WO2020251271A1 - Platform for improving drug delivery to liver, using w/o/w-type triolein emulsion - Google Patents

Platform for improving drug delivery to liver, using w/o/w-type triolein emulsion Download PDF

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WO2020251271A1
WO2020251271A1 PCT/KR2020/007568 KR2020007568W WO2020251271A1 WO 2020251271 A1 WO2020251271 A1 WO 2020251271A1 KR 2020007568 W KR2020007568 W KR 2020007568W WO 2020251271 A1 WO2020251271 A1 WO 2020251271A1
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triolein
water
emulsion
drug
drug delivery
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PCT/KR2020/007568
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French (fr)
Korean (ko)
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김학진
유진욱
전병학
김용우
최선희
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부산대학교 산학협력단
부산대학교병원
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Priority claimed from KR1020190108879A external-priority patent/KR102280309B1/en
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Publication of WO2020251271A1 publication Critical patent/WO2020251271A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a platform for enhancing drug delivery to the liver using an internal/oil/external (Water/Oil/Water; W/O/W) type triolein emulsion.
  • Treatment of malignant tumors that develops in the liver includes surgery, drug therapy, hi-fu, and embolism.
  • drug therapy the anticancer drug is administered intravenously to reach cancer tissues, thereby showing the efficacy.
  • the effectiveness of anticancer drugs is affected by how much anticancer drugs enter cancer tissues in blood vessels. That is, it is affected by the degree of vascular distribution of cancer tissues and the vascular permeability of normal tissues around cancer tissues.
  • liver tissues there is increasing interest in techniques for increasing the vascular permeability of liver tissues to allow more anticancer agents to reach cancer tissues from blood vessels.
  • An object of the present invention is an oily droplet containing triolein, an internal water / oil / external water (Water / Oil / Water; W / O / W) type structure triolein emulsion in which the water droplets are enclosed in the oily droplet It is to provide a composition for drug delivery to liver tissue comprising as an active ingredient.
  • Another object of the present invention is to provide a method of manufacturing a drug delivery system to liver tissue.
  • the present invention is an internal water phase / oil phase / external water phase (Water/Oil/Water; W/O/W) type structure in which an oily droplet contains triolein, and a water droplet is enclosed in the oily droplet. It provides a composition for drug delivery to liver tissue comprising the triolein emulsion of as an active ingredient.
  • the present invention comprises the steps of preparing a first triolein emulsion by mixing triolein and water containing a surfactant; And triolein droplets having an average diameter of more than 5 ⁇ m and less than 15 ⁇ m by treating a power source after adding water containing polyvinyl alcohol to the first triolein emulsion. It provides a method of manufacturing a drug delivery system to liver tissue comprising the step of preparing a W/O/W type triolein emulsion.
  • the present invention relates to a platform for enhancing drug delivery to the liver using an internal/oil/external aqueous phase (Water/Oil/Water; W/O/W) type triolein emulsion, and to a platform for promoting drug delivery between water and triolein in a conventional triolein emulsion. It solves the problem that the emulsion is rapidly destroyed due to the large difference in density between humans, and it is possible to adjust the particle size during manufacture, thereby reducing the size variation between particles, and making stable particles.
  • W/O/W internal/oil/external aqueous phase
  • the present invention is a technique of increasing the vascular permeability of liver tissue to allow more anticancer agents to reach cancer tissues from blood vessels, and since the effect of the anticancer agent is doubled, it can be usefully utilized as a composition for drug delivery to the liver.
  • FIG. 1 schematically shows the state of the double structure triolein emulsion according to an embodiment of the present invention.
  • Figure 5 is a result of confirming the drug delivery activity to the liver using a W/O/W dual structure triolein emulsion.
  • REU relative fluorescence unit
  • the present invention is effective in a triolein emulsion having an internal water/oil/external water phase (Water/Oil/Water; W/O/W) structure in which the oily droplets contain triolein, and the water droplets are enclosed in the oily droplets. It provides a composition for drug delivery to liver tissue, including as a component.
  • W/O/W water/Oil/Water
  • Triolein is a lipid normally present in the body. Triolein can be artificially mixed with water to make an emulsion in which the size of fat particles is reduced, and by applying this, the hepatic artery wall can be loosened and opened by injecting a certain amount of triolein emulsion of a specific size. Triolein emulsion of /O/W type structure maintains such hepatic artery opening activity, but can contain surfactant in triolein droplets, improving particle stability, and water droplets are encapsulated inside triolein droplets. Since it is possible to minimize the disruption of the formulation due to the difference in density between triolein and water, it can be usefully used as a composition for drug delivery, especially to the liver, among tissues having a tight junction.
  • the average diameter of the oily droplets may be more than 5 ⁇ m and less than 15 ⁇ m, and preferably, the diameters of all the oily droplets may be more than 5 ⁇ m and less than 10 ⁇ m, when the average diameter is less than 5 ⁇ m, temporary increase in vascular permeability If the phenomena cannot be caused, and if the thickness exceeds 15 ⁇ m, it is not preferable because it causes severe clogging of blood vessels and deteriorates safety.
  • a water-soluble drug or a water-soluble pigment may be further included in the inner water.
  • triolein By including a water-soluble substance in the inner water enclosed in the triolein drop, triolein has a close junction. When the hepatic artery wall is loosened and penetrates into the liver tissue, it is preferable that drugs contained in the internal water can be effectively delivered into the liver tissue.
  • the drug used in the present invention is a substance capable of inducing a desired biological or pharmacological effect by promoting or inhibiting a physiological function in the body of an animal or human, and a chemical or biological substance or compound suitable for administration to an animal or human It means that it has a preventive effect on organic matter by preventing unwanted biological effects such as infection prevention, alleviates the condition caused by a disease, relieves pain or infection resulting from a disease, for example, and relieves disease from organic matter. It can play a role that can be mitigated, reduced or completely eliminated.
  • the water-soluble drug may be an anticancer agent, an aminoglycoside antibiotic, an antifungal agent, an anti-aging agent, or an antibody drug, and more preferably, doxorubicin, cytarabine, vinblastine, rituxi Mab (rituximab), trastuzumab (trastuzumab), gentamicin (gentamicin) and may be any one or more selected from the group consisting of tobramycin (tobramycin), but is not limited thereto.
  • tobramycin tobramycin
  • the water-soluble pigment may be any one or more selected from the group consisting of trypan blue, evans blue, Congo red, and methylene blue, but is not limited thereto.
  • a fat-soluble drug may be further included in the oil phase.
  • the composition can deliver the drug to the liver by making the triolein loosen the tight junction of the hepatic artery wall.
  • composition for drug delivery may further include one or more pharmaceutically acceptable carriers, excipients or diluents in addition to a pharmaceutically effective amount of a W/O/W-type triolein emulsion or drug.
  • the "pharmaceutically effective amount” refers to an amount sufficient for the drug to be administered to an animal or human to exhibit a desired physiological or pharmacological activity, and the age, weight, health condition, sex, administration It can be changed appropriately depending on the route and treatment period.
  • the "pharmaceutically acceptable" in the present invention means that when administered to a human being physiologically acceptable, usually does not cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions.
  • Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
  • the drug delivery composition may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative.
  • composition for drug delivery according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular, and the dosage of the drug may include the route of administration, the age, sex, weight, and severity of the patient. It can be appropriately selected according to several factors.
  • the composition for drug delivery of the present invention may be administered in parallel with a known compound capable of enhancing the desired effect of the drug.
  • the present invention comprises the steps of preparing a first triolein emulsion by mixing triolein and water containing a surfactant; And triolein droplets having an average diameter of more than 5 ⁇ m and less than 15 ⁇ m by treating a power source after adding water containing polyvinyl alcohol to the first triolein emulsion. It provides a method of manufacturing a drug delivery system to liver tissue comprising the step of preparing a W/O/W type triolein emulsion.
  • triolein emulsion was prepared by mixing triolein and water several times using a 3-way syringe valve, but since triolein and water are not mixed at all, layer separation occurs very quickly. There was a limit to the destruction of the emulsion system. Moreover, there is a problem that it is also very difficult to control the particle size of the triolein emulsion in this manner.
  • the average diameter of the particles can be easily adjusted during the manufacturing process, only a large amount of particles having the most effective average diameter can be manufactured, so that even a small amount of triolein can provide sufficient hepatic artery opening effect.
  • it can be easily and conveniently manufactured using a commonly used syringe, and reproducibility is also very good.
  • the first triolein emulsion may be prepared by mixing 0.2 parts by weight to 0.8 parts by weight of a surfactant and 20 parts by weight to 50 parts by weight of water containing the same based on 100 parts by weight of triolein, but is limited thereto. It is not.
  • the water containing the surfactant may further contain a water-soluble drug or a water-soluble pigment.
  • the water-soluble drug may be an anticancer agent, an aminoglycoside antibiotic, an antifungal agent, an anti-aging agent, or an antibody drug, and more preferably, doxorubicin, cytarabine, vinblastine, rituxi Mab (rituximab), trastuzumab (trastuzumab), gentamicin (gentamicin) and may be any one or more selected from the group consisting of tobramycin (tobramycin), but is not limited thereto.
  • tobramycin tobramycin
  • the water-soluble pigment may be any one or more selected from the group consisting of trypan blue, evans blue, Congo red, and methylene blue, but is not limited thereto.
  • the power source may be selected from the group consisting of an ultrasonic generator, a homogenizer, and a syringe, but is not limited thereto.
  • the triolein droplet may further contain a fat-soluble drug.
  • the average diameter of the triolein droplets may be more than 5 ⁇ m and less than 10 ⁇ m.
  • triolein emulsion As shown in the schematic diagram disclosed in FIG. 1, in order to prepare a W/O/W dual structure triolein emulsion (right) that is more stabilized than the conventional triolein emulsion (left), first, span 80 as a surfactant and a water-soluble pigment A first emulsion was prepared by mixing a small amount of water containing Congo red and triolein (sigma aldrich), and then using an ultrasonic generator to emulsify red water droplets in the triolein solution.
  • Congo red and triolein sigma aldrich
  • the average particle diameter of the W/O/W dual structure triolein emulsion prepared according to the method disclosed in Example 1 above was randomly sampled using an optical microscope, and a scale bar (scale) was performed using the image J program. bar) was measured by measuring the particle diameter and performing statistical processing.
  • the triolein emulsion mainly exhibited an average particle diameter of 5-20 ⁇ m, and the average was about 7.58 ⁇ m. At this time, it is estimated that particles having an average particle diameter of 5-20 ⁇ m are involved in the temporary BBB opening. When an emulsion containing a large number of particles larger than 20 ⁇ m is used, safety may be rather affected.
  • a triolein emulsion was prepared according to the method performed in Example 1, but the average diameter was set to 8 ⁇ m, and the concentration of the emulsion was adjusted to 3%.
  • a microtubule was injected into the central auricular artery for rabbits (2.5 Kg, male) sold in Semtaco, and the tip was placed in the hepatic artery, and the emulsion prepared above was injected at a rate of 15 ml per rabbit. . Thereafter, 3 ml of trypan blue was immediately injected into the rabbit, and after 2 hours, the rabbit liver was excised and the blue-stained area was observed. At this time, when the hepatic artery is opened, the principle that the area to be opened is stained blue was used.
  • triolein emulsion having a W/O/W double structure and an average particle diameter of 8 ⁇ m was prepared.
  • 8 ml of the emulsion diluted in the same procedure as in the experiment in which trypan blue was added to 2.5 kg male rabbits sold by Samtaco.
  • doxorubicin a water-soluble drug, was injected, and 2 hours later, the liver of the rabbit was excised and the concentration of doxorubicin was measured using a fluorometer. At this time, six liver tissues were removed and measured three times.
  • a triolein emulsion having a W/O/W double structure, an average particle diameter of 8 ⁇ m, and encapsulation of a contrast agent was prepared.
  • 15 ml of the emulsion was injected into a 2.5 kg male rabbit sold by Samtaco, followed by 3 ml of trypan blue.
  • trypan blue a dye that permeates the liver tissue when the hepatic artery is opened, and the trypan blue that has penetrated into the liver tissue is stained blue and appears.
  • the triolein W/O/W double droplet structure emulsion with water droplets encapsulated therein is prepared in a stable formulation while showing the activity of opening by loosening the hepatic artery as it is. Therefore, it is possible to efficiently perform drug delivery to a tissue having a tight junction, that is, a liver.

Abstract

The present invention relates to a platform for improving drug delivery to the liver, using a water/oil/water (W/O/W)-type triolein emulsion, and may: resolve the problem in which an emulsion is quickly destroyed due to a significant density difference between water and triolein in a conventional triolein emulsion; decrease the size difference between particles as the particle sizes can be adjusted during production; and produce stable particles. The present invention relates to a technique which increases the vascular permeability of a liver tissue and enables a greater amount of an anticancer drug from a blood vessel to reach a cancer tissue, and the present invention redoubles the effect of the anticancer drug and, thus, can be usefully used as a composition for delivering a drug to the liver.

Description

W/O/W형 트리올레인 에멀전을 이용한 간의 약물전달 증진 플랫폼Hepatic drug delivery enhancement platform using W/O/W type triolein emulsion
본 발명은 내부수상/유상/외부수상(Water/Oil/Water; W/O/W)형 트리올레인 에멀전을 이용한 간의 약물전달 증진 플랫폼에 대한 것이다.The present invention relates to a platform for enhancing drug delivery to the liver using an internal/oil/external (Water/Oil/Water; W/O/W) type triolein emulsion.
간에 발병한 악성종양(원발암 및 전이암)의 치료법에는 수술, 약물요법, 하이푸, 색전요법 등이 있다. 약물요법에는 항암제의 정맥투여로 암조직에 항암제가 도달함으로써 약효를 나타내는 치료법이다. 항암제의 효과는 혈관에서 항암제가 암조직으로 얼마나 많이 들어가느냐에 영향을 받는다. 즉, 암조직의 혈관분포 정도와 암 조직 주변 정상조직의 혈관투과성에 의해 영향을 받는다.Treatment of malignant tumors (primary and metastatic cancer) that develops in the liver includes surgery, drug therapy, hi-fu, and embolism. In drug therapy, the anticancer drug is administered intravenously to reach cancer tissues, thereby showing the efficacy. The effectiveness of anticancer drugs is affected by how much anticancer drugs enter cancer tissues in blood vessels. That is, it is affected by the degree of vascular distribution of cancer tissues and the vascular permeability of normal tissues around cancer tissues.
이에, 간조직의 혈관투과성을 증가시켜 혈관에서 암조직으로 항암제가 더 많이 도달하게 하는 기법에 대한 관심이 증가되고 있다.Accordingly, there is increasing interest in techniques for increasing the vascular permeability of liver tissues to allow more anticancer agents to reach cancer tissues from blood vessels.
본 발명의 목적은 유상 방울이 트리올레인을 포함하고, 상기 유상 방울 내부에 물방울을 봉입한 내부수상/유상/외부수상(Water/Oil/Water; W/O/W)형 구조의 트리올레인 에멀전을 유효성분으로 포함하는 간조직으로의 약물 전달용 조성물을 제공하는 것이다.An object of the present invention is an oily droplet containing triolein, an internal water / oil / external water (Water / Oil / Water; W / O / W) type structure triolein emulsion in which the water droplets are enclosed in the oily droplet It is to provide a composition for drug delivery to liver tissue comprising as an active ingredient.
본 발명의 다른 목적은 간조직으로의 약물 전달체 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method of manufacturing a drug delivery system to liver tissue.
상기 목적을 달성하기 위하여, 본 발명은 유상 방울이 트리올레인을 포함하고, 상기 유상 방울 내부에 물방울을 봉입한 내부수상/유상/외부수상(Water/Oil/Water; W/O/W)형 구조의 트리올레인 에멀전을 유효성분으로 포함하는 간조직으로의 약물 전달용 조성물을 제공한다.In order to achieve the above object, the present invention is an internal water phase / oil phase / external water phase (Water/Oil/Water; W/O/W) type structure in which an oily droplet contains triolein, and a water droplet is enclosed in the oily droplet. It provides a composition for drug delivery to liver tissue comprising the triolein emulsion of as an active ingredient.
상기 다른 목적을 달성하기 위하여, 본 발명은 트리올레인과, 계면활성제가 포함된 물을 혼합하여 1차 트리올레인 에멀전을 제조하는 단계; 및 상기 1차 트리올레인 에멀전에 폴리비닐알코올(poly vinyl alcohol)이 포함된 물을 첨가한 후, 동력원(power source)을 처리하여, 평균직경이 5 ㎛ 초과 15 ㎛ 미만인 트리올레인 방울을 포함하는 W/O/W형 트리올레인 에멀전을 제조하는 단계를 포함하는 간조직으로의 약물 전달체 제조방법을 제공한다.In order to achieve the above other object, the present invention comprises the steps of preparing a first triolein emulsion by mixing triolein and water containing a surfactant; And triolein droplets having an average diameter of more than 5 µm and less than 15 µm by treating a power source after adding water containing polyvinyl alcohol to the first triolein emulsion. It provides a method of manufacturing a drug delivery system to liver tissue comprising the step of preparing a W/O/W type triolein emulsion.
본 발명은 내부수상/유상/외부수상(Water/Oil/Water; W/O/W)형 트리올레인 에멀전을 이용한 간의 약물전달 증진 플랫폼에 관한 것으로, 종래의 트리올레인 에멀전에서 물과 트리올레인 간의 큰 밀도차로 인해 유제가 빠르게 파괴되는 문제점을 해결하고, 제조 시에 입자 크기 조절이 가능하여 입자 간의 크기 편차를 줄일 수 있으며, 안정한 입자를 만들 수 있다. 본 발명은 간조직의 혈관투과성을 증가시켜 혈관에서 암조직으로 항암제가 더 많이 도달하게 하는 기법으로 항암제의 효과를 배가시키므로, 간으로의 약물 전달용 조성물로 유용하게 활용할 수 있다.The present invention relates to a platform for enhancing drug delivery to the liver using an internal/oil/external aqueous phase (Water/Oil/Water; W/O/W) type triolein emulsion, and to a platform for promoting drug delivery between water and triolein in a conventional triolein emulsion. It solves the problem that the emulsion is rapidly destroyed due to the large difference in density between humans, and it is possible to adjust the particle size during manufacture, thereby reducing the size variation between particles, and making stable particles. The present invention is a technique of increasing the vascular permeability of liver tissue to allow more anticancer agents to reach cancer tissues from blood vessels, and since the effect of the anticancer agent is doubled, it can be usefully utilized as a composition for drug delivery to the liver.
도 1은 본 발명의 일 실시예에 따른 이중 구조의 트리올레인 에멀전의 모습을 도식적으로 나타낸 것이다.1 schematically shows the state of the double structure triolein emulsion according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에서 제조한 붉은색 색소를 내부에 봉입한 W/O/W 이중 구조의 트리올레인 에멀전을 현미경으로 관찰한 결과이다.2 is a result of observing under a microscope a W/O/W dual-structure triolein emulsion in which a red pigment prepared in an embodiment of the present invention is enclosed therein.
도 3은 본 발명의 일 실시예에서 제조한 W/O/W 이중 구조의 트리올레인 에멀전의 평균입경을 확인하기 위해 현미경으로 관찰한 결과이다.3 is a result of observation with a microscope to confirm the average particle diameter of the W/O/W dual structure triolein emulsion prepared in an embodiment of the present invention.
도 4는 본 발명의 일 실시예에서 제조한 트리판 블루를 내부에 봉입한 W/O/W 이중 구조의 트리올레인 에멀전이 간동맥을 오프닝하여 간 조직 내부로 전달되는 것을 확인한 결과이다.4 is a result of confirming that the W/O/W dual-structure triolein emulsion containing trypan blue prepared in an embodiment of the present invention is delivered to the liver tissue by opening the hepatic artery.
도 5는 W/O/W 이중 구조의 트리올레인 에멀전를 이용한 간으로의 약물 전달 활성을 확인한 결과이다. 실험군의 간조직에서 독소루비신 농도(RFU; relative fluorescence unit, 상대적 형광 단위) 및 대조군의 간조직에서 독소루비신 농도(RFU).Figure 5 is a result of confirming the drug delivery activity to the liver using a W/O/W dual structure triolein emulsion. Doxorubicin concentration (RFU; relative fluorescence unit) in liver tissue of the experimental group and doxorubicin concentration (RFU) in liver tissue of the control group.
도 6은 트리판 블루 염색에 의한 트리올레인 에멀전의 간동맥 오프닝 확인 결과를 나타낸다. 6 shows the results of confirming hepatic artery opening of triolein emulsion by trypan blue staining.
본 발명은 유상 방울이 트리올레인을 포함하고, 상기 유상 방울 내부에 물방울을 봉입한 내부수상/유상/외부수상(Water/Oil/Water; W/O/W)형 구조의 트리올레인 에멀전을 유효성분으로 포함하는 간조직으로의 약물 전달용 조성물을 제공한다.The present invention is effective in a triolein emulsion having an internal water/oil/external water phase (Water/Oil/Water; W/O/W) structure in which the oily droplets contain triolein, and the water droplets are enclosed in the oily droplets. It provides a composition for drug delivery to liver tissue, including as a component.
트리올레인은 체내에 정상적으로 존재하는 지질이다. 트리올레인에 인위적으로 물을 섞어 지방 입자의 크기를 줄인 에멀젼을 만들 수 있고 이를 응용하여 특정 크기의 트리올레인 에멀젼을 일정량 주사하면 간동맥벽을 느슨하게 하여 오프닝할 수 있는 바, 본 발명에 따른 W/O/W형 구조의 트리올레인 에멀전은 이러한 간동맥 오프닝 활성을 유지하면서도, 트리올레인 방울 내에 계면활성제를 포함할 수 있어 입자의 안정성이 향상되고, 트리올레인 방울 내부에 물방울이 봉입되어 있어 트리올레인과 물과의 밀도 차에 의한 제형 파괴 현상을 최소화할 수 있으므로, 밀착 연접부를 갖는 조직 중 특히 간으로의 약물 전달을 위한 조성물로 유용하게 활용될 수 있다.Triolein is a lipid normally present in the body. Triolein can be artificially mixed with water to make an emulsion in which the size of fat particles is reduced, and by applying this, the hepatic artery wall can be loosened and opened by injecting a certain amount of triolein emulsion of a specific size. Triolein emulsion of /O/W type structure maintains such hepatic artery opening activity, but can contain surfactant in triolein droplets, improving particle stability, and water droplets are encapsulated inside triolein droplets. Since it is possible to minimize the disruption of the formulation due to the difference in density between triolein and water, it can be usefully used as a composition for drug delivery, especially to the liver, among tissues having a tight junction.
이때, 상기 유상 방울의 평균 직경은 5 ㎛ 초과 15 ㎛ 미만일 수 있고, 바람직하게는, 모든 유상 방울의 직경이 5 ㎛ 초과 10 ㎛ 미만일 수 있는 바, 평균 직경이 5 ㎛ 미만인 경우에는 일시적 혈관 투과성 증가 현상을 일으킬 수 없고, 15 ㎛ 초과인 경우에는 혈관 막힘 현상을 심하게 일으켜 안전성이 저하되므로 바람직하지 않다.At this time, the average diameter of the oily droplets may be more than 5 μm and less than 15 μm, and preferably, the diameters of all the oily droplets may be more than 5 μm and less than 10 μm, when the average diameter is less than 5 μm, temporary increase in vascular permeability If the phenomena cannot be caused, and if the thickness exceeds 15 µm, it is not preferable because it causes severe clogging of blood vessels and deteriorates safety.
본 발명의 일 실시예에서, 상기 내부수상에 수용성 약물 또는 수용성 색소를 더 포함할 수 있는 바, 이와 같이 트리올레인 방울에 봉입된 내부수상에 수용성 물질을 포함함으로써 트리올레인이 밀착 연접부를 갖는 간동맥벽을 느슨하게 하여 간조직 내부로 침투하면, 내부수상에 포함된 약물이 간조직 내부로 효과적으로 전달될 수 있어 바람직하다.In one embodiment of the present invention, a water-soluble drug or a water-soluble pigment may be further included in the inner water. By including a water-soluble substance in the inner water enclosed in the triolein drop, triolein has a close junction. When the hepatic artery wall is loosened and penetrates into the liver tissue, it is preferable that drugs contained in the internal water can be effectively delivered into the liver tissue.
본 발명에서 사용되는 상기 약물은 동물 또는 사람의 체내에서 생리적인 기능을 촉진 또는 억제하여 목적하는 생물학적 또는 약리학적 효과를 유도할 수 있는 물질로서, 동물 또는 사람에게 투여하기 적합한 화학적 또는 생물학적 물질 또는 화합물을 의미하며, 감염 예방과 같은 원하지 않은 생물학적 효과를 예방하여 유기물에 대한 예방효과를 가지고, 질병으로 생기는 컨디션을 경감시키며, 예를 들어 질병의 결과로 생기는 고통 또는 감염을 완화시키며, 유기물로부터 질병을 완화, 감소 또는 완전히 제거할 수 있는 역할을 할 수 있다.The drug used in the present invention is a substance capable of inducing a desired biological or pharmacological effect by promoting or inhibiting a physiological function in the body of an animal or human, and a chemical or biological substance or compound suitable for administration to an animal or human It means that it has a preventive effect on organic matter by preventing unwanted biological effects such as infection prevention, alleviates the condition caused by a disease, relieves pain or infection resulting from a disease, for example, and relieves disease from organic matter. It can play a role that can be mitigated, reduced or completely eliminated.
이때, 상기 수용성 약물은 항암제, 아미노글리코시드계 항생제, 항진균제, 항노화제 또는 항체 약물일 수 있고, 보다 바람직하게는 독소루비신(Doxorubicin), 시타라빈(cytarabine), 빈블라스틴(vinblastine), 리툭시맙(rituximab), 트라스트주맙(trastuzumab), 젠타마이신(gentamicin) 및 토브라마이신(tobramycin)으로 이루어진 군에서 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지는 않는다.At this time, the water-soluble drug may be an anticancer agent, an aminoglycoside antibiotic, an antifungal agent, an anti-aging agent, or an antibody drug, and more preferably, doxorubicin, cytarabine, vinblastine, rituxi Mab (rituximab), trastuzumab (trastuzumab), gentamicin (gentamicin) and may be any one or more selected from the group consisting of tobramycin (tobramycin), but is not limited thereto.
또한, 상기 수용성 색소는 트리판블루, 에반스블루, 콩고 레드 및 메틸렌블루로 이루어진 군에서 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지는 않는다.In addition, the water-soluble pigment may be any one or more selected from the group consisting of trypan blue, evans blue, Congo red, and methylene blue, but is not limited thereto.
본 발명의 일 실시예에서, 상기 유상에 지용성 약물을 더 포함할 수 있다.In one embodiment of the present invention, a fat-soluble drug may be further included in the oil phase.
즉, 상기 조성물은 트리올레인이 간동맥벽의 밀착연접을 느슨하게 만들어 약물을 간으로 전달할 수 있다.That is, the composition can deliver the drug to the liver by making the triolein loosen the tight junction of the hepatic artery wall.
본 발명에서 상기 약물 전달용 조성물은 약학적으로 유효한 양의 W/O/W형 구조의 트리올레인 에멀전 내지 약물 외에 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 더 포함할 수 있다.In the present invention, the composition for drug delivery may further include one or more pharmaceutically acceptable carriers, excipients or diluents in addition to a pharmaceutically effective amount of a W/O/W-type triolein emulsion or drug.
본 발명에서 상기 "약학적으로 유효한 양"은 약물이 동물 또는 사람에게 투 여되어 목적하는 생리학적 또는 약리학적 활성을 나타내기에 충분한 양을 의미하며 투여 대상의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있다. In the present invention, the "pharmaceutically effective amount" refers to an amount sufficient for the drug to be administered to an animal or human to exhibit a desired physiological or pharmacological activity, and the age, weight, health condition, sex, administration It can be changed appropriately depending on the route and treatment period.
또한, 본 발명에서 상기 "약학적으로 허용되는"은 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 의미한다.In addition, the "pharmaceutically acceptable" in the present invention means that when administered to a human being physiologically acceptable, usually does not cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions.
상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
또한, 이외에도 상기 약물 전달용 조성물은 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In addition, the drug delivery composition may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative.
본 발명에 따른 약물 전달용 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 약물의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있다. 또한, 본 발명의 약물 전달용 조성물은 약물이 목적하는 효과를 상승시킬 수 있는 공지의 화합물과도 병행하여 투여될 수 있다.The composition for drug delivery according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular, and the dosage of the drug may include the route of administration, the age, sex, weight, and severity of the patient. It can be appropriately selected according to several factors. In addition, the composition for drug delivery of the present invention may be administered in parallel with a known compound capable of enhancing the desired effect of the drug.
더불어, 본 발명은 트리올레인과, 계면활성제가 포함된 물을 혼합하여 1차 트리올레인 에멀전을 제조하는 단계; 및 상기 1차 트리올레인 에멀전에 폴리비닐알코올(poly vinyl alcohol)이 포함된 물을 첨가한 후, 동력원(power source)을 처리하여, 평균직경이 5 ㎛ 초과 15 ㎛ 미만인 트리올레인 방울을 포함하는 W/O/W형 트리올레인 에멀전을 제조하는 단계를 포함하는 간조직으로의 약물 전달체 제조방법을 제공한다.In addition, the present invention comprises the steps of preparing a first triolein emulsion by mixing triolein and water containing a surfactant; And triolein droplets having an average diameter of more than 5 µm and less than 15 µm by treating a power source after adding water containing polyvinyl alcohol to the first triolein emulsion. It provides a method of manufacturing a drug delivery system to liver tissue comprising the step of preparing a W/O/W type triolein emulsion.
종래에는 3방 주사기 밸브(3-way syringe valve)를 이용하여 트리올레인과 물을 여러 번 혼합하여 트리올레인 에멀전을 제조하였으나, 트리올레인과 물은 전혀 섞이지 않으므로 매우 빠르게 층 분리가 일어나면서 에멀전 시스템이 파괴된다는 한계가 있었다. 더욱이, 이러한 방식으로는 트리올레인 에멀전의 입자 크기를 조절하는 것 또한 매우 어렵다는 문제가 있다.Conventionally, triolein emulsion was prepared by mixing triolein and water several times using a 3-way syringe valve, but since triolein and water are not mixed at all, layer separation occurs very quickly. There was a limit to the destruction of the emulsion system. Moreover, there is a problem that it is also very difficult to control the particle size of the triolein emulsion in this manner.
반면에, 본 발명에 따르면, 상기 제조과정에서 입자의 평균직경을 쉽게 조절할 수 있어, 가장 효과가 좋은 평균직경의 입자만을 다량 제조할 수 있으므로, 적은 양의 트리올레인으로도 충분한 간동맥 오프닝 효과를 나타낼 수 있게 되는 바, 효과적으로 밀착 연접부를 갖는 간조직으로 약물을 전달할 수 있는 W/O/W형 트리올레인 에멀전을 제조할 수 있다. 또한, 흔히 사용되는 주사기를 이용하여 용이하고 간편하게 제조할 수 있고, 재현성 또한 매우 우수하다.On the other hand, according to the present invention, since the average diameter of the particles can be easily adjusted during the manufacturing process, only a large amount of particles having the most effective average diameter can be manufactured, so that even a small amount of triolein can provide sufficient hepatic artery opening effect. As can be seen, it is possible to prepare a W/O/W-type triolein emulsion capable of effectively delivering drugs to liver tissues having a tight junction. In addition, it can be easily and conveniently manufactured using a commonly used syringe, and reproducibility is also very good.
이때, 상기 1차 트리올레인 에멀전은 트리올레인 100 중량부에 대하여, 계면활성제 0.2 중량부 내지 0.8 중량부 및 이를 포함하는 물 20 중량부 내지 50 중량부를 혼합하여 제조될 수 있으나, 이에 제한되는 것은 아니다.At this time, the first triolein emulsion may be prepared by mixing 0.2 parts by weight to 0.8 parts by weight of a surfactant and 20 parts by weight to 50 parts by weight of water containing the same based on 100 parts by weight of triolein, but is limited thereto. It is not.
본 발명의 일 실시예에서, 상기 계면활성제가 포함된 물은 수용성 약물 또는 수용성 색소를 더 포함할 수 있다.In one embodiment of the present invention, the water containing the surfactant may further contain a water-soluble drug or a water-soluble pigment.
이때, 상기 수용성 약물은 항암제, 아미노글리코시드계 항생제, 항진균제, 항노화제 또는 항체 약물일 수 있고, 보다 바람직하게는 독소루비신(Doxorubicin), 시타라빈(cytarabine), 빈블라스틴(vinblastine), 리툭시맙(rituximab), 트라스트주맙(trastuzumab), 젠타마이신(gentamicin) 및 토브라마이신(tobramycin)으로 이루어진 군에서 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지는 않는다.At this time, the water-soluble drug may be an anticancer agent, an aminoglycoside antibiotic, an antifungal agent, an anti-aging agent, or an antibody drug, and more preferably, doxorubicin, cytarabine, vinblastine, rituxi Mab (rituximab), trastuzumab (trastuzumab), gentamicin (gentamicin) and may be any one or more selected from the group consisting of tobramycin (tobramycin), but is not limited thereto.
또한, 상기 수용성 색소는 트리판블루, 에반스블루, 콩고 레드 및 메틸렌블루로 이루어진 군에서 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지는 않는다.In addition, the water-soluble pigment may be any one or more selected from the group consisting of trypan blue, evans blue, Congo red, and methylene blue, but is not limited thereto.
본 발명의 일 실시예에서, 상기 동력원은 초음파 발생기(sonicator), 균질화기(homogenizer) 및 주사기로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the power source may be selected from the group consisting of an ultrasonic generator, a homogenizer, and a syringe, but is not limited thereto.
본 발명의 일 실시예에서, 상기 트리올레인 방울은 지용성 약물을 더 포함할 수 있다.In one embodiment of the present invention, the triolein droplet may further contain a fat-soluble drug.
또한, 바람직하게는, 상기 트리올레인 방울의 평균직경은 5 ㎛ 초과 10 ㎛ 미만일 수 있다.In addition, preferably, the average diameter of the triolein droplets may be more than 5 μm and less than 10 μm.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이며 본 발명의 내용을 예시하는 것일 뿐이므로 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are provided to more fully describe the present invention to those with average knowledge in the art, and are only illustrative of the contents of the present invention, so that the scope of the present invention is limited to the following examples. no.
<실시예 1> W/O/W 이중 구조의 트리올레인 에멀전 제조<Example 1> W/O/W dual structure triolein emulsion preparation
도 1에 개시된 모식도와 같이, 기존의 트리올레인 에멀전(왼쪽)보다 안정화된 W/O/W 이중 구조의 트리올레인 에멀전(오른쪽)을 제조하기 위해, 먼저 계면활성제인 span 80과 수용성 색소인 콩고 레드를 넣은 소량의 물과 트리올레인(sigma aldrich)을 혼합한 후 초음파 발생기를 이용하여, 트리올레인 용액 중에 붉은색을 띠는 수상 방울이 유화되도록 함으로써 1차 에멀전을 제조하였다.As shown in the schematic diagram disclosed in FIG. 1, in order to prepare a W/O/W dual structure triolein emulsion (right) that is more stabilized than the conventional triolein emulsion (left), first, span 80 as a surfactant and a water-soluble pigment A first emulsion was prepared by mixing a small amount of water containing Congo red and triolein (sigma aldrich), and then using an ultrasonic generator to emulsify red water droplets in the triolein solution.
이때, 광학 현미경을 이용하여 에멀전을 관찰한 결과, 도 2A에 나타난 바와 같이, 붉은색의 수용성 색소가 방울모양으로 트리올레인 내부에 위치하는 것을 확인할 수 있었다.At this time, as a result of observing the emulsion using an optical microscope, as shown in FIG. 2A, it could be confirmed that the red water-soluble pigment was located inside the triolein in a droplet shape.
이후, 상기 1차 에멀전에 1%의 폴리비닐알코올(poly vinyl alcohol)을 함유하는 물을 일정량 첨가하고, 동력원으로 주사기를 이용하여 섞어 5 ㎛ 초과 20 ㎛ 미만의 평균입경을 가지면서, 내부에 수상 방울이 포함된 트리올레인 방울을 포함하는 W/O/W 구조의 트리올레인 에멀전을 제조하였다. 이때, 콩고레드를 이용하여 이중 에멀전을 관찰한 결과 도 2B와 같았으며, 전술한 바와 같이, 수용성 색소가 대부분 트리올레인 방울 내부에 봉입되어 있는 것을 확인하였다.Thereafter, a certain amount of water containing 1% polyvinyl alcohol was added to the first emulsion, and mixed using a syringe as a power source, while having an average particle diameter of more than 5 µm and less than 20 µm, the water phase inside A triolein emulsion having a W/O/W structure was prepared including triolein droplets containing droplets. At this time, as a result of observing the double emulsion using Congo red, it was as shown in FIG. 2B, and as described above, it was confirmed that most of the water-soluble pigments were enclosed in the triolein droplets.
이후, 실험에 사용 시에는 생리식염수에 녹여 원하는 농도로 희석하여 사용하였으며, 이때, 광학 현미경을 이용하여 에멀전을 관찰한 결과가 도 2C에 나타난 바와 같았다.Thereafter, when used in the experiment, it was dissolved in physiological saline and diluted to a desired concentration. At this time, the result of observing the emulsion using an optical microscope was as shown in FIG. 2C.
<실시예 2> W/O/W 이중 구조 트리올레인 에멀전의 평균입경 분포 측정<Example 2> Measurement of average particle size distribution of W/O/W double structure triolein emulsion
상기 실시예 1에서 개시한 방법대로 제조한 W/O/W 이중 구조 트리올레인 에멀전의 평균입경을 광학 현미경을 이용하여 200개 이상의 입자를 무작위로 샘플링하고 image J 프로그램을 이용하여 스케일 바(scale bar)와의 길이 비교를 통해 입자 직경을 측정, 통계 처리를 하여 측정하였다.The average particle diameter of the W/O/W dual structure triolein emulsion prepared according to the method disclosed in Example 1 above was randomly sampled using an optical microscope, and a scale bar (scale) was performed using the image J program. bar) was measured by measuring the particle diameter and performing statistical processing.
그 결과, 도 3 및 하기 표 1에 나타난 바와 같이, 상기 트리올레인 에멀전은 5-20 ㎛의 평균입경을 주로 나타내었으며, 평균은 약 7.58 ㎛이었다. 이때, 5-20 ㎛의 평균입경을 가지는 입자가 일시적인 BBB 오프닝에 관여하는 것으로 추정되는 바, 20 ㎛ 이상의 큰 입자가 많이 존재하는 에멀전을 사용할 경우에는 오히려 안전성에 영향을 줄 수 있다.As a result, as shown in FIG. 3 and Table 1 below, the triolein emulsion mainly exhibited an average particle diameter of 5-20 μm, and the average was about 7.58 μm. At this time, it is estimated that particles having an average particle diameter of 5-20 μm are involved in the temporary BBB opening. When an emulsion containing a large number of particles larger than 20 μm is used, safety may be rather affected.
평균Average 7.581127.58112
표준편차Standard Deviation 3.804863.80486
입도 분포 (%)Particle size distribution (%)
5 ㎛ 이하5 μm or less 28.128.1
5-7.5 ㎛5-7.5 μm 30.830.8
7.5-10 ㎛7.5-10 μm 21.221.2
10-20 ㎛10-20 μm 18.518.5
20 ㎛ 이상20 ㎛ or more 1.41.4
전체all 100.0100.0
<< 실시예Example 3> W/O/W 이중 구조 3> W/O/W dual structure 트리올레인Triolein 에멀전의Emulsion 간으로의 약물 전달 효과 확인 Confirming the effect of drug delivery to the liver
(1) 트리올레인 에멀전의 간동맥 오프닝 활성 확인 (1) Confirmation of hepatic artery opening activity of triolein emulsion
먼저, 상기 실시예 1에서 수행한 방법대로 트리올레인 에멀전을 제조하되, 평균직경을 8 ㎛이 되도록 하였고, 에멀전의 농도를 3%로 맞추어주었다. 셈타코에서 분양받은 토끼(2.5 Kg, 수컷)를 대상으로 미세도관을 이동맥(central auricular artery)에 주입하여 그 끝을 간동맥에 위치시킨 후 상기에서 제조한 에멀전을 토끼 한 마리당 15 ml씩 주입하였다. 이후, 곧바로 3 ml의 트리판 블루를 토끼에 주입하였고, 2시간이 지난 후 토끼 간을 적출하여 파랗게 염색된 곳을 관찰하였다. 이때 간동맥이 오프닝되는 경우, 그 오프닝되는 부위가 파랗게 염색되는 원리를 이용하였다. First, a triolein emulsion was prepared according to the method performed in Example 1, but the average diameter was set to 8 µm, and the concentration of the emulsion was adjusted to 3%. A microtubule was injected into the central auricular artery for rabbits (2.5 Kg, male) sold in Semtaco, and the tip was placed in the hepatic artery, and the emulsion prepared above was injected at a rate of 15 ml per rabbit. . Thereafter, 3 ml of trypan blue was immediately injected into the rabbit, and after 2 hours, the rabbit liver was excised and the blue-stained area was observed. At this time, when the hepatic artery is opened, the principle that the area to be opened is stained blue was used.
그 결과, 도 4에 나타난 바와 같이, 트리올레인 에멀전에 의해 간 조직의 간동맥이 오프닝된 부위가 트리판 블루로 파랗게 염색된 것으로 나타났다. As a result, as shown in FIG. 4, it was found that the area where the hepatic artery of the liver tissue was opened was stained blue with trypan blue by the triolein emulsion.
(2) 간으로의 약물 전달 활성 확인(2) Confirmation of drug delivery activity to the liver
상기와 동일한 방법으로, W/O/W 이중 구조의, 평균 입경이 8 ㎛인 트리올레인 에멀전을 제조하였다. 생리식염수 10 ml에 상기 에멀전 0.3 ml (3%)를 혼합하여 희석한 후, 샘타코에서 분양받은 2.5 kg의 수컷 토끼에, 상기 트리판 블루를 투입한 실험에서와 동일한 과정으로 희석한 에멀전 8 ml 및 수용성 약물인 독소루비신을 주입하였고, 2시간 후, 상기 토끼의 간을 적출하여 독소루비신의 농도를 플루오로메터를 이용하여 측정하였다. 이때, 간 조직을 여섯 군데 떼어내어 3번 측정하였다.In the same manner as described above, a triolein emulsion having a W/O/W double structure and an average particle diameter of 8 μm was prepared. After diluting by mixing 0.3 ml (3%) of the emulsion in 10 ml of physiological saline, 8 ml of the emulsion diluted in the same procedure as in the experiment in which trypan blue was added to 2.5 kg male rabbits sold by Samtaco. And doxorubicin, a water-soluble drug, was injected, and 2 hours later, the liver of the rabbit was excised and the concentration of doxorubicin was measured using a fluorometer. At this time, six liver tissues were removed and measured three times.
그 결과, 도 5에 나타난 바와 같이, 간에서 독소루비신의 농도가 대조군에 비해 독소루비신의 농도의 평균 2배 가량 더 많이 포함되어 있는 것을 확인할 수 있었다. As a result, as shown in FIG. 5, it was confirmed that the concentration of doxorubicin in the liver was contained twice as much as the average concentration of doxorubicin compared to the control group.
(3) 트리판 블루 염색에 의한 트리올레인 에멀전의 간동맥 오프닝 확인(3) Confirmation of hepatic artery opening of triolein emulsion by trypan blue staining
상기와 동일한 방법으로, W/O/W 이중 구조의, 평균 입경이 8 ㎛이며 조영제가 봉입된 트리올레인 에멀전을 제조하였다. 생리식염수 10 ml에 상기 에멀전 0.3 ml (3%)를 혼합하여 희석한 후, 샘타코에서 분양받은 2.5 kg의 수컷 토끼에, 에멀전 15 ml을 주입하였고, 이어서 트리판 블루 3 ml를 주입하였다. 2시간 후, 상기 토끼의 간을 적출하였다. 이는 간동맥이 오프닝 될 경우에 간 조직으로 스며드는 염색약 트리판 블루의 성질을 이용한 촬영법이며 간 조직으로 스며든 트리판 블루는 푸르게 염색되어 나타나게 된다.In the same manner as described above, a triolein emulsion having a W/O/W double structure, an average particle diameter of 8 μm, and encapsulation of a contrast agent was prepared. After mixing and diluting 0.3 ml (3%) of the emulsion in 10 ml of physiological saline, 15 ml of the emulsion was injected into a 2.5 kg male rabbit sold by Samtaco, followed by 3 ml of trypan blue. After 2 hours, the rabbit liver was excised. This is a photographing method using the property of trypan blue, a dye that permeates the liver tissue when the hepatic artery is opened, and the trypan blue that has penetrated into the liver tissue is stained blue and appears.
그 결과, 도 6에 나타난 바와 같이, 트리올레인 에멀전에 의해 열린 간동맥으로 인해 간 조직이 대조군에 비해 푸르게 염색되어 나타나는 것을 알 수 있었다(화살표).As a result, as shown in FIG. 6, it was found that the liver tissue was stained blue compared to the control group due to the hepatic artery opened by the triolein emulsion (arrow).
따라서, 상기의 실험 결과들을 종합하면, 내부에 수상 방울이 봉입되어 있는 트리올레인 W/O/W 이중 방울 구조의 에멀전은 트리올레인이 간동맥을 느슨하게 하여 오프닝하는 활성을 그대로 나타내면서도 안정적인 제형으로 제조될 수 있으므로, 밀착 연접부를 갖는 조직, 즉, 간으로의 약물 전달을 효율적으로 수행할 수 있다.Therefore, when the above experimental results are summarized, the triolein W/O/W double droplet structure emulsion with water droplets encapsulated therein is prepared in a stable formulation while showing the activity of opening by loosening the hepatic artery as it is. Therefore, it is possible to efficiently perform drug delivery to a tissue having a tight junction, that is, a liver.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다. As described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it is obvious that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereby. Do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (12)

  1. 유상 방울이 트리올레인을 포함하고, 상기 유상 방울 내부에 물방울을 봉입한 내부수상/유상/외부수상(Water/Oil/Water; W/O/W)형 구조의 트리올레인 에멀전을 유효성분으로 포함하는 간조직으로의 약물 전달용 조성물.The oily droplet contains triolein, and contains a triolein emulsion of an internal/oil/external (Water/Oil/Water; W/O/W) structure in which a water droplet is enclosed in the oil droplet as an active ingredient A composition for drug delivery to liver tissue.
  2. 제1항에 있어서, 상기 유상 방울의 평균직경은 5 ㎛ 초과 15 ㎛ 미만인 것을 특징으로 하는 간조직으로의 약물 전달용 조성물.The composition for drug delivery to liver tissue according to claim 1, wherein the average diameter of the oil droplets is more than 5 µm and less than 15 µm.
  3. 제1항에 있어서, 상기 내부수상에 수용성 약물 또는 수용성 색소를 더 포함하는 것을 특징으로 하는 간조직으로의 약물 전달용 조성물.The composition for drug delivery to liver tissue according to claim 1, further comprising a water-soluble drug or a water-soluble pigment in the internal water phase.
  4. 제3항에 있어서, 상기 수용성 약물은 독소루비신인 것을 특징으로 하는 간조직으로의 약물 전달용 조성물.The composition for delivery of drugs to liver tissue according to claim 3, wherein the water-soluble drug is doxorubicin.
  5. 제1항에 있어서, 상기 유상에 지용성 약물을 더 포함하는 것을 특징으로 하는 간조직으로의 약물 전달용 조성물.The composition for drug delivery to liver tissue according to claim 1, further comprising a fat-soluble drug in the oil phase.
  6. 제1항에 있어서, 상기 조성물은 트리올레인이 간동맥의 밀착연접을 느슨하게 만들어 약물을 간으로 전달하는 것을 특징으로 하는 간조직으로의 약물 전달용 조성물.According to claim 1, wherein the composition is a composition for drug delivery to liver tissue characterized in that the triolein loosens the tight junction of the hepatic artery to deliver the drug to the liver.
  7. 트리올레인과, 계면활성제가 포함된 물을 혼합하여 1차 트리올레인 에멀전을 제조하는 단계; 및Preparing a first triolein emulsion by mixing triolein and water containing a surfactant; And
    상기 1차 트리올레인 에멀전에 폴리비닐알코올(poly vinyl alcohol)이 포함된 물을 첨가한 후, 동력원(power source)을 처리하여, 평균직경이 5 ㎛ 초과 15 ㎛ 미만인 트리올레인 방울을 포함하는 W/O/W형 트리올레인 에멀전을 제조하는 단계를 포함하는 간조직으로의 약물 전달체 제조방법.After adding water containing polyvinyl alcohol to the first triolein emulsion, treating a power source, including triolein droplets having an average diameter of more than 5 μm and less than 15 μm A method for producing a drug delivery system to liver tissue comprising the step of preparing a W/O/W-type triolein emulsion.
  8. 제7항에 있어서, 상기 1차 트리올레인 에멀전은 트리올레인 100 중량부에 대하여, 계면활성제 0.2 중량부 내지 0.8 중량부 및 이를 포함하는 물 20 중량부 내지 50 중량부를 혼합하여 제조되는 것을 특징으로 하는 간조직으로의 약물 전달체 제조방법.The method of claim 7, wherein the first triolein emulsion is prepared by mixing 0.2 parts by weight to 0.8 parts by weight of a surfactant and 20 parts by weight to 50 parts by weight of water containing the same based on 100 parts by weight of triolein. A method of manufacturing a drug delivery system to liver tissue.
  9. 제7항에 있어서, 상기 계면활성제가 포함된 물은 수용성 약물 또는 수용성 색소를 더 포함하는 것을 특징으로 하는 간조직으로의 약물 전달체 제조방법.The method of claim 7, wherein the water containing the surfactant further comprises a water-soluble drug or a water-soluble pigment.
  10. 제9항에 있어서, 상기 수용성 약물은 독소루비신인 것을 특징으로 하는 간조직으로의 약물 전달체 제조방법.The method of claim 9, wherein the water-soluble drug is doxorubicin.
  11. 제7항에 있어서, 상기 동력원은 초음파 발생기(sonicator), 균질화기(homogenizer) 및 주사기로 이루어진 군에서 선택되는 것을 특징으로 하는 간조직으로의 약물 전달체 제조방법.The method of claim 7, wherein the power source is selected from the group consisting of an ultrasonic generator, a homogenizer, and a syringe.
  12. 제7항에 있어서, 상기 트리올레인 방울은 지용성 약물을 더 포함하는 것을 특징으로 하는 간조직으로의 약물 전달체 제조방법.The method of claim 7, wherein the triolein droplet further comprises a fat-soluble drug.
PCT/KR2020/007568 2019-06-13 2020-06-11 Platform for improving drug delivery to liver, using w/o/w-type triolein emulsion WO2020251271A1 (en)

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KR1020190108879A KR102280309B1 (en) 2019-06-13 2019-09-03 Increased drug delivery platform using W/O/W triolein emulsion in the liver
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