CN1200028C - Polyasparamide derivative and process for preparing its nano capsules - Google Patents
Polyasparamide derivative and process for preparing its nano capsules Download PDFInfo
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- CN1200028C CN1200028C CNB02111451XA CN02111451A CN1200028C CN 1200028 C CN1200028 C CN 1200028C CN B02111451X A CNB02111451X A CN B02111451XA CN 02111451 A CN02111451 A CN 02111451A CN 1200028 C CN1200028 C CN 1200028C
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Abstract
The present invention relates to a polyasparamide derivative and a method for preparing a nanometer capsule thereof. The polymer does not exist in the prior art, and the report of a nanometer capsule prepared from the polymer is not heard. The polyasparamide derivative of the present invention contains hydrophilic N-low grade aliphatic radical asparamide repeating units, hydrophobic asparamide repeating units or N-high grade aliphatic radical or aryl radical asparamide repeating units. The polymer is dissolved into an organic solvent by using the hydrophilic and hydrophobic characteristics of the polymer, and is dropped into a certain amount of water, a nanometer grade capsule can be prepared. A medicament can be wrapped in the preparation process of the nanometer grade capsule to achieve a controlled release purpose. The nanometer grade capsule has a favorable effect. The present invention has the advantages of simple and convenient method, low cost and wide application.
Description
Technical field
The invention discloses a kind of polymkeric substance (polyasparamide derivative) that contains the repeating unit of short-chain alkyl side group to small part that has, the synthetic method of this polymkeric substance, and by the Nano capsule of this base polymer preparation.
Background technology
Polyamino acid has the biocompatibility of height, nontoxic, characteristics such as can degrade voluntarily, and the research of polyamino acid material, development and application have become the focus in the field of new, wherein being most widely used with poly-asparagine and derivative thereof.The poly-asparagine synthesis technique is simple, and the productive rate height is easy to industrialization most in each seed amino acid, so poly-asparagine all is widely used in fields such as coating, water conditioner, washing composition, makeup and pharmaceutical carriers.Because polyasparamide derivative has the advantage of temperature sensitivity, soda acid susceptibility and close and distant water sensitivity, and be easy to transport in vivo, degraded, metabolism, therefore can be used as good controlled capability pharmaceutical carrier.The polymer materials that is used for pharmaceutical carrier in the market with biocompatibility, main form carrying medicament with chemical bonding, drug effect is affected on the one hand, be unfavorable for medicine slowly-releasing in vivo on the other hand, thereby coat or the carrier of the form carrying medicament of absorption has more development prospect with physics.
Summary of the invention
First purpose of the present invention provides a kind of novel polyasparamide derivative that can be used for pharmaceutical carrier.Second purpose of the present invention provides easy, effective means, with above-mentioned polymer manufacture stabilized nano capsule.The 3rd purpose of the present invention is that polymkeric substance of the present invention is used for pharmaceutical carrier.
The polyasparamide derivative structural formula that the present invention obtains is shown in (1):
H
2N-R
1 (6)
H
2N-R
2 (7)
R in the formula
1Be the lower aliphatic alkyl of 1-6 carbon atom, R
1Specific examples comprise alkyl, as methyl, ethyl, propyl group, butyl, amyl group, hexyl; Hydroxyalkyl is as methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl, hydroxyl amyl group, hydroxyl hexyl.R
2Be the senior aliphatic group or the aryl radical of 8-24 carbon atom.N=0～99mol% in the formula, x=1～100mol%, m=0～99mol%.Poly-asparagine shown in the formula (5) be by aspartic acid under 200 ℃ temperature, the phosphoric acid with 85% is catalyzer, the polymkeric substance that obtained in condensation 2-3 hour, molecular weight be 5,000-50 between 000, becomes with reaction conditions is different.Be prior art, this technical field technician all can realize.
The present invention is an analog derivative that produces based on poly-asparagine.The method for preparing this polyasparamide derivative is that the low-grade aliphatic amine reaction shown in poly-asparagine shown in the through type (5) and the formula (6) obtains, and perhaps the reaction of the alkylamine shown in low-grade aliphatic amine shown in poly-asparagine shown in the formula (5) and the formula (6) and the formula (7) obtains required polymkeric substance (1).Difference according to R1, R2 group in formula (6), the formula (7) can obtain having the derivative of different hydrophilic, hydrophobic property groups, optionally with conveniently decides.Reaction method is this technical field prior art, seldom gives unnecessary details.N-lower aliphatic alkyl l-asparagine repeating unit possess hydrophilic property shown in the formula (2), and senior aliphatic group of N-shown in formula (3) and the formula (4) or aryl radical l-asparagine repeating unit and l-asparagine repeating unit have hydrophobicity.The amphipathic polymkeric substance of this class can be assembled the capsule that forms nanoscale in water, have senior aliphatic group of hydrophobic N-or aryl radical l-asparagine repeating unit and l-asparagine repeating unit and be gathered into hydrophobic nuclear, the N-lower aliphatic alkyl l-asparagine repeating unit of possess hydrophilic property then constitutes hydrophilic shell, to keep capsular stable.
The realization of above-mentioned second purpose be by: the polyasparamide derivative shown in the formula (1) is dissolved in a kind of organic solvent that can dissolve each other with water or two kinds and the two or more organic solvent that can dissolve each other with water, organic solvent is for example: N, dinethylformamide, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), make the solution of polyasparamide derivative, above-mentioned solution slowly is added drop-wise in the water of 10-1000 times of volume under violent stirring or sonic oscillation, the dispersion system that obtains dialysed in water remove organic solvent, obtain stable polyasparamide derivative Nano capsule at last.
Polyasparamide derivative can be dissolved in N, dinethylformamide, methyl alcohol, ethanol, in the dimethyl sulfoxide (DMSO) equal solvent, also can be in them in the wantonly mixed solvent more than two kinds these solvent solubilities good, conveniently be easy to get.
Above-mentioned polymers soln is added drop-wise in the water of 10-10000 times of volume, can obtains the stabilized nano capsule.
If polymers soln is added drop-wise to 100-1, in the water of 000 times of volume, obtains the capsular better effects if of stabilized nano, and greatly facilitate technological operation.Violent stirring or sonic oscillation better effects if when dripping.
Violent stirring or sonic oscillation were advisable with 0.1～1.0 hour.
In order to remove organic solvent, the 1-7 days time of dialysing can effectively be removed organic solvent like this for well, can improve preparation efficiency again.
Can obtain the polymer nanocomposite capsule that particle diameter is the 10-1000 nanometer as above-mentioned method.
The present invention adds medicine in polymer dissolution simultaneously in organic solvent, and for example the cancer therapy drug nimodipine after treating to dissolve fully, is added drop-wise in the excessive water, and organic solvent is removed in dialysis then, promptly obtains the Nano capsule of carrying medicament.The slowly-releasing and the controlled-release effect of medicine are better than chemical bonding behind the formation capsule.
The Nano capsule of the polyasparamide derivative that the present invention obtains can be as the additive of coating or makeup.
The Nano capsule of the polyasparamide derivative that the present invention obtains can be used for water conditioner or washing composition.
The present invention is main raw material with the poly-asparagine, because it is synthetic conveniently, productive rate is high, be easy to industrialization, so cost is not high, wide material sources.The present invention makes the derivative with good hydrophilic, hydrophobic property advantage according to the differential responses thing that adds, and such polymer derivant is easy to transport in vivo and metabolism, therefore has bright development prospect as pharmaceutical carrier.The inventive method is simple, and cost is not high, and the Nano capsule carrying medicament of acquisition is respond well, is the ideal carrier of physically trapping of new generation or absorption medicine.
Specific implementation method
The present invention is described further by following example, but these embodiments do not limit protection scope of the present invention.
Example 1.
The preparation of polyasparamide derivative A:
Obtain poly-asparagine with the polymerization of L-aspartic acid, take by weighing 1.0g poly-asparagine (the about 0.01mol of repeating unit mole number), be dissolved in 10ml N, in the dinethylformamide, in 0 ℃ of ice bath, dropwise add the 1.36mL normal hexyl Amine, drip in 25 ℃ of water-baths of back immigration and reacted 8 hours.Reaction solution precipitates in acetone/normal hexane mixed precipitant, and repetitive scrubbing is drained, productive rate 97.4%.
1HNMR analysis revealed product structure is the polyasparamide derivative shown in the formula (7), and the molecular fraction of repeating unit (1) is 48%, and the molecular fraction of repeating unit (3) is 52%.
Example 2.
The preparation of polyasparamide derivative B:
Take by weighing the 1.0g poly-asparagine, be dissolved in 10mL N, in the dinethylformamide, in 0 ℃ of ice bath, dropwise add the 0.28mL Tri N-Propyl Amine, drip in 25 ℃ of water-baths of back immigration and reacted 8 hours.Reaction solution precipitates in acetone/normal hexane mixed precipitant, and repetitive scrubbing is drained, productive rate 95.4%.
1HNMR analysis revealed product structure is the polyasparamide derivative shown in the formula (7), and the molecular fraction of repeating unit (1) is 30%, and the molecular fraction of repeating unit (2) is 40%, and the molecular fraction of repeating unit (3) is 30%.
Example 3.
The preparation of polyasparamide derivative C:
Take by weighing positive two tetradecy lamines of 1.0g poly-asparagine and 0.365g, be dissolved in 10mL N, in the dinethylformamide, reaction is 72 hours in 100 ℃ of oil baths.After the reaction solution cooling, dropwise add the 1.70ml Tri N-Propyl Amine in 0 ℃ of ice bath, drip in 25 ℃ of water-baths of back immigration and reacted 8 hours.Reaction solution precipitates in acetone/normal hexane mixed precipitant, and repetitive scrubbing is drained, productive rate 97.3%.
1HNMR analysis revealed product structure is the polyasparamide derivative shown in the formula (7), and the molecular fraction of repeating unit (1) is 92%, and the molecular fraction of repeating unit (2) is 8%.
Example 4.
The preparation of polyasparamide derivative C:
Take by weighing the positive amino dodecane of 1.0g poly-asparagine and 0.382g, be dissolved in 10mL N, in the dinethylformamide, reaction is 8 hours in 100 ℃ of oil baths.After the reaction solution cooling, dropwise add the 1.70ml Tri N-Propyl Amine in 0 ℃ of ice bath, drip in 25 ℃ of water-baths of back immigration and reacted 8 hours.Reaction solution precipitates in acetone/normal hexane mixed precipitant, and repetitive scrubbing is drained, productive rate 98.1%.
1HNMR analysis revealed product structure is the polyasparamide derivative shown in the formula (7), and the molecular fraction of repeating unit (1) is 81%, and the molecular fraction of repeating unit (2) is 19%.
Example 5.
The preparation of polyasparamide derivative Nano capsule I:
Take by weighing 0.1g polyasparamide derivative A, be dissolved in 1mL N, in the dinethylformamide, under the violent stirring, slowly be added dropwise in the 10mL water and sonic oscillation 0.1 hour, transferred in the dialysis tubing dialysis 3 days, obtain the stabilized nano capsule.The laser light scattering characterization result shows that capsule grain diameter is 26.4 nanometers.
Example 6.
The preparation of polyasparamide derivative Nano capsule II:
Take by weighing 0.1g polyasparamide derivative B, be dissolved in N, in the dinethylformamide, add 900mL water, violent stirring 1 hour left standstill 3 days, obtained the stabilized nano capsule.The laser light scattering characterization result shows that capsule grain diameter is 35.4 nanometers.
Example 7.
The preparation of polyasparamide derivative Nano capsule III:
Take by weighing 0.1g polyasparamide derivative C, be dissolved in N, in the dinethylformamide, add 500mL water, sonic oscillation 0.5 hour left standstill 7 days, obtained the stabilized nano capsule.The laser light scattering characterization result shows that capsule grain diameter is 79.3 nanometers.
Example 8.
Method with polyasparamide derivative Nano capsule embedding medicinal:
Take by weighing 50mg polyasparamide derivative A and 20mg nimodipine, be dissolved in N, in the dinethylformamide, add 20mL water, stirred 0.5 hour, left standstill 1 day, obtain the stable Nano capsule that is embedded with medicine.
Claims (11)
1. polyasparamide derivative is characterized in that polymer molecular structure is as described below:
R in the formula
1Be the lower aliphatic alkyl of 1-6 carbon atom, R
2Be the aliphatic group or the aryl radical of 8-24 carbon atom, n=0～99mol% in the formula, x=1～100mol%, m=0～99mol%.
2. the Nano capsule of polyasparamide derivative according to claim 1 is characterized in that the capsular particle diameter of polymer nanocomposite is between the 10-1000 nanometer.
3. the preparation method of polyasparamide derivative Nano capsule according to claim 2, the preparation method who it is characterized in that its Nano capsule is dissolved in polymkeric substance in the organic solvent, be added drop-wise to then in the excessive water, organic solvent is removed in dialysis, obtains the stabilized nano capsule.
4. the preparation method of polyasparamide derivative Nano capsule according to claim 3 is characterized in that polymer dissolution at N, in dinethylformamide or methyl alcohol or ethanol or dimethyl sulfoxide (DMSO) or their mixed solvent.
5. the preparation method of polyasparamide derivative Nano capsule according to claim 3 is characterized in that polymers soln is added drop-wise in the water of 10-10000 times of volume.
6. the preparation method of polyasparamide derivative Nano capsule according to claim 3 is characterized in that polymers soln is added drop-wise to 100-1, in the water of 000 times of volume, and violent stirring or sonic oscillation.
7. the preparation method of polyasparamide derivative Nano capsule according to claim 6 is characterized in that polymers soln added in the entry and violent stirring or sonic oscillation 0.1～1.0 hour.
8. the preparation method of polyasparamide derivative Nano capsule according to claim 3 is characterized in that dialysing 1-7 days, to remove organic solvent.
9. the preparation method of polyasparamide derivative Nano capsule according to claim 3 is characterized in that polymkeric substance is dissolved in organic solvent adds medicine simultaneously, is added drop-wise to then in the excessive water, and the organic solvent of dialysing away obtains the Nano capsule of carrying medicament.
10. the described polyasparamide derivative of claim 1 is as the Application of Additives of coating or makeup.
11. the described polyasparamide derivative of claim 1 is as the application of water conditioner or washing composition.
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| CNB02111451XA CN1200028C (en) | 2002-04-22 | 2002-04-22 | Polyasparamide derivative and process for preparing its nano capsules |
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|---|---|---|---|
| CNB02111451XA CN1200028C (en) | 2002-04-22 | 2002-04-22 | Polyasparamide derivative and process for preparing its nano capsules |
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| CN1379052A CN1379052A (en) | 2002-11-13 |
| CN1200028C true CN1200028C (en) | 2005-05-04 |
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