simple, cheap, easily operates, and has the advantage such as stability well.
With example, 5-fluorouracil blot gel method for preparing microsphere is described below.
Example 1:
0.7g ethyl cellulose and 20mL toluene are placed in four-hole bottle composition oil phase, at 65 DEG C, heat 1.5 hours.By 2.0g sodium p styrene sulfonate, 0.13g 5-fluorouracil, 0.1142 g N, N '-methylene-bisacrylamide is dissolved in 10 mL distilled water composition aqueous phase, under nitrogen protection, drops to, in above-mentioned four-hole bottle, about drip 5min；Again 0.0243 g Ammonium persulfate. being dissolved in 3mL distilled water, dripping method is continuously added in four-hole bottle, about drips 3min, constant temperature 70 DEG C, divides with 250 rpm/, and the response time is 7h.With the aqueous solution cyclic washing of the pH=11 containing 1mol/L NaCl, until ultraviolet detection does not go out in eluent to have template molecule 5-fluorouracil, then with ethanol, distilled water washs successively, is dried to constant weight, prepares 5-fluorouracil blot gel microsphere.
Example 2:
0.7g ethyl cellulose and 20mL toluene are placed in four-hole bottle composition oil phase, at 70 DEG C, heat 1 hour.By 2.0g sodium p styrene sulfonate, 0.24g 5-fluorouracil, 0.1150 g N, N '-methylene-bisacrylamide is dissolved in 10 mL distilled water composition aqueous phase, under nitrogen protection, drops to, in above-mentioned four-hole bottle, about drip 5min；Again 0.0247 g Ammonium persulfate. being dissolved in 5mL distilled water, dripping method is continuously added in four-hole bottle, about drips 3min, constant temperature 60 DEG C, divides with 400 rpm/, and the response time is 6h.With the aqueous solution cyclic washing of the pH=11 containing 1mol/L NaCl, until ultraviolet detection does not go out in eluent to have template molecule 5-fluorouracil, then with ethanol, distilled water washs successively, is dried to constant weight, prepares 5-fluorouracil blot gel microsphere.
Example 3:
0.7g ethyl cellulose and 20mL toluene are placed in four-hole bottle composition oil phase, at 60 DEG C, heat 2 hours.By 2.0g sodium p styrene sulfonate, 0.2g 5-fluorouracil, 0.1147 g N, N '-methylene-bisacrylamide is dissolved in 10 mL distilled water composition aqueous phase, under nitrogen protection, drops to, in above-mentioned four-hole bottle, about drip 5min；Again 0.0245 g Ammonium persulfate. being dissolved in 2mL distilled water, dripping method is continuously added in four-hole bottle, about drips 3min, constant temperature 65 DEG C, divides with 300 rpm/, and the response time is 6.5h.With the aqueous solution cyclic washing of the pH=11 containing 1mol/L NaCl, until ultraviolet detection does not go out in eluent to have template molecule 5-fluorouracil, then with ethanol, distilled water washs successively, is dried to constant weight, prepares 5-fluorouracil blot gel microsphere.
Example 4:
0.7g ethyl cellulose and 20mL toluene are placed in four-hole bottle composition oil phase, at 65 DEG C, heat 1.5 hours.By 2.0g sodium p styrene sulfonate, 0.22g 5-fluorouracil, 0.1150 g N, N '-methylene-bisacrylamide is dissolved in 10 mL distilled water composition aqueous phase, under nitrogen protection, drops to, in above-mentioned four-hole bottle, about drip 5min；Again 0.0245 g Ammonium persulfate. being dissolved in 4 mL distilled water, dripping method is continuously added in four-hole bottle, about drips 3min, constant temperature 65 DEG C, divides with 350 rpm/, and the response time is 6.5h.With the aqueous solution cyclic washing of the pH=11 containing 1mol/L NaCl, until ultraviolet detection does not go out in eluent to have template molecule 5-fluorouracil, then with ethanol, distilled water washs successively, is dried to constant weight, prepares 5-fluorouracil blot gel microsphere.
5-fluorouracil blot gel microsphere drug carrying ability is studied
50 mg 5-fluorouracil gel micro-balls of precise examples detailed above 2 preparation add to the 5-fluorouracil solution of the pH=1 that 25mL initial concentration is 1.4mg/mL, 25 DEG C of constant temperature oscillation 2h, filter, measuring the absorbance of 5-fluorouracil in supernatant, being calculated 5-fluorouracil gel micro-ball to the drug loading of medicine 5-fluorouracil is 86.7mg/g.Again with 0.1mol/L hydrochloric acid cyclic washing to remove the 5-FU being attached to gel micro-ball surface, until ultraviolet detection is less than there is 5-FU in solution, vacuum drying obtains 5-FU medicine carrying blot gel microsphere.
The pH sensitivity Release behavior of 5-fluorouracil blot gel microsphere
0.05g medicine carrying blot gel microsphere is placed on pH=1(37 DEG C, 100mL, mixing speed be 100rpm/min) release medium in 12h, medicine does not discharges.
0.05g medicine carrying blot gel microsphere is placed on pH=6.8(37 DEG C, 100mL, mixing speed be 100rpm/min) release medium in 12h, the preparation of medicine is 48%.
0.05g medicine carrying blot gel microsphere is placed on pH=6.8(37 DEG C, 100mL, mixing speed be 100rpm/min) release medium in 12h, the preparation of medicine is 80%.
The pH sensitivity of 5-fluorouracil medicine carrying blot gel microsphere and time lag Journal of Sex Research
0.05g medicine carrying blot gel microsphere is placed sequentially in 100 mL temperature be 37 DEG C, mixing speed be 100rpm/min pH=1 HCl (simulated gastric fluid) in 2 h, pH=6.8 PBS(simulated intestinal fluids) in 3 h and pH=7.4 PBS(simulate colonic fluid) in 10 h.Medicine carrying blot gel microsphere 2h not release substantially in simulated gastric fluid, in simulated intestinal fluid, 3h preparation is 16%, and the 5～7h preparations proceeding to simulate in colonic fluid are 42%, and sustained drug discharges until 75% slowly afterwards.
Claims (5)
1.5-fluorouracil blot gel method for preparing microsphere, it is characterised in that carry out in accordance with the following steps:
The first step, is placed in ethyl cellulose and toluene in container composition oil phase, is heated for a period of hours under uniform temperature；
Second step, by function monomer sodium p styrene sulfonate, template molecule 5-fluorouracil, cross-linking agent N, N '-methylene-bisacrylamide is dissolved in distilled water composition aqueous phase, under nitrogen protection, adds in the container to the first step；Add initiator, the lower stoichiometric number hour of constant temperature stirring, with the aqueous solution cyclic washing of the pH=11 containing 1mol/L NaCl, until ultraviolet detection does not go out in eluent to have template molecule 5-fluorouracil, again with ethanol, distilled water washs successively, is dried to constant weight, prepares 5-fluorouracil blot gel microsphere.
5-fluorouracil blot gel method for preparing microsphere the most according to claim 1, it is characterised in that: in the first step, the quality of toluene is 23～26 times of ethyl cellulose, and heating-up temperature is 60～70 DEG C, and heat time heating time is 0.5～2h.
5-fluorouracil blot gel method for preparing microsphere the most according to claim 1, it is characterized in that: in second step, oil phase with the volume ratio of aqueous phase is: 1.3/1～1.7/1, described monomer sodium p styrene sulfonate is strong anion electrolyte, the quality of distilled water is 6～7.5 times of described sodium p styrene sulfonate quality, N, the molal quantity of N '-methylene-bisacrylamide is the 1/14～1/12 of described sodium p styrene sulfonate, the molal quantity of 5-fluorouracil is the 1/9～1/5 of described sodium p styrene sulfonate, aqueous phase is added dropwise in oil phase, time for adding is about 5 minutes.
5-fluorouracil blot gel method for preparing microsphere the most according to claim 1, it is characterized in that: in second step, initiator used is Ammonium persulfate., the quality of Ammonium persulfate. is the 1.1%～1.3% of sodium p styrene sulfonate, and feed postition is for being added dropwise over, and time for adding is about 3 minutes.
5-fluorouracil blot gel method for preparing microsphere the most according to claim 1, it is characterised in that: mixing speed described in second step is 250～400 rpm, and reaction temperature is 60～70 DEG C, and the response time is 6～7h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111036183A (en) * | 2018-10-15 | 2020-04-21 | 中国石油天然气股份有限公司 | Zirconium sulfate imprinted gel microspheres and preparation method thereof |
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| WO2012035561A2 (en) * | 2010-09-17 | 2012-03-22 | Lovely Professional University | Improved oral targetted drug delivery system |
| CN102895195A (en) * | 2012-07-20 | 2013-01-30 | 中北大学 | Preparation method of 5-fluorouracil molecular surface imprinting microsphere |
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- 2016-07-04 CN CN201610516103.2A patent/CN105997937A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012035561A2 (en) * | 2010-09-17 | 2012-03-22 | Lovely Professional University | Improved oral targetted drug delivery system |
| CN102895195A (en) * | 2012-07-20 | 2013-01-30 | 中北大学 | Preparation method of 5-fluorouracil molecular surface imprinting microsphere |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111036183A (en) * | 2018-10-15 | 2020-04-21 | 中国石油天然气股份有限公司 | Zirconium sulfate imprinted gel microspheres and preparation method thereof |
| CN111036183B (en) * | 2018-10-15 | 2023-03-24 | 中国石油天然气股份有限公司 | Zirconium sulfate imprinted gel microspheres and preparation method thereof |
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