Patent Description:
A drug delivery system is aimed to maximize treatment efficacy and effect by selectively delivering a drug to a target site and optimizing an effective blood concentration according to a disease for a long time, and to minimize a side effect of the drug.

A nano drug delivery system, which is most of these drug delivery systems, can be prepared by various methods. The nano drug delivery system obtained by a representative preparation method may include nanoparticles obtained by using a self-emulsifying diffusion method, nanoparticles obtained by a micelle formation using a block copolymer, nanoparticles obtained by using a magnetism, nanoparticles obtained by a complex reaction of an ionic polymer, and the likes.

The nanoparticles are delivered into a human body through various routes such as an injection, an oral, and a skin. In this case, distribution of the drug indicates distribution of the drug that is distinct from other delivery systems and this distribution is varied depending on properties of the nanoparticles.

Further, in order to enhance a target delivery efficiency to these nanoparticles, various studies have been conducted in several fields to maximize the drug delivery such as binding between various target ligands, controlling a release rate of the drug through near-infrared irradiation, and improving penetration ability by an ultrasound, but there is still a need to develop an excellent drug delivery technology for controlling drug release to a target site at an appropriate timing and in an appropriate amount.

Nanoparticle based systems have been described, for example <CIT> discloses echogenic microcapsules with an aqueous core comprising a therapeutic agent and microbubbles, and <NPL>) discloses echogenic nanobubble formulations for ultrasound imaging and intracellular drug delivery.

A purpose of the present invention is to provide a drug delivery system that contains a plurality of nanobubbles together with a drug in a microcapsule, and can effectively deliver the drug by an ultrasound.

Another purpose of the present invention is to provide a method for preparing a drug delivery system that is easily dispersed in an aqueous solution, by generating nanobubbles in an oil into which a fat-soluble drug that is difficult to disperse in water is dissolved, using a nanobubble generator, and then microencapsulating an oil (nanobubble solution) containing the fat-soluble drug and the nanobubbles.

However, the technical challenge to be achieved by the present invention is not limited to the above-mentioned challenges, and other challenges that are not mentioned may be clearly understood from the following descriptions by a person who has an ordinary knowledge in the art.

As an aspect for attaining the above purposes, the present invention first provides a method for preparing a drug delivery system that is easily dispersed in an aqueous solution, by generating nanobubbles in an oil into which a fat-soluble drug that is difficult to disperse in water is dissolved, using a nanobubble generator, and then microencapsulating the oil containing the oil-soluble drug and the nanobubbles. The term "drug delivery system" in this specification may be used interchangeably with a 'microcapsule' or a 'nanobubble microcapsule'.

In the present invention, a nanobubble solution contains nanobubbles having a diameter in the range of <NUM> to <NUM>, for example, in particular, a diameter in the range of <NUM> to less than <NUM>, and the term "bubble" refers to a foam, that is, a bubble pocket present in a liquid. A concentration of the nanobubble solution according to the present invention, that is, the number of nanobubbles present in the nanobubble solution contains the nanobubbles of <NUM> million/ml, <NUM> billion/ml to <NUM> billion/ml or more. These nanobubbles can be stably maintained at a temperature lower than a room temperature for <NUM> to <NUM> months or more. If a size of the nanobubbles is larger than the above range, a stability of the nanobubble solution may be remarkably deteriorated due to floating, and the nanobubble solution having the number of nanobubbles lower than the above range may significantly reduce an ultrasound-induced drug delivery efficiency because the number of nanobubbles in a single microcapsule is small.

The method according to the present invention may comprise the steps of:.

According to the present invention, the drug delivery system may be characterized by being dispersed in an aqueous solution in the form of an emulsion.

In the step (c), a mixing ratio of the oil containing the drug and the oil containing the nanobubbles is not particularly limited, and the nanobubble solution of the present invention can be prepared by mixing those oils in an appropriate ratio according to the purpose of a person skilled in the art.

Further, according to the present invention, the step (d) may be to prepare a drug delivery system in the form of a microcapsule having both the drug and the nanobubbles encapsulated therein by passing the oil (nanobubble solution) containing the drug and nanobubbles through a membrane in an aqueous solution containing a surfactant. As an example, the drug delivery system having both the drug and the nanobubbles encapsulated therein may be prepared using an emulsion generator (IMK-<NUM>, MC Tech, etc.).

In particular, the drug may be prepared as a drug delivery system in the form of microcapsules by encapsulating the drug with the nanobubbles in the form contained in an oil.

According to the present invention, the drug may be a fat-soluble drug, and may all include a drug having an affinity for a lipid, a drug having a stronger affinity for the lipid or a lipoid than water, a drug having an affinity for a non-polar fluid, and a drug having a functional group capable of binding for the lipid or the lipoid. In addition, the drug is not particularly limited to the above types, and may all include a chemical drug, a protein drug, a peptide drug, a nucleic acid molecule for gene therapy, nanoparticles, an iodide contrast agent, a gadolinium contrast agent, a barium contrast agent, a contrast material such as a fluorescent particle and a magnetic particle, an active ingredient of (functional) cosmetics, or a cosmetically used active ingredient. For example, the active ingredient of (functional) cosmetics or the cosmetically used active ingredient may include niacinamide, arbutin, Atractylodes macrocephala Koidzumi oil, <NUM>-en-butylresorcinol, and ethylascorbyl ether, which exhibit a whitening effect; adenosine, asiaticoside, retinol, and retinyl palmitate, which exhibit an anti-wrinkle effect; and cosmetic ingredients that exhibit an antioxidant effect or a UV protection effect, in addition to allantoin, aloe vera extract, azulene, and centella asiatica extract, which exhibit an anti-inflammatory effect, but are not particularly limited thereto.

The fat-soluble drug that can be used in the present invention may include, for example, an anticancer drug, a therapeutic agent for a (degenerative) brain disease, an anti-inflammatory drug, an analgesic, an antiarthritic, an antispasmodic, an antidepressant, an antipsychotic drug, a tranquilizer, an anti-anxiety drug, a drug antagonist, an anti-Parkins disease drug, a cholinergic agonist, an antiangiogenic drug, an immunosuppressant, an antiviral drug, an antibiotic, an appetite suppressant, a pain reliever, an anticholinergic drug, an antihistamine, an antimigraine drug, a hormone drug, a coronary vascular, cerebrovascular or peripheral vasodilator, a contraceptive pill, an antithrombotic agent, a diuretic, an antihypertensive agent, a therapeutic agent for a cardiovascular disease, a cosmetic ingredient (e.g., an anti-wrinkle agent, a skin aging inhibitor and a skin whitening agent), and the like, but are not limited thereto. For example, the fat-soluble drug may be a drug such as doxorubicin, paclitaxel, vincristine, daunorubicin, vinblastine, actinomycin-D, docetaxel, etoposide, teniposide, bisantren, homoharringtonine, Gleevec (STI-<NUM>), cisplatin, <NUM>-fluorouracil, adriamycin, methotrexate, busulfan, chlorambucil, cyclophosphamide, melphalan, nitrogen mustard or nitrosourea.

According to the present invention, the organic solvent may be a solvent having a high drug solubility without any particular limitation, and include dichloromethane, ethyl acetate, acetone, ethanol, methanol, methyl ethyl ketone, methylene chloride, dichloroethane, chloroform, dioxane, dimethyl sulfoxide, acetonitrile, acetic acid, or the like.

According to the present invention, the drug may be dissolved in the organic solvent at a concentration of <NUM> to <NUM>/mL. In addition, the organic solvent has a low boiling point in a solution in which the drug is dissolved, and is completely removed using a vacuum or rotary concentrator.

According to the present invention, the dissolved drug is mixed with oil. As disclosed herein oil may include a paraffin oil, , a hydrogenated castor oil, mono-glycerides, diglycerides, triglycerides, a mineral oil, squalene, squalane, medium chain glyceride, myglyol, cremophor, a corn oil, a sesame oil, a cottonseed oil, or the like. As disclosed herein alternatively instead of an oil, a compound selected from alpha-bisabolol, stearyl glycyrrhetinate, salicylic acid, tocopheryl acetate, panthenol, glyceryl stearate, cetyl octanolate, isopropyl myristate, <NUM>-ethylene isopelargonate, di-C<NUM>-<NUM> alkyl malate, cetearyl octanoate, butylene glycol dicaprylate / dicaprate, isononyl isostearate , isostearyl isostearate, cetyl octanoate, octyldodecyl myristate, cetyl esters, C<NUM>-<NUM> cholesterol / lanosterol ester, beeswax, Canauba wax, sucrose distearate, PEG-<NUM> beeswax, candelilla (euphorbia cerifera) wax, or glycerol may be used.

According to the present invention, the oil may be mixed in a volume ratio of <NUM> to <NUM> to the organic solvent depending on solubility of the drug in the oil.

According to the present invention, the method for generating nanobubbles in a mixed liquid from which the organic solvent is removed or an oil containing a drug may utilize various methods existing in the relevant technical field, for example, a mechanical stirring method, an ultrasonic bubble generation method, a membrane passing-through method and a fluid circulation method. As an example, the nanobubble solution of the present invention may be prepared using an apparatus and method disclosed in <CIT> entitled "An apparatus for generating a nanobubble Water".

According to the present invention, a type of a gas in the nanobubbles is not greatly limited, and may include an air, CO<NUM>, N<NUM>, O<NUM>, H<NUM>, Ar, perfluorobutane, perfluoropropane (octafluoropropane), etc..

According to the present invention, the aqueous solution containing the surfactant refers to a solution containing the surfactant in an aqueous solvent such as water, and a concentration thereof may range from <NUM> to <NUM> parts by weight based on <NUM> parts by weight of the total aqueous solution.

According to the present invention, the surfactant may include a cationic surfactant such as CTAB (cetyltrimethylammonium bromide), an anionic surfactant such as citrate, a non-ionic surfactant such as PVA (polyvinyl alcohol), a biopolymeric surfactant, and an amphoteric surfactant, without being limited to any type thereof.

For example, the cationic surfactant may be selected, without any limitation, from the group consisting of a quaternary ammonium compound, benzalkonium chloride, cetyltrimethylammonium bromide, chitosan, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochloride, alkylpyridinium halide, cetyl pyridinium chloride, a cationic lipid, polymethylmethacrylate trimethylammonium bromide, a sulfonium compound, polyvinylpyrrolidone-<NUM>-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, a phosphonium compound, benzyl-di(<NUM>-chloroethyl)ethyl ammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, (C<NUM>-C<NUM>)dimethyl hydroxyethyl ammonium chloride, (C<NUM>-C<NUM>)dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methylsulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl(ethenoxy)<NUM> ammonium chloride, lauryl dimethyl(ethenoxy)<NUM> ammonium bromide, N-alkyl (C<NUM>-C<NUM>)dimethylbenzyl ammonium chloride, N-alkyl (C<NUM>-C<NUM>)dimethylbenzyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl (C<NUM>-C<NUM>)dimethyl-<NUM>-naphthylmethyl ammonium chloride, trimethyl ammonium halide alkyl-trimethyl ammonium salt, dialkyl-dimethyl ammonium salt, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkyl ammonium salt, ethoxylated trialkyl ammonium salt, dialkylbenzene dialkyl ammonium chloride, N- didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, N-alkyl (C<NUM>-C<NUM>)dimethyl-<NUM>-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C<NUM> trimethyl ammonium bromide, C<NUM> trimethyl ammonium bromide, C<NUM> trimethyl ammonium bromide, dodecylbenzyl triethyl ammonium chloride, polydiallyldimethyl ammonium chloride, dimethyl ammonium chloride, alkyldimethyl ammonium halogenide, tricetyl methyl ammonium chloride, decyltrimethyl ammonium bromide, dodecyltriethyl ammonium bromide, tetradecyltrimethyl ammonium bromide, methyl trioctyl ammonium chloride, POLYQUAT <NUM>, tetrabutyl ammonium bromide, benzyl trimethyl ammonium bromide, choline ester, benzalkonium chloride, stearalkonium chloride, cetyl pyridinium bromide, cetyl pyridinium chloride, a halide salt of quaternized polyoxyethylalkylamine, "MIRAPOL" (polyquaternium-<NUM>), "Alkaquat" (alkyl dimethyl benzyl ammonium chloride, prepared by Rhodia), an alkyl pyridinium salt, amine, an amine salt, an imide azolinium salt, protonated quaternary acrylamide, a methylated quaternary polymer, a cationic guar gum, benzalkonium chloride, dodecyl trimethyl ammonium bromide, triethanolamine, and poloxamin.

The anionic surfactants may be selected from the group consisting of ammonium lauryl sulfate, sodium <NUM>-heptanesulfonate, sodium hexanesulfonate, sodium dodecylsulfate, triethanol ammonium dodecylbenzenesulfate, potassium laurate, triethanolamine stearate, lithium dodecylsulfate, sodium laurylsulfate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acid and a salt thereof, glyceryl ester, sodium carboxymethylcellulose, bile acid and a salt thereof, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, alkyl sulfonate, aryl sulfonate, alkyl phosphate, alkyl phosphonate, stearic acid and a salt thereof, palmitic acid and a salt thereof, calcium stearate, phosphate, sodium carboxymethylcellulose, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinic acid, phospholipid, and calcium carboxymethylcellulose, but are not limited thereto.

The non-ionic surfactant in the present specification may be selected from the group consisting of a Tween-based surfactant, a SPAN-based surfactant, polyoxyethylene fatty alcohol ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkylether, a polyoxyethylene castor oil derivative, sorbitan ester, glyceryl ester, glycerol monostearate, polyethylene glycol, polypropylene glycol, polypropylene glycol ester, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, arylalkyl polyether alcohol, a polyoxyethylene polyoxypropylene copolymer, poloxamer, poloxamine, methylcellulose, hydroxycellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, an amorphous cellulose, a polysaccharide, a starch, a starch derivative, a hydroxyethyl starch, polyvinyl alcohol, triethanolamine stearate, amine oxide, dextran, glycerol, an acacia gum, cholesterol, tragacanth, and polyvinylpyrrolidone, but is not limited thereto.

The biopolymeric surfactant in the present specification may be selected from the group consisting of various polypeptides such as albumin, chitosan, heparin, polysaccharide, polyglycolic acid, polylactic acid, polyhydroxybutigic acid, a rubber, suberine, melanie, lignin and cellulose, a nucleic acid, and carbohydrate, but is not limited thereto.

The amphoteric surfactant in the present specification may be selected from the group consisting of N-dodecyl-N,N-dimethyl-<NUM>-ammonio-<NUM>-propanesulfonate, betaine, alkyl betaine, alkylamido betaine, amido propyl betaine, cocoamphocarboxyglycinate, sacosinate aminopropionate, aminoglycinate, imidazolinium betaine, an amphoteric midazoline, N-alkyl-N,N-dimethylammonio-<NUM>-propanesulfonate, <NUM>-cholamido-<NUM>-propyldimethylammonio-<NUM>-propanesulfonate, dodecylphosphocholine, and sulfo-betain, but is not limited thereto.

According to the present invention, in case the nanobubble solution is mixed with an aqueous solution containing the surfactant, the microcapsule particles of various sizes can be made using an emulsion generator as shown in <FIG>. For example, in case the nanobubble solution containing a drug is mixed with the aqueous solution through a membrane (by automatically pushing it out using a pump built into the IMK-<NUM> device), a pore size of the membrane may be <NUM> to <NUM>.

As another aspect for achieving the above purposes, the present invention provides a drug delivery system in which both the nanobubbles and the drug are encapsulated, the system being prepared according to the above method.

The drug delivery system according to the present invention is prepared according to the above preparation method, and has an emulsion type in which the microcapsules containing a model drug (red, Nile red), nanobubbles (black within the microcapsule) and an oil are dispersed in an aqueous solution, as shown in <FIG>.

According to the present invention, the microcapsule may have a size of about <NUM> to <NUM>, which varies with the pore size of the membrane used.

According to the present invention, the drug delivery system maximizes a drug delivery efficiency by causing instantaneous high temperature and high pressure as the nanobubbles collapse or aggregate when an ultrasound is applied to the drug delivery system (<FIG> and <FIG>). Such ultrasound is not particularly limited and may include, for example, a focused ultrasound. In particular, by using the focused ultrasound, it is possible to effectively control release of the drug to a selected site of the human body from the outside.

As yet another aspect for achieving the above purposes, there is provided a cosmetic composition comprising the drug delivery system in the form of microcapsules in which both the drug and the nanobubbles are encapsulated.

The cosmetic composition comprising the drug delivery system may have effects such as skin whitening, skin elasticity improvement and wrinkle improvement, skin moisturizing, antioxidant, anti-inflammatory, etc., but is not limited thereto. Specifically, in case the drug delivery system of the present invention is used as the cosmetic composition, a drug contained in the drug delivery system may include active ingredients of (functional) cosmetics or cosmetically used active ingredients without limitation. The active ingredients of the cosmetics or the cosmetically used active ingredients are as described above.

The cosmetic composition according to the present invention may be prepared as a formulation selected from the group consisting of a solution, an external ointment, a cream, a foam, a nutrient lotion, an emollient lotion, a pack, a softening water, a milky lotion, a makeup base, an essence, a soap, a liquid cleaning agent, a bathing agent, a sunscreen cream, a sun oil, a suspension, an emulsion, a paste, a gel, a lotion, a powder, a soap, a surfactant-containing cleansing, an oil, a powder foundation, an emulsion foundation, a wax foundation, a patch, and a spray, but is not limited thereto.

Further, the cosmetic composition of the present invention may additionally include one or more of cosmetically acceptable carriers that are blended in common skin cosmetics, and may be appropriately blended with, for example, an oil, water, a surfactant, a moisturizer, a lower alcohol, a thickener, a chelating agent, a colorant, a preservative, a fragrance, and the like, as a conventional ingredient, but is not limited thereto.

Furthermore, as another aspect for achieving the above purposes, there is provided a contrast agent comprising the drug delivery system.

In the present invention, the term "contrast agent" refers to a formulation used to artificially make a difference in contrast and display it as an image so that a blood vessel or a tissue can be seen better for the purpose of determining a condition of the body organ and diagnosing a disease. More specifically, it may mean "an ultrasonic contrast agent". A typical example of the ultrasonic contrast agent may be the one using microbubbles or nanobubbles, and shows contrast characteristics due to a difference in an ultrasonic reactivity generated at the interface of microbubbles or nanobubbles injected into the body.

Since the drug delivery system of the present invention contains a plurality of nanobubbles within the microcapsules, it can be used not only as the drug delivery system, but also as the contrast agent. Further, the drug delivery system prepared according to the method of the present invention has characteristics that can perform both in vivo diagnosis and treatment at the same time, and the microcapsules containing a plurality of nanobubbles prepared without drugs have an excellent biocompatibility and an excellent stability in vivo. In addition, since the plurality of nanobubbles within one microcapsule can react with the ultrasound together, the drug delivery system can be used as an efficient ultrasonic contrast agent.

Further, if a contrast material such as an iodide contrast agent, a gadolinium contrast agent, a barium contrast agent, sulfahexafluoride, a fluorescent particle and a magnetic particle is contained together with the nanobubbles within the microcapsules, depending on the diagnostic method and purpose to be used, the drug delivery system can be used as the contrast agent having various characteristics. Embodiments to which the contrast agent can be applied may include X-ray imaging technology, Computer Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Nuclear imaging including ultrasonic image, etc., but are not particularly limited thereto.

As another aspect for achieving the above purposes, there is provided a method for delivering a drug, comprising the steps of administering, to an object, the drug delivery system in the form of a microcapsule in which both the drug and nanobubbles are encapsulated; and releasing the drug by irradiating an ultrasound to the administration site of the drug delivery system. The drug is as described above.

According to the present invention, the drug delivery system maximizes a drug delivery efficiency by causing instantaneous high temperature and high pressure as the nanobubbles collapse or aggregate when the ultrasound is applied to the drug delivery system. Specifically, a type of the ultrasound may be characterized by being a focused ultrasound, but is not particularly limited thereto. As an example, the method for delivering the drug according to the present invention utilizes a blood-brain barrier (BBB) disruption induced by irradiation of the ultrasound. In this case, when the drug delivery system is administered to the object and the ultrasound is irradiated to the administration site, the BBB disruption occurs instantaneously due to a hyperthermia caused by the ultrasound, which can increase drug permeability into a brain parenchyma.

The object may be a mammal including a mouse, a rat, a dog, a cat, a cattle, a horse, a pig, and a human, but is not particularly limited thereto. The administration of the drug delivery system may be performed by appropriately selecting the administration methods known to those skilled in the art in consideration of a type of the disease, an affected site, and a condition of the object.

As another aspect for achieving the above purposes, there is provided a method for treating a brain disease or a cancer, comprising the step of administering, to an object, the drug delivery system in the form of a microcapsule in which both a drug and nanobubbles are encapsulated; and releasing the drug by irradiating an ultrasound to an administration site of the drug delivery system.

The object and the administration are as described above. Specifically, the brain disease may be one or more selected from the group consisting of a thrombosis, an embolism, a stroke, a cerebral stroke, a cerebral infarction, a cerebral hemorrhage, a subarachnoid hemorrhage, and a brain tumor. The cancer may, for example, include a colon cancer, a pancreatic cancer, a gastric cancer, a liver cancer, a breast cancer, a cervical cancer, a thyroid cancer, a parathyroid cancer, a lung cancer, a non-small cell lung cancer, a prostate cancer, a gallbladder cancer, a biliary tract cancer, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a blood cancer, a bladder cancer, a kidney cancer, an ovarian cancer, a melanoma, a colon cancer, a bone cancer, a skin cancer, a head cancer, an uterine cancer, a rectal cancer, a brain tumor, an anal muscle cancer, a fallopian tube carcinoma, an endometrial carcinoma, a vaginal cancer, a vulvar carcinoma, an esophageal cancer, a small intestine cancer, an endocrine adenocarcinoma, an adrenal cancer , a soft tissue sarcoma, an urethral cancer, a penile cancer, an ureter cancer, a kidney cell carcinoma, etc., but is not particularly limited thereto.

As another aspect for achieving the above purposes, there is provided a pharmaceutical composition for preventing or treating a brain disease or a cancer, comprising the drug delivery system in the form of a microcapsule in which both a drug and nanobubbles are encapsulated. The brain disease and the cancer are as described above.

In the present invention, the term "preventing" refers to any action that suppresses or delays the brain disease or the cancer by administrating the drug delivery system of the present invention, and the term "treating" refers to any action that improves or favorably changes the symptoms of the brain disease or the cancer by administrating the drug delivery system of the present invention.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, an excipient or a diluent that is commonly used in the preparation of the pharmaceutical composition. The carrier may include a non-naturally occurring carrier. The pharmaceutical composition may be formulated in the form of an oral dosage such as a powder, a granule, a tablet, a capsule, a suspension, an emulsion, a syrup and an aerosol, an external preparation, a suppository, and s sterile injectable solution, respectively, according to a conventional method. The expression "pharmaceutically acceptable" means exhibiting the property that is not toxic to a cell or a human exposed to the composition. Specifically, the carrier may be used without being particularly limited as long as it is commonly used in the art and is pharmaceutically acceptable. Non-limiting examples of the carrier may include a saline solution, a sterile water, a Ringer's solution, a buffered saline solution, an albumin injection solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and the like. They may be used alone or in combination of two or more. In addition, the pharmaceutical composition may be used by adding other conventional additives such as an antioxidant, a buffer solution and/or a bacteriostatic agent, if necessary, and may be formulated as a formulation for injection such as an aqueous solution, a suspension and an emulsion, a pill, a capsule, a granule or a tablet by additionally adding a diluent, a dispersant, a surfactant, a binder, a lubricant, and the like.

The pharmaceutical composition for preventing or treating the brain disease or the cancer according to the present invention may be administered in the manner commonly used in the art without being particularly limited. As a non-limiting example of the administration manner, the pharmaceutical composition may be administered orally or parenterally. In addition, the pharmaceutical composition for preventing or treating the brain disease or the cancer according to the present invention may be prepared in various formulations according to the intended administration manner.

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

Further, since a plurality of nanobubbles are contained in one microcapsule together, the prepared microcapsules can be utilized as an ultrasonic contrast agent.

Meanwhile, the effects described above are merely exemplary, and effects that are predicted or expected from the detailed constitutions of the present invention can also be added to the inherent effects of the present invention in terms of a person skilled in the art.

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.

A model drug (Nile red) and a fat-soluble drug (Doxorubicin) of each <NUM> were dissolved in dichloromethane of <NUM>, and then mixed with a corn oil of <NUM>. Subsequently, the dichloromethane was removed completely using a rotary concentrator, and then a nanobubble solution was prepared using the "nanobubble water generator" of <CIT> disclosed in the detailed description of the invention (see the container on the left in <FIG>). The number of nanobubbles present in the prepared nanobubble solution was diluted in half and measured using a nanoparticle tracking analyzer (NTA). <FIG> shows that the nanobubbles of about <NUM> billion exist in the nanobubble solution of <NUM>.

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

As shown in <FIG>, 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 <NUM>.

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>. A solution used in a lower portion (Receptor compartment) of the Franz Cell was an aqueous DMSO solution of <NUM>%. 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 <NUM>, taking the sample at regular intervals through an sampling area and replenishing it with a pure solution. As a result, <FIG> 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.

Additionally, an experiment for confirming enhancement of the drug release by irradiation of an ultrasound was conducted in an ultrasonic cleaner containing water of <NUM>. As a result of comparing a rate of the drug release according to whether the ultrasound was irradiated or not, <FIG> 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.

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 <NUM>, and then, an ultrasonic probe (frequency of <NUM> and power of <NUM> 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 (<NUM>/min).

Claim 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.