CN1257887A - High-molecular material of poly-(2-hydroxybutyl)-DL-asparagine - Google Patents
High-molecular material of poly-(2-hydroxybutyl)-DL-asparagine Download PDFInfo
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- CN1257887A CN1257887A CN 98126272 CN98126272A CN1257887A CN 1257887 A CN1257887 A CN 1257887A CN 98126272 CN98126272 CN 98126272 CN 98126272 A CN98126272 A CN 98126272A CN 1257887 A CN1257887 A CN 1257887A
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Abstract
A high-molecular material poly-(2-hydroxybutyl)-DL-aspartamide (PHBA) is disclosed, which has its changed side chain to improve the lipophilicity, benefit the absorption and release of medicine in body and raise the biological utilization rate of medicine. It can be used as the precursor carrier of medicines, especially the long-acting release-controlled medicines.
Description
The invention belongs to macromolecular compound, especially belong to the polyamino acid macromolecular compound, can be applicable to pharmaceutics, pharmaceutical chemistry field, as the prodrug carrier.
The biocompatible polymer material that is used for the prodrug carrier in the market mainly contains the product of U.S. Signam company: poly--(hydroxyethyl)-DL-l-asparagine [Poly-(hydroxyethyl)-DL-aspartamide, PHEA], structural formula is:
It mainly can be used for plasma substitute, the prodrug carrier.This product side chain is NH
2-CH
2-CH
2-OH as pharmaceutical carrier, discharges comparatively slowly, is unfavorable for that medicine absorbs in vivo and discharges, and has also limited its range of application to a certain extent, and because of it is an imported product, has cost an arm and a leg, and every gram valency is 151.7 dollars.
The objective of the invention is to overcome the weak point that above-mentioned currently available products exists, provide a kind of lipotropy better, help multiple medicine bonding, and the biocompatible polymer material that absorbs in vivo, discharges gathers-(2-hydroxyl butyl)-DL-l-asparagine.
Macromolecular material provided by the invention, its chemistry is by name: poly--(2-hydroxyl butyl)-DL-l-asparagine [Poly-(2-hydroxybutyl)-DL-aspartamide, PHBA], molecular weight is 8.0 * 10
5Structural formula is
Product of the present invention has increased the lipotropy of product by the change of side chain radical, helps medicine absorption in vivo and release, is suitable for multiple medicine, has widened the purposes of this material.In addition, on price, be significantly less than external like product.Make prodrug behind the product bonding medicine of the present invention and can be used as the long-acting controlled release medicine, and improve bioavailability of medicament.
The present invention is further described by following examples.
Embodiment 1: the preparation of poly--(2-hydroxyl butyl)-DL-l-asparagine
In flask, will count the gram polysuccinimide and be dissolved in a certain amount of dimethyl formamide (DMF), under agitation add a certain amount of 2-amino butanol, stoichiometric number hour is separated out precipitation in ethyl acetate solution at ambient temperature, is washed till neutrality, drain, promptly get the white powder product.Reaction product is weighed: 9.8g, should calculate by poly-DL-succimide monomer and 2-amino butanol branch: the monomer molecule amount is: 97, the 2-amino butanol: 88, so theoretical product should have 11.44g (=185 * 6 ÷ 97).So yield is: 9.8/11.44 * 100%=85.7%.
With infrared spectra, nucleus magnetic resonance
1HNMR,
13CNMR, differential thermal analysis characterize material.Material through repeatedly dialysing with dialysis tubing after the washing precipitation, is obtained the narrower superpolymer of molecular weight distribution, is relative molecular weight with dextran standard, and recording its molecular weight with gel chromatography is 8.0 * 10
5
Structural formula is
Embodiment 2: phenylformic acid-PHBA medicine synthetic
Product of the present invention is synthetic as prodrug carrier and phenylformic acid:
In a dry Florence flask, add a certain amount of phenylformic acid and benzotriazole, with a certain amount of DMF and CHCl
3Make its dissolving in the mixing solutions, other gets a certain amount of N, and N-dicyclohexyl carbimide (DCCI) is used CHCl
3Dissolving merges two liquid under ice bath stirs, the adularescent precipitation produces, suction filtration, and concentrated filtrate, the adularescent crystal is separated out, and promptly gets phenylformic acid-benzotriazole.
In a dry ground Florence flask, add 0.4g (0.002mol) PHBA and 0.5g (0.002mol) phenylformic acid-benzotriazole, add 1.0ml DMF, stir and make its dissolving; Add 0.2g triethylamine (Et again
3N), reaction solution is splashed in the 100ml ethyl acetate, have precipitation to produce.Suction filtration, oven dry, porphyrize.Reaction process thin-layer chromatography follow-up investigations, product do not see that through the thin layer inspection free phenylformic acid exists.This medicine can be used as sterilizing agent.Structural formula is
Embodiment 3: para-amino benzoic acid-PHBA medicine synthetic
In a dry Florence flask, add a certain amount of benzaminic acid and benzotriazole, with a certain amount of DMF and CHCl
3Make its dissolving in the mixing solutions, other gets a certain amount of DCCI CHCl
3Dissolving merges two liquid under ice bath stirs, the adularescent precipitation produces, suction filtration, and concentrated filtrate, the adularescent crystal is separated out, and promptly gets benzaminic acid-benzotriazole.
In a dry ground Florence flask, take by weighing 0.2g (0.0013mol) PHBA and 0.3g (0.0013mol) para-amino benzoic acid-benzotriazole, add 1.0ml DMF, stir and make its dissolving; Add 0.1g Et again
3N behind the stirring reaction 48hr., under agitation, splashes into reaction solution in the 100ml acetone under the room temperature, has precipitation to produce.Filter oven dry, porphyrize.Reaction process thin-layer chromatography follow-up investigations, product are not seen free to the stupid formic acid existence of amino through the thin-layer chromatography inspection.This medicine can be used as sterilizing agent.Structural formula is
Embodiment 4: nicotinic acid-PHBA's is synthetic
Add a certain amount of nicotinic acid and benzotriazole in a dry Florence flask, with a certain amount of methyl-sulphoxide dissolving, other gets a certain amount of DCCI CHCl
3Dissolving merges two liquid under ice bath stirs, the adularescent precipitation produces, suction filtration, and concentrated filtrate, cooling adds a spot of CHCl
3, get the beige product, promptly get nicotinic acid-benzotriazole.
In a dry ground Florence flask, take by weighing 0.4g (0.002mol) PHBA and 0.5g (0.002mol) nicotinic acid-benzotriazole, add 1.0ml DMF, stir and make its dissolving; Add 0.2g (0.002mol) Et again
3N behind the stirring reaction 48hr., under agitation, splashes into reaction solution in the 100ml ethyl acetate under the room temperature, has precipitation to produce.Filter oven dry, porphyrize.Reaction process thin-layer chromatography follow-up investigations, product do not see that through the thin-layer chromatography inspection free nicotinic acid exists.Structural formula is
Embodiment 5: Ibuprofen BP/EP-PHBA's is synthetic:
In a dry Florence flask, add a certain amount of Ibuprofen BP/EP and benzotriazole, with a certain amount of DMF and CHCl
3Make its dissolving in the mixing solutions, other gets a certain amount of DCCI CHCl
3Dissolve, merge two liquid under ice bath stirs, the adularescent precipitation produces, suction filtration, and concentrated filtrate gets brown oil, is Ibuprofen BP/EP-benzotriazole.
In a dry ground Florence flask, take by weighing 2.0g (0.0112mol) PHBA and 3.2g (0.0112mol) Ibuprofen BP/EP-benzotriazole, add 5.0ml DMF, stir and make its dissolving; Add 1.1g (0.0112mol) Et again
3N behind the stirring reaction 48hr., under agitation, splashes into reaction solution in the 100ml distilled water under the room temperature, has precipitation to produce.Filter oven dry, porphyrize.The follow-up investigations of reaction process thin-layer chromatography, product do not see that through the thin-layer chromatography inspection free Ibuprofen BP/EP exists.This medicine has antipyretic-antalgic, antiinflammation.Structural formula is
Embodiment 6: Naproxen Base-PHBA's is synthetic:
In a dry Florence flask, add a certain amount of Naproxen Base and benzotriazole, with a certain amount of DMF and CHCl
3Make its dissolving in the mixing solutions, other gets a certain amount of DCCI CHCl
3Dissolve, merge two liquid under ice bath stirs, the adularescent precipitation produces, suction filtration, and concentrated filtrate gets brown oil, adds methyl alcohol while hot, cooling, the adularescent crystal is separated out, and is Naproxen Base-benzotriazole.
In a dry ground Florence flask, take by weighing 0.4g (0.0223mol) PHBA and 0.7g (0.00223mol) Naproxen Base-benzotriazole, add 2.0ml DMF, stir and make its dissolving; Add 0.2g (0.00223mol) Et again
3N behind the stirring reaction 48hr., under agitation, splashes into reaction solution in the 100ml ethyl acetate under the room temperature, has precipitation to produce.Filter oven dry, porphyrize.The follow-up investigations of reaction process thin-layer chromatography, product does not see that through the thin-layer chromatography inspection the general existence of free naphthalene exists.This medicine has antipyretic-antalgic, antiinflammation.Structural formula is
Above-mentioned each bonding medicine is carried out the inside and outside release experiment, and the result shows that faster than the medicine release of using the PHEA bonding with the medicine of PHBA material bonding, the while easily is distributed in the lipid layer, and makes drug absorption better because the lipotropy of material of the present invention is better.
Claims (1)
1, a kind of bioabsorbable polymer material gathers-(2-hydroxyl butyl)-DL-l-asparagine, it is characterized in that with the poly-asparagine being parent, connect 2-hydroxyl butyl on side chain, its English chemical name is: Poly-(2-hydroxybutyl)-DL-aspartamide (PHBA), molecular weight is 8.0 * 10
5, structural formula is
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98126272A CN1089348C (en) | 1998-12-24 | 1998-12-24 | High-molecular material of poly-(2-hydroxybutyl)-DL-asparagine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98126272A CN1089348C (en) | 1998-12-24 | 1998-12-24 | High-molecular material of poly-(2-hydroxybutyl)-DL-asparagine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1257887A true CN1257887A (en) | 2000-06-28 |
| CN1089348C CN1089348C (en) | 2002-08-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN98126272A Expired - Fee Related CN1089348C (en) | 1998-12-24 | 1998-12-24 | High-molecular material of poly-(2-hydroxybutyl)-DL-asparagine |
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Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS253069B1 (en) * | 1984-11-09 | 1987-10-15 | Jaroslav Drobnik | Macromolecular anticarcinogenetic remedy containing platinum and method of its production |
| US4812532A (en) * | 1987-07-29 | 1989-03-14 | Bio-Affinity Systems, Inc. | Solid phase oxime reagent |
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1998
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