ULTRASOUND-INDUCED DRUG DELIVERY SYSTEM USING DRUG CARRIER COMPRISING NANOBUBBLES AND DRUG

Abstract

The present invention relates to an ultrasound-induced drug delivery system using a drug carrier containing a plurality of nanobubbles and a high concentration of a drug in one microcapsule, and specifically is directed to a method for preparing a drug delivery system having a high concentration of a drug and a plurality of nanobubbles encapsulated therein, by generating the nanobubbles in an oil into which the drug is dissolved using a nanobubble generator, and then microencapsulating them; and an ultrasound-induced drug delivery system using the same.

The drug delivery system using the nanobubbles according to the present invention is prepared in the form of microcapsules in which both the drug and the nanobubbles are encapsulated, and, in particular, has an effect of maximizing drug delivery efficiency as the nanobubbles collapse or aggregate when the ultrasound is applied to the drug delivery system.

Further, since the drug delivery system of the present invention contains a plurality of nanobubbles within the microcapsules, it can also be used as a contrast agent. The drug delivery system prepared according to the method described in this specification and having both the drug and the nanobubbles encapsulated therein has a feature that can simultaneously perform in vivo diagnosis and treatment.

Claims

1. A method for preparing a drug delivery system in the form of microcapsules in which both a drug and nanobubbles are microencapsulated, the method comprising the steps of: (a) dissolving the drug in an organic solvent, and then mixing it with an oil to prepare a mixed solution; (b) removing the organic solvent from the mixed solution; (c) preparing an oil solution (nanobubble solution) containing both the drug and the nanobubbles, by generating the nanobubbles in the mixed solution from which the organic solvent has been removed, or by preparing an oil containing the drug and an oil containing the nanobubbles, respectively, and then mixing them; and (d) mixing the nanobubble solution in an aqueous solution containing a surfactant.

2. The method according to claim 1, characterized in that the nanobubble solution contains the nanobubbles having a diameter of 50 nm to less than 200 nm.

3. The method according to claim 1, characterized in that the drug delivery system is dispersed in an aqueous solution in the form of an emulsion.

4. The method according to claim 1, wherein the step (d) is to prepare the drug delivery system in the form of the microcapsules in which both the drug and the nanobubbles are encapsulated by passing the nanobubble solution through a membrane in the aqueous solution containing the surfactant.

5. The method according to claim 1, characterized in that the drug delivery system in the form of the microcapsules is prepared by encapsulating the drug together with the nanobubbles in the form contained in an oil.

6. The method according to claim 1, characterized in that the drug is a fat-soluble drug.

7. The method according to claim 1, characterized in that the drug is an active ingredient of cosmetics.

8. The method according to claim 1, characterized in that a concentration of the surfactant ranges from 2 to 30 parts by weight based on 100 parts by weight of the total aqueous solution.

9. A drug delivery system having both nanobubbles and a drug encapsulated therein, characterized in that it is prepared by the method according to claim 1.

10. The drug delivery system according to claim 9, characterized by being dispersed in an aqueous solution in the form of an emulsion.

11. The drug delivery system according to claim 9, characterized in that a drug delivery efficiency is enhanced as the nanobubbles collapse or aggregate by irradiating an ultrasound.

12. The drug delivery system according to claim 9, characterized in that the drug is a fat-soluble drug.

13. The drug delivery system according to claim 9, characterized in that the drug is an active ingredient of cosmetics.

14. A contrast agent comprising the drug delivery system prepared by the method according to claim 1.

15. The contrast agent according to claim 14, characterized by being an ultrasonic contrast agent.

16. A method for delivering a drug, comprising the steps of administering, to an object, the drug delivery system prepared by the method according to claim 1 and having both the drug and nanobubbles encapsulated therein; and releasing the drug by irradiating an ultrasound to the administration site of the drug delivery system.

17. The method according to claim 16, characterized in that the ultrasound is a focused ultrasound.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0060] FIG. 1 is a diagram showing a process for preparing a microencapsulated drug delivery system by passing an oil containing a drug and nanobubbles according to the present invention through a porous membrane.

[0061] FIG. 2 is results obtained by measuring the number of bubbles within the nanobubble solution prepared according to the present invention, using an Nanoparticle Tracking Analyzer (NTA), and an image of nanobubbles.

[0062] FIG. 3 is images of drug delivery systems in the form of microcapsules prepared according to the present invention. Specifically, A to C of FIG. 3 show fluorescent images of various concentrations in which the microcapsules having a uniform size are dispersed, wherein the red color is caused due to a fluorescence characteristic of the drug used (Nile red, doxorubicin). D to F of FIG. 3 shows appearances that each microcapsule is enlarged to contain nanobubbles therein. Specifically, E of FIG. 3 simultaneously shows microcapsules that the focus of a confocal analyzer matches and microcapsules that the focus does not match.

[0063] FIG. 4 shows fluorescent images of microcapsules prepared using albumin (Bovine serum albumin, BSA) to which a fluorescent pigment is fixed with a surfactant. Specifically, FIG. 4A shows a red color because the drug (Doxorubicin) is contained within the microcapsule, FIG. 4B shows a green shell image showing albumin formed outside the microcapsule, and FIG. 4C is an image obtained by combining the images of FIGS. 4A and 4B. Further, FIG. 4D is a fluorescent image showing albumin present on a capsule surface by preparing a microcapsule containing no drug so as to clearly see the green color of albumin.

[0064] FIG. 5 shows a schematic diagram of a drug delivery through a Franz cell and a membrane used to measure a skin permeability characteristic. Specifically, FIG. 5A shows a schematic diagram of the Franz cell used for analyzing the skin permeability, and FIG. 5B shows a schematic diagram for analyzing a drug release characteristic using an artificial skin/a human skin as the membrane.

[0065] FIG. 6 shows skin permeability characteristics of drugs measured using a Franz cell and an artificial skin membrane. Specifically, FIG. 6A is a graph which shows a result of enhancing the skin permeability of a model drug (Nile Red) over time by pure nanobubbles without irradiating an ultrasound. FIG. 6B is a graph which compares the skin permeability for each of the case where the drug release is improved in a drug delivery system in the form of microcapsules containing a drug (Doxorubicin) and nanobubbles by irradiating the ultrasound, the case where the ultrasound is irradiated to the microcapsules containing no the nanobubbles, and the case where the microcapsules containing the nanobubbles are not irradiated with the ultrasound.

[0066] FIG. 7 is images showing characteristics generated when an ultrasound is irradiated to a drug delivery system in the form of microcapsules containing a drug and nanobubbles. Specifically, it can be confirmed that, when the microcapsules are irradiated with the ultrasound, there is no significant change in a size and a shape of each microcapsule, but sizes of the bubbles increase due to aggregation of the nanobubbles present inside each microcapsule.

[0067] FIG. 8 is images showing ultrasonic contrast characteristics of the prepared microcapsules containing nanobubble. Specifically, FIG. 8 shows results of observing a Doppler effect responding to irradiation of the ultrasound when a distilled water (A, E), an aqueous microcapsule solution without the nanobubbles (C, G), and an aqueous microcapsule solution containing the nanobubbles (B, D, F, H) are sequentially flowed into a rubber tube fixed between agarose gels.

DETAILED DESCRIPTION

[0068] Hereinafter, preferred embodiments of the present invention will be described with reference to the accompanying drawings. However, the embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments as described below. Further, the embodiments of the present invention are provided in order to more completely explain the present invention to a person who has an average knowledge in the art.

EXAMPLE

Preparation of a Drug Delivery System Dispersed in an Emulsion Form, in Which Both a Drug and Nanobubbles are Encapsulated

[0069] A model drug (Nile red) and a fat-soluble drug (Doxorubicin) of each 1 g were dissolved in dichloromethane of 100 mL, and then mixed with a corn oil of 1000 mL. Subsequently, the dichloromethane was removed completely using a rotary concentrator, and then a nanobubble solution was prepared using the “nanobubble water generator” of Korean Patent Application No. 10-2019-0068228 disclosed in the detailed description of the invention (see the container on the left in FIG. 1). The number of nanobubbles present in the prepared nanobubble solution was diluted in half and measured using a nanoparticle tracking analyzer (NTA). FIG. 2 shows that the nanobubbles of about 2 billion exist in the nanobubble solution of 1 mL.

[0070] The nanobubble solution prepared in this way was passed through a membrane having a pore size of “1 um” using an emulsion generator (IMK-40, MC Tech), and dispersed into an aqueous solution containing polyvinyl alcohol (PVA) or albumin as shown in FIG. 1 (see the right vessel of FIG. 1) to finally prepare an aqueous solution of a drug delivery system in the form of an emulsion.

[0071] As shown in FIG. 3, it was found that an oil containing nanobubbles and a fluorescent drug (Nile red or Doxorubicin) was encapsulated and prepared in the form of microcapsules using a confocal fluorescence analyzer, and a size of the microcapsule was around 5 um.

Experimental Example 1

Comparative Experiment of Drug Release According to Whether an Ultrasound is Irradiated or Not

[0072] A drug release characteristic of the prepared micro drug delivery system was measured by adding a solution in which the drug delivery system was dispersed in an upper portion (dosage compartment) of a Franz Cell in FIG. 5A. A solution used in a lower portion (Receptor compartment) of the Franz Cell was an aqueous DMSO solution of 20%. An amount of the drug delivered through a membrane was measured by circulating an aqueous solution having a constant temperature through a thermal jacket to maintain a temperature of the experimental device at 37° C., taking the sample at regular intervals through an sampling area and replenishing it with a pure solution. As a result, FIG. 6A showed that the microcapsule in which both the model drug (Nile Red) and the nanobubbles were microencapsulated improved a skin permeability of the drug compared to the microcapsule which did not contain the nanobubbles.

[0073] Additionally, an experiment for confirming enhancement of the drug release by irradiation of an ultrasound was conducted in an ultrasonic cleaner containing water of 1 L. As a result of comparing a rate of the drug release according to whether the ultrasound was irradiated or not, FIG. 6B showed that the microcapsule in which both the drug (Doxorubicin) and the nanobubbles were microencapsulated improved the skin permeability compared to the microcapsule which did not contain the nanobubbles, and also that the skin permeability of the microcapsule containing the nanobubbles was significantly deteriorated when the ultrasound was not irradiated.

Experimental Example 2

Comparative Experiment of an Ultrasonic Contrast Characteristic of a Microcapsule Containing Nanobubbles

[0074] In order to investigate an ultrasonic contrast characteristic of the nanobubble microcapsule prepared according to the method of the above Example, an agarose gel having a rubber tube fixed therein was prepared. Each of samples (a distilled water (A, E), an aqueous solution of the microcapsule without nanobubbles (C, G), and an aqueous solution of the microcapsule containing nanobubbles (B, D, F, H)) was taken with a syringe of 1 mL, and then, an ultrasonic probe (frequency of 11.43 MHz and power of 50 dB)was placed on the agarose gel and the sampled were imaged while each of the samples was flowed into the rubber tube fixed in the prepared agarose gel using a syringe pump (1 mL/min).

[0075] As a result, when the distilled water and the aqueous solution of the microcapsule without the nanobubbles were flowed, no special Doppler effect was observed even with irradiation of the ultrasound, but when the aqueous solution of the microcapsule containing the nanobubbles was flowed, a strong Doppler effect was observed, which confirmed the characteristic of the nanobubble microcapsules according to the present invention as the ultrasonic contrast agent.

[0076] It will be self-evident to a person who has an ordinary knowledge in the art that, although the present invention has been described in detail above, the scope of the present invention is not limited thereto, and various modifications and variations are possible without departing from the technical spirit of the present invention described in the claims.