KR101495652B1 - Core cross-linked polymeric micelle and method of manufacturing the same - Google Patents

Abstract

The present invention relates to a core cross linked micelle polymer composition, wherein the core cross linked micelle polymer composition may contain a drug therein.

Description

TECHNICAL FIELD [0001] The present invention relates to a core cross-linked polymeric micelle compound and a method for producing the same. BACKGROUND ART < RTI ID = 0.0 >

The present invention relates to a corer cross-linked polymeric micelle composition, and more particularly, to a core cross-linked polymeric micelle composition capable of enclosing a drug therein.

Drugs used for the treatment of diseases such as anticancer drugs or therapeutic agents for inflammatory diseases are disadvantageous in that they can exhibit side effects due to their toxicity and can not maximize the therapeutic effect due to low solubility. To overcome these disadvantages (i.e., to minimize side effects from drug toxicity and improve solubility), the development of new drug formulations such as nanoparticles or drug delivery vehicles such as micelles is actively underway.

Among these drug formulations, the polymeric micelles having a hydrophilic group and a hydrophobic group can form a thermodynamically stable and uniform spherical structure, and the hydrophobic drug can be enclosed in the hydrophobic part to improve the solubility of the drug. Most of the blood vessels in cancerous or inflammatory disease tissues are looser than normal tissues, and micelles of appropriate size are easily accumulated around cancer or inflammatory disease tissues by the EPR (Enhanced Permeability and Retention) effect. Despite these advantages, micelles have a problem that it is difficult to maintain a uniform spherical structure under various physiological conditions.

Accordingly, the present invention provides a drug capable of maintaining the stability in the body by minimizing side effects due to toxicity of the drug by enclosing the drug therein, maximizing the therapeutic effect by increasing the solubility of the drug, maintaining a uniform spherical structure under various physiological conditions, Lt; / RTI >

The present invention provides a terpolymer polymer composition represented by the following formula (1).

In the above formula, X is a water-soluble polymer,

Y is a lipid soluble polymer,

And Z is polylysine having 2 to 10 lysine.

According to a preferred embodiment of the present invention, the water-soluble polymer X is at least one selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, and poly (N-2- (hydroxypropyl) methacrylamide) Block, graft or dendrimer polymer selected from the group consisting of hydroxypropyl (meth) acrylamide and hydroxypropyl (meth) acrylamide. The polymer composition may have a molecular weight of 500 to 20,000 daltons.

According to another preferred embodiment of the present invention, the liposoluble polymer Y is selected from the group consisting of polylactide (PLA), poly (lactic-co-glycolic acid) (PLGA) Block, graft or dendrimer polymer selected from the group consisting of poly (caprolactone), poly (caprolactone), and the like. The polymer composition may have a molecular weight of 500 to 20,000 daltons.

In addition, the present invention can provide a core cross-linked polymeric micelle composition formed by the polymer composition of Formula 1 and a cross-linking agent.

According to another preferred embodiment of the present invention, the core cross-linked polymeric micelle composition may be a drug carrier in which a drug is encapsulated.

The drug may be an anti-inflammatory agent or an anti-cancer agent.

The polymer composition according to the present invention has improved in vivo stability, minimizes adverse effects due to drug toxicity, and can be utilized as a carrier for delivering a therapeutic agent for cancer or inflammatory diseases.

Figure 1 is a schematic view of a polymeric micelle composition core cross-linked from a polyethylene terephthalate (PEG) -polylactide (PLA) -Polysine (PLys) (PEG-PLA-PLys) FIG.
FIG. 2 is an image comparing the size of a polymeric micelle composition before and after core cross-linking of the polymeric micelle composition.
3 is a graph showing the relative scattering intensity of a polymeric micelle composition according to addition of dodecylsodium sulfate (SDS) in order to compare the stability of the polymeric micelle composition before and after core cross linking.
4 is a graph showing drug release characteristics in a polymeric micelle composition.

The present invention provides a polymer composition represented by the following formula (2).

In the above formula, X is a water-soluble polymer,

Y is a lipid soluble polymer,

And Z is polylysine having 2 to 10 lysine.

According to a preferred embodiment of the present invention, the water-soluble polymer X is at least one selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, and poly (N-2- (hydroxypropyl) methacrylamide) Block, graft or dendrimer polymer selected from the group consisting of hydroxypropyl (meth) acrylamide and hydroxypropyl (meth) acrylamide. The polymer composition may have a molecular weight of 500 to 20,000 daltons.

According to another preferred embodiment of the present invention, the oil-soluble polymer Y is at least one selected from the group consisting of polylactide (PLA), poly (lactic-co-glycolic acid) (PLGA) Block, graft, or dendrimer polymer selected from the group consisting of poly (caprolactone), and a polymer composition having a molecular weight of 500 to 20,000 daltons.

The present invention also relates to a method for producing a polymeric micelle, which comprises dissolving the polymer composition in distilled water to produce polymer micelles; And

Reacting the resulting polymeric micelle with a cross-linking agent to produce a core cross-linking polymeric micelle composition;

To provide a core cross-linked polymeric micelle composition.

As used herein, the term "micelle" refers to a collection of materials that have both a hydrophilic moiety and a hydrophobic moiety at the same time. Substances having a hydrophilic portion and a hydrophobic portion at the same time, in a solvent such as water, a hydrophobic portion forms a core toward the inside, and a hydrophilic portion forms a corona toward the outside. When a drug or a functional substance is mixed with the micelle, a drug or a functional substance may be contained in the core portion of the micelle, and thus the micelle may serve as a storage or carrier for a drug or a functional substance. In particular, since the core of the micelle is hydrophobic, it may contain a hydrophobic drug or a functional substance.

The average size (diameter) of the micelle is preferably 40 to 100 nm. When the size of the micelle is larger than 100 nm, the micelle is directly discharged as a kidney, and thus the drug or the functional substance can not be delivered into the human body. In addition, when the size of the micelle is smaller than 40 nm, the micelle is easily absorbed by the macrophages and is easily decomposed, so that the drug or the functional substance can not be effectively delivered into the human body.

When the drug or the functional material is contained in the core of the micelle, the drug or the functional material may be slowly released.

According to a preferred embodiment of the present invention, the crosslinking agent is bis (N-succinimido-succinate), diisocyanate, dicarboxylic acid, And diacetaldehyde may be used as the cross-linking agent.

The present invention also provides a core-crosslinked polymeric micelle composition formed from a polymeric micelle comprising a polymer composition represented by the following formula (3) and a crosslinking agent.

In the above formula, X is a water-soluble polymer,

Y is a lipid soluble polymer,

And Z is polylysine having 2 to 10 lysine.

According to another preferred embodiment of the present invention, the crosslinking agent is bis (N-succinimido-succinate), diisocyanate, dicarboxylic acid (dicarboxylic acid ), And diacetaldehyde. The cross-linked polymeric micelle composition may further comprise at least one crosslinking agent selected from the group consisting of diacetaldehyde and diacetaldehyde.

According to another preferred embodiment of the present invention, the water-soluble polymer X is at least one selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, and poly (N-2- (hydroxypropyl) methacrylamide) Block, graft or dendrimer polymer selected from the group consisting of N-2- (hydroxypropyl) methacrylamide, and a polymer composition having a molecular weight of 500 to 20,000 daltons.

According to another preferred embodiment of the present invention, the oil-soluble polymer Y is at least one of polylactide (PLA), poly (lactic-co-glycolic acid) Block, graft or dendrimer polymer selected from the group consisting of poly (caprolactone), poly (caprolactone), and the like. The polymer composition may have a molecular weight of 500 to 20,000 daltons.

In addition, the present invention can provide a drug delivery system containing a drug in the core cross-linked polymeric micelle composition. In addition, the drug may include an anti-cancer agent or an anti-inflammatory agent.

According to a preferred embodiment of the present invention, the drug is selected from the group consisting of salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, methotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, And one or more anti-inflammatory agents selected from the group consisting of nimesulide, cortisone, and corticosteroid.

According to another preferred embodiment of the present invention, the drug is selected from the group consisting of paclitaxel, doxorubicin, cis-platin, docetaxel, tamoxifen, camtothecin, At least one anticancer drug selected from the group consisting of anastrozole, carboplatin, topotecan, belotecan, irinotecan, gleevec, and vincristine. . ≪ / RTI >

Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.

[ Example ]

Example  1. Preparation of polymer composition

The polymer composition is shown in Reaction Scheme 1 below to prepare a polyethylene-polylactide-polylysine (PEG-PLA-PLys) polymer composition comprising polyethylene, polylactide and polylysine.

[Reaction Scheme 1]

A method for preparing a polyethylene-polylactide-polylysine (PEG-PLA-PLys) polymer composition according to Reaction Scheme 1 is as follows. 2 g of polyethylene glycol and 2 g of lactide are mixed with 10 g of tin (II) (Tin (II) 2-ethylhexanoate) catalyst at 125 DEG C for 24 hours to obtain polyethylene glycol-polylactide (step (a) of Scheme 1).

Subsequently, 3.2 g of the compound obtained in the above step (a) and 0.5 g of BOC-aminohexanoic acid were dissolved in methylene chloride. To this was added dicyclohexylcarbodiimide (DCC) (0.5 g) and 4- (dimethylamino) pyridine (DMAP) (0.1 g) were added and stirred for 24 hours. Then, the solvent and the reaction catalyst were removed, To obtain a polyethylene glycol-polylactide having an aminohexanoic group introduced therein (step (b) of Scheme 1).

3 g of the polyethylene glycol-polylactide obtained in the step (b) was dissolved in methylenechloride, trifluoroacetic acid was added to remove the BOC group, and the amine group-introduced polyethylene glycol - polylactide (step (c) of Scheme 1).

1.9 g of the substance obtained in the above step (c) and 0.2 g of carbobenzyloxy-lysine N-carboxy amino acid anhydride (ZLC-cyctein NCA) were dissolved in dimethylformamide (DMF) to prepare Z- To obtain the introduced polyethylene glycol-polylactide (step (d) of Scheme 1).

1.5 g of the substance obtained in the above step (d) was dissolved in 10 ml of trifluoroacetic acid and 3 ml of hydrogen bromide, and the mixture was allowed to react for 3 hours and then precipitated in ether to obtain polyethylene-polylactide-polylysine (PEG- PLys) polymer (step (e) of Scheme 1).

Example  2. Polymers Micelle  Preparation of composition

0.01 g of the polyethylene-polylactide-polylysine polymer composition (obtained in Example 1) prepared in accordance with the above Reaction Scheme 1 was dissolved in 100 ml of distilled water to form macromolecular micelle. Then, a cross-linking agent bis (n-succinimide- Bis (N-succinimido) -6,6-dithiobis (hexyl succinate) was added to the macromolecular micelle in an amount of 2% by weight of the polymer composition, followed by reaction for 4 hours To give a core cross-linking polymeric micelle.

1 shows a process for preparing a core-crosslinked polymeric micelle composition from a polyethylene-polylactide-polylysine (PEG-PLA-PLys) polymer composition.

Example  3. Core Cross-linked  Polymer Micelle  Drug inclusion of the composition

According to the procedure of Scheme 1, 0.01 g of the polyethylene-polylactide-polylysine polymer composition prepared in Example 1 was dissolved in 100 ml of phosphate buffer solution (PBS). After plate cleaners paclitaxel in the solution; the (paclitaxel PTX) 0.01 g into a solution in methylene chloride, 10 ㎖, after removal of the methylene chloride under stirring at room temperature for 24 hours, the bis (yen crosslinking agent for 4 hours-seat shinny polyimide -6,6- diciobis Succinate) (bis (N- succinimido) -6,6 -dithiobis (hexyl succinate)) ?? To prepare a core cross-linked polymeric micelle composition in which pharmacological cleavage of phclitaxel was carried out.

Experimental Example  1. Core Cross-linked  Polymer Micelle  Comparison of the size of the composition.

The sizes of the polymeric micelle compositions before and after core cross-linking of the polymeric micelle composition of Example 2 were observed using a transmission electron microscope (TEM) to compare the sizes of the polymeric micelle compositions (FIG. 2).

As can be seen from FIG. 2, it can be seen that the size of the polymeric micelle composition after core cross-linking was slightly larger than the size of the polymeric micelle composition before core cross-linking.

Experimental Example  2. Core Cross-linked  Polymer Micelle  Confirm the stability of the composition

In order to confirm the stability of the core cross-linked polymeric micelle composition obtained in Example 2, various amounts of sodium dodecyl sulfate (SDS) were added to the polymeric micelle composition, and the core cross- The stability of the linked polymer micelles was observed.

The relative scattering intensity of the polymeric micelle composition according to the addition of sodium dodecyl sulfate was plotted (FIG. 3) in order to compare the stability of the polymeric micelle composition before and after core cross linking.

3, sodium dodecyl sulfate, which is 10 times thicker than the polymer concentration, was added to the polymer micelle composition before and after the core cross linking, and the relative scattering intensity with time was measured. As a result, The stability of the micelles was poor, while the core-crossed micelles did not show a significant change in the relative scattering intensity, indicating high stability.

Experimental Example  3. The drug Enclosed  core Cross-linked  Polymer Micelle  Drug release of the composition

30 ml of the core cross-linked polymeric micelle composition obtained in Example 3, in which the pellicles were encapsulated, was placed in a test bag (Spectra / por membrane, MWCO 10,000), and 3 ml Samples were taken and high performance liquid chromatography (HPLC) was used to confirm drug release characteristics. In order to compare the drug release characteristics, the same experiment was conducted on the polymeric micelle composition not subjected to core cross linking.

As can be seen in FIG. 4, the core cross-linked polymeric micelle composition showed a delayed release of the drug due to slower release of the drug than the non-core cross-linked polymeric micelle composition, thereby confirming the long-lasting effect of the drug. Therefore, it was found that the core cross-linked polymeric micelle composition of the present invention had sustained release properties.

As can be seen from the above Examples and Experimental Examples, the core cross-linked polymeric micelle composition obtained according to the present invention can maintain high stability under various physiological conditions, and the drug encapsulated in the core cross-linked polymeric micelle composition It was confirmed that it is possible to provide a drug having sustained release properties by gradually releasing it.

Claims (13)

delete delete delete A polymeric micelle comprising a polymer compound represented by the following formula (1) and cross-linked with a cross-linking agent:
(Formula 1)

In the above formula (1), X is a group selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone and poly (N-2- (hydroxypropyl) methacrylamide) At least one linear, block, graft or dendrimer polymer selected from the group consisting of a water-soluble polymer having a weight average molecular weight of from 500 to 20,000 daltons;
Y is selected from the group consisting of polylactide (PLA), poly (lactic-co-glycolic acid) (PLGA) and poly (caprolactone) At least one linear, block, graft or dendrimer polymer having a weight average molecular weight of from 500 to 20,000 daltons;
And Z is polylysine having 2 to 10 lysines. 5. The composition of claim 4, wherein the cross-linking agent is selected from the group consisting of bis (N-succinimido-succinate), diisocyanate, dicarboxylic acid and diacetaldehyde (diacetaldehyde). < RTI ID = 0.0 > 11. < / RTI > delete delete A drug delivery system comprising an anticancer agent or an anti-inflammatory agent in the core cross-linked polymeric micelle compound of claim 4. delete 9. The composition of claim 8, wherein the anti-inflammatory agent is selected from the group consisting of salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, But are not limited to, methotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, ), Cortisone, and corticosteroid. ≪ RTI ID = 0.0 > 8. < / RTI > 9. The method of claim 8, wherein the anticancer agent is selected from the group consisting of paclitaxel, doxorubicin, cis-platin, docetaxel, tamoxifen, camtothecin, anasterozole, At least one selected from the group consisting of carboplatin, topotecan, belotecan, irinotecan, gleevec, and vincristine is included. Lt; / RTI > Dissolving a polymer compound represented by the following formula (1) in distilled water to produce polymer micelles; And
The resulting polymeric micelle and bis (N-succinimido-succinate), diisocyanate, dicarboxylic acid, and diacetaldehyde Reacting a cross-linking agent comprising at least one member selected from the group consisting of the above components to produce a core cross-linking polymeric micelle compound;
A method for preparing a core cross-linked polymeric micelle compound comprising:
(Formula 1)

In the above formula (1), X is a group selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone and poly (N-2- (hydroxypropyl) methacrylamide) At least one linear, block, graft or dendrimer polymer selected from the group consisting of a water-soluble polymer having a weight average molecular weight of from 500 to 20,000 daltons;
Y is selected from the group consisting of polylactide (PLA), poly (lactic-co-glycolic acid) (PLGA) and poly (caprolactone) At least one linear, block, graft or dendrimer polymer having a weight average molecular weight of from 500 to 20,000 daltons;
And Z is polylysine having 2 to 10 lysines. delete

Images