KR20190047628A - Porous magnetic nanoparticle based drug delivery system and preparation method thereof - Google Patents

Abstract

The present invention relates to a drug carrier and a manufacturing method thereof. The drug carrier comprises: a porous magnetic nanoparticle core having a hydrophilic drug; and a liposome-shell having hydrophobic drugs collected therein and surrounding the core. The drug carrier has a core-shell structure in order to include two kinds of drug in the internal side and the external side thereof. The particle of the core has a porous structure. In addition, thermal-sensitive liposome is placed in the shell unit. Therefore, the drug carrier can be expected to improve arrival efficiency thereof to a tumor through the enhanced permeability and retention (EPR) effect, that is, an advantage of the existing drug carrier nanoparticle, can prevent drug resistance, one of the obstacles of contemporary cancer treatment, and can reduce side effects including an abnormal condition caused in a normal cell by releasing a drug at a desired time through various remote stimuli outside the body.

Description

TECHNICAL FIELD The present invention relates to a porous magnetic nanoparticle-based drug delivery system and a preparation method thereof,

The present invention relates to a porous magnetic nanoparticle-based drug delivery system and a method of manufacturing the same.

Chemotherapy using drugs for tumor removal is one of the most widely used cancer treatments currently available. However, this method has several disadvantages such as side effects. Techniques for using nanoparticles or targeting them to increase the drug reaching efficiency have been developed and one of the ways of reducing drug resistance has been multimetal treatment .

When the cancer cells become resistant to the drug being treated, the cancer cells recover and regenerate themselves and grow again. Drug tolerance is divided into two main categories: natural tolerance, which is considered to exist before use of the drug, and the other, resistance to the drug in the early stage. However, drug resistance to be. Various methods have been proposed to solve this resistance. Among them, studies on the simultaneous use of multiple drugs have been conducted most frequently.

On the other hand, the drug delivery system is the most important subject in the field of nanomedicine, and a lot of efforts are being made to control the release rate or triggering of the drug in the drug delivery system. One of the efforts to control this drug release is to design a drug delivery system that triggers by in vitro stimulation. Near infrared ray laser, focused ultrasound, and AC magnetic fields are used for remote stimulation in vitro. Different remote stimulation uses different locations and ranges, and design of drug delivery system is different.

However, the related art related to the related art is a nano-sized single drug delivery system (Korean Patent No. 10-1761692) capable of remote stimulation but can not support multiple drugs and consequently can not solve the immunity problem, (US Patent No. 8,911,426), which is capable of reaching the vicinity of typical tumors characterized by microvascularity of nanometer level in the body due to the presence of multiple drugs, Of nanomedicine and methods for overcoming drug resistance are not satisfactory in both aspects. Therefore, there is an urgent need to study a drug delivery system capable of simultaneously carrying two or more drugs having different properties and capable of triggering a drug through various extracorporeal remote stimulation.

The inventors of the present invention discovered iron oxide-based porous magnetic nanoparticles while studying a drug delivery system capable of releasing drugs by extracorporeal remote stimulation, capable of simultaneously supporting hydrophilic and hydrophobic anticancer agents, and completed the present invention.

Accordingly, an object of the present invention is to provide a porous magnetic nanoparticle core on which a hydrophilic drug is supported; And a liposome-shell surrounding the core, wherein the hydrophobic drug is captured.

Another object of the present invention is to provide a method for producing a drug delivery vehicle.

The inventors of the present invention discovered iron oxide-based porous magnetic nanoparticles while studying a drug delivery system capable of releasing drugs by extracorporeal remote stimulation, capable of simultaneously supporting hydrophilic and hydrophobic anticancer agents, and completed the present invention.

Hereinafter, the present invention will be described in more detail.

One aspect of the present invention relates to a porous magnetic nanoparticle core on which a hydrophilic drug is supported; And a liposome-shell surrounding the core, wherein the hydrophobic drug is captured.

The term "porous" as used herein refers to an array of pores, channels, and cages, and the arrangement of pores, channels, and cages may be irregular, regular, or periodic.

The pores or channels may be separate or interconnected and may be one-dimensional, two-dimensional or three-dimensional. In the present invention, since the magnetic nanoparticles exhibit the porous form as described above, the hydrophobic drug can be effectively carried into the pores, the channels, and the cage.

In the present invention, the magnetic nanoparticles refer to nanoparticles of various materials having a magnetic susceptibility including a magnetic substance therein, and the magnetic nanoparticles are not particularly limited as long as they are magnetic susceptible particles. However, Alloy.

Wherein the magnetic material is Fe, Co, Mn, Ni, Gd, Mo, MM ' ₂ O ₄ or M _x O _y where M and M' x is an integer from 1 to 3, and y is an integer from 1 to 5).

The magnetic alloy may be, but is not limited to, CoCu, CoPt, FePt, CoSm, NiFe or NiFeCo.

The magnetic nanoparticle diameter may be 1-1,000 nm or 10-100 nm. If the particle diameter is less than 1 nm, the magnetic sensitivity may be lowered and the imaging efficiency may be lowered. If the particle diameter is more than 1,000 nm, the applicability to the living body may be lowered.

The core may be coated with a surface coating.

The surface coating agent may be polyethyleneimine (PEI), dextran, citrate, carboxydextran, starch, PEG (polyethyleneglycol) or a derivative thereof, It is not.

The polyethyleneimine is a hydrophilic particle, and can be coated on the porous magnetic nanoparticles having hydrophobic characteristics to maximize the effect of supporting the hydrophilic drug.

The hydrophilic drug may be a protein, a peptide, a vitamin, a nucleic acid, a synthetic drug or a natural extract.

The synthetic drug may be selected from the group consisting of Doxorubicine, Epirubicin, Gemsitabin, Cisplatin, Carboplatin, Procarbazine, Cyclophosphamide, Dactinomycin, Daunorubicin, Etoposide, Tamoxifen, Mitomycin, Bleomycin, Plicomycin, Transplatinum, and the like. , Vinblastine, or methotrexate, but is not limited thereto.

The liposome-shell can allow the porous magnetic nanoparticles to stably exist in the particle, and at the same time, it is possible to simultaneously transfer the two drugs in vivo by carrying a hydrophobic drug having different properties to the hydrophilic drug supported on the core in the liposome .

The liposome may be a thermal-sensitive liposome.

In the present invention, " thermal-sensitive " means reacting to heat or heat generated by focused ultrasound.

The term " liposome " in the present invention means a liposome used in the pharmaceutical, cosmetic and food fields to stably transmit a physiologically active ingredient and to maximize penetration effect.

The hydrophobic drug may be contained in liposomes and contained.

The liposome in which the hydrophobic drug is captured (stabilized) can be prepared by a mixture including a polyol, an edge activator, a phospholipid, a fatty acid and water, but is not limited thereto.

The phospholipid may be selected from the group consisting of Dipalmitoylphosphatidylcholine (DPPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) 2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC).

The hydrophobic drug may be a protein, a peptide, a vitamin, a nucleic acid, a synthetic drug or a natural extract.

The synthetic drug may be, but is not limited to, Paclitaxel, Docetaxel or Sorafenib.

The drug delivery vehicle may further comprise pharmaceutically acceptable excipients such as diluents, release retardants, inert oils or binders, and the like.

Another aspect of the present invention relates to a method of manufacturing a drug delivery vehicle, comprising the steps of:

A step of preparing a porous magnetic nanoparticle core for producing a porous magnetic nanoparticle core;

A supporting step of supporting a hydrophilic drug on the porous magnetic nanoparticle core; And

A binding step of binding a liposome captured by a hydrophobic drug to the outside of the porous magnetic nanoparticle core.

The method for preparing the porous magnetic nanoparticles is not particularly limited, but may be prepared by a solvothermal synthesis method.

Specifically, the porous magnetic nanoparticles are prepared by a solvent thermal synthesis method using a solution in which ethylene glycol (EG) and DEG (diethylene glycol) are mixed in a ratio of 1: 1-10, 1: 4-7 or 1: 5-6 ≪ / RTI >

The porous magnetic nanoparticles may be mesoporous.

The method for producing the liposome in which the hydrophobic drug is captured is not particularly limited, but it is possible to prepare a liposome by mixing a mixture containing a polyol, an edge activator, a phospholipid, a fatty acid and water and a hydrophobic drug in a microfluidizer And the like.

The preparation of the liposome by the above-described microdissolving apparatus has an advantage that it can be carried out under various conditions (e.g., pressure, number of times, etc.) depending on the desired particle size.

The method of binding the liposome capturing the hydrophobic drug to the porous magnetic nanoparticles carrying the hydrophilic drug is not particularly limited. However, the porous magnetic nanoparticle carrying the hydrophilic drug is added to the liposome solution in which the hydrophobic drug is captured, Can be used.

The method for preparing a drug delivery vehicle may comprise the steps of mixing a porous magnetic nanoparticle core with a polymer selected from the group consisting of polyethyleneimine, Dextran, Citrate, Carboxydextran, Starch, PEG and derivatives thereof And a coating step of coating at least one selected from the group consisting of the above.

The coating step may be performed after the hydrophilic drug is supported on the porous magnetic nanoparticle core, and may be performed even before the hydrophilic drug is supported.

Another aspect of the present invention relates to an anticancer pharmaceutical composition comprising the above drug delivery vehicle.

Wherein said cancer is selected from the group consisting of blood cancer, breast cancer, brain cancer, neuroendocrine tumors, gastric cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, , Skin cancer, thyroid cancer, pituitary cancer, or urothelial cancer.

The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier. Such pharmaceutically acceptable carriers are those conventionally used in the field of manufacture and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.

The solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. Such solid preparations can be prepared by adding to the pharmaceutical composition at least one excipient such as starch, calcium carbonate, sucrose, lactose , Gelatin and the like are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions, syrups and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, .

Examples of preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried agents, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.

The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate and responsiveness of the patient, , A skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis. The daily dosage of the pharmaceutical composition of the present invention may be 0.001-10000 mg / kg.

The pharmaceutical composition of the present invention may be prepared in a unit dosage form by formulating it with a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those having ordinary skill in the art to which the present invention belongs Or into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

Another aspect of the present invention relates to a method of treating cancer comprising administering the above drug delivery vehicle to a subject in need thereof.

The cancer treatment method of the present invention uses an anti-cancer pharmaceutical composition containing the above-mentioned drug delivery vehicle of the present invention, and the description common to both of them is omitted in order to avoid the excessive complexity of the present specification.

In the present invention, " administration " means providing a predetermined substance to the patient in any suitable manner, and the administration route of the pharmaceutical composition of the present invention is oral or parenteral ≪ / RTI > The composition of the present invention may also be administered using any device capable of delivering an effective ingredient to a target cell.

An "individual" in the present invention includes, but is not limited to, a human, a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rabbit or a guinea pig do.

Another aspect of the invention relates to the use of said drug delivery vehicle for the treatment of cancer.

The present invention relates to a core comprising magnetic nanoparticles on which a hydrophilic drug is supported; And a shell portion surrounding the core, wherein the hydrophobic drug is captured. The drug delivery system has a core-shell structure for supporting two drugs on the inside and the outside, Since the core has magnetic particles of porous structure and the heat-sensitive liposome is disposed in the shell part, it is expected that the enhancement of drug tumor reaching efficiency can be expected through the EPR (enhanced permeability and retention) effect, which is advantageous of existing drug delivery nanoparticles It can prevent drug resistance, which is one of the obstacles of current chemotherapy treatment. And it can induce drug at desired time by various extracorporeal remote stimulation (near infrared ray laser, focused ultrasound, AC magnetic field, etc.) It is expected to be able to reduce.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram of a method for producing a magnetic nanostructure of the present invention. FIG.
2 is an electron micrograph of a magnetic nanocluster of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Preparation Example 1. Preparation of the drug delivery vehicle of the present invention

1-1. Preparation of Porous Iron Oxide Particles

2 mmol of FeCl ₃ .6H ₂ O was injected into 20 ml of a 3:17 mixture of EG (ethylene glycol) and DEG (diethylene glycol) simultaneously with stirring. After 30 minutes, 1.5 g of polyvinylpyrrolidone (PVP) was added to the solution and heated at 120 ° C for 1 hour until clear. Then, 1.5 g of sodium acetate was added to this solution, and the mixture was stirred for 30 minutes and then transferred to a Teflon-treated stainless steel autoclave and reacted at 200 ° C. for 12 hours. After the reaction solution was cooled to room temperature, the solution containing the magnetic nanoclusters was exchanged with ethanol and water three times or more to remove the remaining substances, and then completely dried in a vacuum oven.

1-2. Porous iron oxide particles PEI (polyethylenimine) coating and doxorubicin (DOX)

500 mg of the iron oxide particles prepared in Preparation Example 1-1 were placed in 20 ml of toluene and completely dispersed by using ultrasonic waves. After dissolving 3 ml of PEI in 20 ml of dimethylformamide, the solution was purged sufficiently with nitrogen gas. The solution was poured into the solution and stirred at 80 ° C for 8 hours. The resultant was collected on one side with a magnet, Was replaced with ethanol and water three times or more to remove the residue. The final concentration of the dispersion was adjusted to 10 mg / ml, mixed with 0.1 to 1.6 mg / ml of DOX solution, and shaken for 10 hours in a light-blocked room. The particles were collected using a magnet to remove the remaining DOX, and the remaining solution was exchanged with water.

1-3. The combination of DOX-loaded porous iron oxide particles and liposomes containing docetaxel (DTX)

10 mg of 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) -Polyethylene glycol (PEG), 70 mg Dipalmitoylphosphatidylcholine (DPPC), 5 mg of 1,2-Distearoyl- And 2 mg of DTX in a 2: 1 mixture of chloroform and methanol. The organic solvent was removed from the rotary evaporator and dried in a vacuum oven for about 8 hours. The dried film was placed in PBS (pH 7.4) containing 0.5 wt% of glycerol and kept at 45 캜 for 10 minutes. The above solution was mixed with the DOX-loaded porous iron oxide particles and kept in the ultrasonic generator for 10 minutes while maintaining the temperature at 45 ° C. To remove the remaining iron oxide particles that did not enter the liposome, the particles dragged for 2 hours were removed by using a magnet of 0.3 T level. The remaining product was dispersed in PBS and stored at 4 ° C.

Claims (14)

A porous magnetic nanoparticle core carrying a hydrophilic drug; And a liposome-shell surrounding the core, wherein the hydrophobic drug is captured. The drug delivery system according to claim 1, wherein the magnetic nanoparticles are mesoporous. The method of claim 1, wherein the magnetic nanoparticles is Fe, Co, Mn, Ni, Gd, Mo, MM _'2 O _4, M _x O _y (M and M' are independently selected from Fe, Co, Ni, Mn, respectively, Zn, Gd or Cr, x is an integer of 1 to 3 and y is an integer of 1 to 5), CoCu, CoPt, FePt, CoSm, NiFe and NiFeCo. , Drug delivery system. The drug delivery system according to claim 1, wherein the core is coated with a surface coating agent. The surface coating agent according to claim 4, wherein the surface coating agent is selected from the group consisting of polyethyleneimine, Dextran, Citrate, Carboxydextran, Starch, PEG (Polyethyleneglycol) Or a pharmaceutically acceptable salt thereof. The composition of claim 1, wherein the hydrophilic drug is selected from the group consisting of Doxorubicine, Epirubicin, Gemsitabin, Cisplatin, Carboplatin, Procarbazine, The compounds of the present invention may be used in combination with other drugs such as cyclophosphamide, Dactinomycin, Daunorubicin, Etoposide, Tamoxifen, Mitomycin, Bleomycin, Plicomycin, Wherein the drug delivery system is at least one selected from the group consisting of Transplatinum, Vinblastine and Methotrexate. The drug delivery system of claim 1, wherein the liposome is a thermal-sensitive liposome. The liposome according to claim 1, wherein the liposome is selected from the group consisting of Dipalmitoylphosphatidylcholine (DPPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- Distearoyl-sn-glycero-3-phosphoethanolamine (PEG) and 1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC). The drug delivery system according to claim 1, wherein the hydrophobic drug is at least one selected from the group consisting of Paclitaxel, Docetaxel, and Sorafenib. A method for preparing a drug delivery vehicle comprising the steps of:
A step of preparing a porous magnetic nanoparticle core for producing a porous magnetic nanoparticle core;
A supporting step of supporting a hydrophilic drug on the porous magnetic nanoparticle core; And
A binding step of binding a liposome captured by a hydrophobic drug to the outside of the porous magnetic nanoparticle core. 11. The method of claim 10, wherein the magnetic nanoparticles are mesoporous. The magnetic nanoparticle core according to claim 10, wherein the magnetic nanoparticle core is prepared by a Solvothermal synthesis method using a solution in which ethylene glycol (EG) and DEG (diethylene glycol) are mixed in a ratio of 1: 5-6. Way. The method of claim 10, wherein the porous magnetic nanoparticle core is selected from the group consisting of Polyethylenimine, Dextran, Citrate, Carboxydextran, Starch, Polyethyleneglycol ) And derivatives thereof. ≪ Desc / Clms Page number 14 > 9. A pharmaceutical composition for anticancer therapy comprising the drug delivery system of any one of claims 1 to 9.

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