CN1341674A - Preparation method of bio-degradable material epsilon-polycaprolactone for medicine - Google Patents
Preparation method of bio-degradable material epsilon-polycaprolactone for medicine Download PDFInfo
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- CN1341674A CN1341674A CN01129727A CN01129727A CN1341674A CN 1341674 A CN1341674 A CN 1341674A CN 01129727 A CN01129727 A CN 01129727A CN 01129727 A CN01129727 A CN 01129727A CN 1341674 A CN1341674 A CN 1341674A
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- polycaprolactone
- degradable material
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Abstract
The present invention relates to a new method for preparing medicinal biodegradable material epsilon-polycaprolactone. Said material is obtained by means of self-body ring-opening polymerization in the presence of initiator Ti(OBu)4. The infrared, NMR and DSC determinations, show that the epsilon-polycaprolactone made up by adopting said invented method and the epsilon-polycaprolactone made up by adopting traditional method are identical in structure and properties, Its structure formula is (I)[CH2]5-Co-O]n-H, it can be used as carrier for several modern medicine preparations.
Description
Technical field
The present invention relates to the preparation of drug carriers method, particularly a kind of novel preparation method of medicine Biodegradable material ε-polycaprolactone.
Background technology
Preparation ε-polycaprolactone material just has report as far back as the seventies, and initiator is mainly with stannous octoate or tin protochloride, and Belgian professor P.Teysiee uses bimetal oxo bridge alkoxide, and 96 years abroad report with Zn again is initiator.
The purpose of this invention is to provide a kind of with Ti (OBu)
4Be initiator, make the novel preparation method of inexpensive, stable, easy preservation, the manageable medicinal organism degradable material of condition ε-polycaprolactone.
Summary of the invention
The objective of the invention is to be achieved by the following scheme: form by degradable material ε-polycaprolactone, it is characterized in that: with butyl (tetra) titanate Ti (OBu)
4Be initiator, the body ring-opening polymerization forms.
Above-mentioned invention is under specific reaction conditions, with Ti (OBu)
4Be initiator, ring-opening polymerization, product is through counting the step purification and getting.
Above-mentioned concrete steps are:
1. monomer ε-CL is through CaH
2Or anhydrous CaCl
2Drying is in high-purity N
2Protection underpressure distillation down, b
p=94 ℃/650Pa;
2. drying is good there-necked flask heats repeatedly, vacuumizes, and fills N
2, 3 times repeatedly, and keep there-necked flask all the time at N
2Protection down;
3. add the monomer of purifying and the initiator of metering, flask is dipped in the oil bath, and magnetic stirring apparatus stirs under temperature control;
4. purification step is: synthetic head product dissolves through toluene, with heptane precipitation under 5～8 times of volumes, leaves standstill 24h in 5 ℃, suction filtration, vacuum-drying is with a certain amount of chloroform dissolving, add the HCl acidifying,, leave standstill with the extraction agent extraction, separate two-phase, with distilled water wash organic phase 3～5 times, with the precipitation agent precipitation, 5 ℃ leave standstill 24h, filter, dry at a certain temperature 24h is to constant weight.
Advantage is: the polycaprolactone of preparation (PCL) material physical and chemical index is:
1. appearance luster (visual inspection): white random solid.
2. proportion (suspension method 25 ℃ measure down): 1.16-1.22g/cm
3
3. molecular-weight average (GPC measure, THF solvent, PS are standard specimen):
Mn＝5000～30000
4. acid number (PH acidometer) PH=6.5～7.5
⑤Tm＝63℃ Tg＝59℃
6. thermostability (TGA thermogravimetric analysis, N
2Protection): 240 ℃ are not decomposed, or conventional
Autoclave sterilization does not decompose for 132 ℃.
7. fugitive constituent (80 ℃ of vacuum-drying 24h) should be less than 0.5%.
8. the PCL crystalline structure is a rhombic system, P222 (D
2 4) spacer, unit cell parameters
a＝0.7472nm b＝0.4995nm c＝1.7050nm
9. acute, the chronic toxicity test of whole body, cell toxicity test, intracutaneous stimulates, subcutaneous,
Muscle implantation test all according to the ISO standard, with the State Standard of the People's Republic of China-
Medicine equipment biological assessment GB/T 16886.1-1997 standard.
The specific embodiment
Embodiment 1
The there-necked flask that drying is good heats repeatedly, vacuumizes, and fills N2Three times, then in high-purity N2Protection is lower, and (concentration is [M] and Ti (OBu) to add ε-CL that purifying is good with syringe4(concentration is [I], and [M]/[I] is 100,100 ℃ of control temperature, and reaction time 4h, Head product dissolves through toluene, and the normal heptane precipitation after the vacuum drying, with the chloroform dissolving, adds the HCl acidifying, adds equal-volume 0.1mol/L EDTA extraction, leaves standstill, separate, and the distilled water washing, With the normal heptane precipitation, leave standstill, filtration drying is to constant weight, and productive rate is 88%, and the degree of polymerization is 33, Molecular weight Mn=3800.
Embodiment 2
The there-necked flask that drying is good heats repeatedly, vacuumizes, and fills N2Three times, then in high-purity N2Protection is lower, and (concentration is [M] and Ti (OBu) to add ε-CL that purifying is good with syringe4(concentration is [I], and [M]/[I] is 400,100 ℃ of control temperature, reaction time 4h, head product dissolves through toluene, and the normal heptane precipitation is after the vacuum drying, with the chloroform dissolving, add the HCl acidifying, add equal-volume 0.1mol/L EDTA extraction, leave standstill, separate, the distilled water washing, with the normal heptane precipitation, leave standstill, filtration drying is to constant weight, productive rate is 92%, and the degree of polymerization is 135, molecular weight Mn=1.6 * 104。
Embodiment 3
The there-necked flask that drying is good heats repeatedly, vacuumizes, and fills N2Three times, then in high-purity N2Protection is lower, and (concentration is [M] and Ti (OBu) to add ε-CL that purifying is good with syringe4(concentration is [I], and [M]/[I] is 800,100 ℃ of control temperature, reaction time 4h, head product dissolves through toluene, and the normal heptane precipitation is after the vacuum drying, with the chloroform dissolving, add the HCl acidifying, add equal-volume 0.1mol/L EDTA extraction, leave standstill, separate, the distilled water washing, with the normal heptane precipitation, leave standstill, filtration drying is to constant weight, productive rate is 86%, and the degree of polymerization is 236, molecular weight Mn=2.7 * 104。
Obtaining material with synthetic method of the present invention can be directly as the carrier of modern preparation, and the application implementation example has:
Application Example 1
Use solvent evaporated method, take nifedipine as the mould medicine, (Mn=2.6 * 10 take above-mentioned ε-PCL as base material4), medicine carries than being 1/2, obtains microsphere average grain diameter 150 μ m, reality Carry medication amount 28.8%, envelop rate is 87.3%, release in vitro 10 days, and cumulative release reaches 89.5%, release curve dynamics is between 0～1 grade.
Application Example 2
Use solvent evaporated method, take laruyl alcohol as activating agent, ε-PCL is base material (Mn=1.3 * 104), medicine carries than being 1/3, obtains microsphere average grain diameter 60 μ m, actual medicine carrying amount 18.5%, Envelop rate is 85.8%, release in vitro 4 days, and cumulative release reaches 82.7%, and the release curve is moving Mechanics is 0 grade of kinetics relation.
Claims (9)
1, a kind of novel preparation method of medicinal organism degradable material ε-polycaprolactone is made up of degradable material ε-polycaprolactone, it is characterized in that: with butyl (tetra) titanate Ti (OBu)
4Be initiator, the body ring-opening polymerization forms.
2, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 1 is characterized in that: under specific reaction conditions, with Ti (OBu)
4Be initiator, ring-opening polymerization, product is through counting the step purification and getting.
3, according to the described novel preparation method of claim 2, it is characterized in that: concrete steps are:
1. monomer ε-CL is through CaH
2Or anhydrous CaCl
2Drying is in high-purity N
2Protection decompression down
Distillation, b
p=94 ℃/650Pa;
2. drying is good there-necked flask heats repeatedly, vacuumizes, and fills N
2, 3 times repeatedly,
And keep there-necked flask all the time at N
2Protection down;
3. add the monomer of purifying and the initiator of metering, flask is dipped in the oil bath, and magnetic force stirs
Mixing device stirs under temperature control;
4. purification step is: synthetic head product dissolves through toluene, with heptane under 5～8 times of volumes
Precipitation leaves standstill 24h in 5 ℃, suction filtration, and vacuum-drying is dissolved with a certain amount of chloroform,
Add the HCl acidifying,, leave standstill, separate two-phase, with the distillation washing with the extraction agent extraction
Wash organic phase 3～5 times, with the precipitation agent precipitation, 5 ℃ leave standstill 24h, filter,
Dry 24h is to constant weight under the certain temperature.
4, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 3 is characterized in that: Heating temperature is 80 ℃～100 ℃ repeatedly.
5, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 3 is characterized in that: the reaction times is 4～6h.
6, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 3 is characterized in that: the initiator Ti (OBu) of metering
4Be 1/50～1/1000.
7, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 3 is characterized in that: extraction agent is EDTA, concentration range 0.01～0.5mol/L.
8, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 3 is characterized in that: precipitation agent is to wash positive heptan, and amount ranges is 8～20 times of organic phase.
9, the novel preparation method of medicinal organism degradable material ε-polycaprolactone according to claim 1 is characterized in that: ε-polycaprolactone material can directly be used as the carrier of various medicines.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01129727A CN1341674A (en) | 2001-10-09 | 2001-10-09 | Preparation method of bio-degradable material epsilon-polycaprolactone for medicine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01129727A CN1341674A (en) | 2001-10-09 | 2001-10-09 | Preparation method of bio-degradable material epsilon-polycaprolactone for medicine |
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|---|---|
| CN1341674A true CN1341674A (en) | 2002-03-27 |
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ID=4669398
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|---|---|---|---|
| CN01129727A Pending CN1341674A (en) | 2001-10-09 | 2001-10-09 | Preparation method of bio-degradable material epsilon-polycaprolactone for medicine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100347217C (en) * | 2006-02-21 | 2007-11-07 | 武汉天生成科技有限公司 | Production process of thermoplastic polycaprolactone |
| CN102134309A (en) * | 2011-02-24 | 2011-07-27 | 朱明强 | Preparation method of biodegradable material (polyester) |
| CN107163237A (en) * | 2017-05-27 | 2017-09-15 | 大连大学 | The method that hydrogen chloride/diethyl ether solution catalysis prepares PCL PDMS PCL stabilizers |
-
2001
- 2001-10-09 CN CN01129727A patent/CN1341674A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100347217C (en) * | 2006-02-21 | 2007-11-07 | 武汉天生成科技有限公司 | Production process of thermoplastic polycaprolactone |
| CN102134309A (en) * | 2011-02-24 | 2011-07-27 | 朱明强 | Preparation method of biodegradable material (polyester) |
| CN102134309B (en) * | 2011-02-24 | 2012-11-21 | 朱明强 | Preparation method of biodegradable material (polyester) |
| CN107163237A (en) * | 2017-05-27 | 2017-09-15 | 大连大学 | The method that hydrogen chloride/diethyl ether solution catalysis prepares PCL PDMS PCL stabilizers |
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