WO2020251271A1 - Plateforme permettant d'améliorer l'administration d'un médicament au foie, à l'aide d'une émulsion de trioléine de type eau/huile/eau - Google Patents

Plateforme permettant d'améliorer l'administration d'un médicament au foie, à l'aide d'une émulsion de trioléine de type eau/huile/eau Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
triolein
water
emulsion
drug
drug delivery
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PCT/KR2020/007568
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English (en)
Korean (ko)
Inventor
김학진
유진욱
전병학
김용우
최선희
Original Assignee
부산대학교 산학협력단
부산대학교병원
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Priority claimed from KR1020190108879A external-priority patent/KR102280309B1/ko
Application filed by 부산대학교 산학협력단, 부산대학교병원 filed Critical 부산대학교 산학협력단
Publication of WO2020251271A1 publication Critical patent/WO2020251271A1/fr

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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.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une plateforme permettant d'améliorer l'administration d'un médicament au foie, à l'aide d'une émulsion de trioléine de type eau/huile/eau, et peut : résoudre le problème selon lequel une émulsion est rapidement détruite en raison d'une différence de densité significative entre l'eau et la trioléine dans une émulsion de trioléine classique ; diminuer la différence de taille entre les particules étant donné que les tailles de particules peuvent être réglées pendant la production ; et produire des particules stables. La présente invention concerne plus précisément une technique qui augmente la perméabilité vasculaire d'un tissu hépatique et qui permet à une quantité plus importante d'un médicament anticancéreux provenant d'un vaisseau sanguin d'atteindre un tissu cancéreux, et la présente invention redouble l'effet du médicament anticancéreux et, par conséquent, peut être utilisée avantageusement en tant que composition permettant d'administrer un médicament au foie.
PCT/KR2020/007568 2019-06-13 2020-06-11 Plateforme permettant d'améliorer l'administration d'un médicament au foie, à l'aide d'une émulsion de trioléine de type eau/huile/eau WO2020251271A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20190069994 2019-06-13
KR10-2019-0069994 2019-06-13
KR10-2019-0108879 2019-09-03
KR1020190108879A KR102280309B1 (ko) 2019-06-13 2019-09-03 W/o/w형 트리올레인 에멀전을 이용한 간의 약물전달 증진 플랫폼

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WO2020251271A1 true WO2020251271A1 (fr) 2020-12-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995031181A1 (fr) * 1994-05-16 1995-11-23 The Board Of Regents Of The University Of Michigan Emulsion aqueuse hepatocyto-selective
WO1996040615A1 (fr) * 1995-06-07 1996-12-19 Molecular Biosystems, Inc. Agents de contrastes lipophiles utilisables dans des emulsions huile-dans-l'eau a selectivite hepatocytaire
KR20190069725A (ko) * 2017-12-12 2019-06-20 부산대학교 산학협력단 혈관-뇌장벽(Blood-brain barrier) 투과성을 증진시키는 W/O/W형 트리올레인 에멀전을 이용한 약물 전달 플랫폼

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995031181A1 (fr) * 1994-05-16 1995-11-23 The Board Of Regents Of The University Of Michigan Emulsion aqueuse hepatocyto-selective
WO1996040615A1 (fr) * 1995-06-07 1996-12-19 Molecular Biosystems, Inc. Agents de contrastes lipophiles utilisables dans des emulsions huile-dans-l'eau a selectivite hepatocytaire
KR20190069725A (ko) * 2017-12-12 2019-06-20 부산대학교 산학협력단 혈관-뇌장벽(Blood-brain barrier) 투과성을 증진시키는 W/O/W형 트리올레인 에멀전을 이용한 약물 전달 플랫폼

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SHINJI SUGIURA, MITSUTOSHI NAKAJIMA, KOJI YAMAMOTO, SATOSHI IWAMOTO, TATSUYA ODA, MITSUO SATAKE, MINORU SEKI: "Preparation characteristics of water-in-oil-in-water multiple emulsions using microchannel emulsification", JOURNAL OF COLLOID AND INTERFACE SCIENCE, ACADEMIC PRESS,INC., US, vol. 270, no. 1, 1 February 2004 (2004-02-01), US, pages 221 - 228, XP055764467, ISSN: 0021-9797, DOI: 10.1016/j.jcis.2003.08.021 *
TAKAHIRO KAWAKATSU, GUN TRÄGÅRDH, CHRISTIAN TRÄGÅRDH: "Production of W/O/W emulsions and S/O/W pectin microcapsules by microchannel emulsification", COLLOIDS AND SURFACES A: PHYSIOCHEMICAL AND ENGINEERING ASPECTS, ELSEVIER, AMSTERDAM, NL, vol. 189, no. 1-3, 1 September 2001 (2001-09-01), AMSTERDAM, NL, pages 257 - 264, XP055764465, ISSN: 0927-7757, DOI: 10.1016/S0927-7757(01)00508-8 *
YOUNGMI PARK: "Effect of Intraarterial Infusion with Triolein Emulsion on the Liver of Rabbits", DOCTORAL THESIS, 1 February 2009 (2009-02-01), pages 1 - 44, XP009524911 *

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