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WO2015083996A1 - Forme posologique pharmaceutique destinée au traitement d'une leucémie myéloïde chronique, contenant un extrait d'écorce de liriodendron tulipifera l. comme principe actif - Google Patents

Forme posologique pharmaceutique destinée au traitement d'une leucémie myéloïde chronique, contenant un extrait d'écorce de liriodendron tulipifera l. comme principe actif Download PDF

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Publication number
WO2015083996A1
WO2015083996A1 PCT/KR2014/011607 KR2014011607W WO2015083996A1 WO 2015083996 A1 WO2015083996 A1 WO 2015083996A1 KR 2014011607 W KR2014011607 W KR 2014011607W WO 2015083996 A1 WO2015083996 A1 WO 2015083996A1
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Prior art keywords
fatty acid
pharmaceutical formulation
bark extract
polyoxyethylene
extract
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Ceased
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PCT/KR2014/011607
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English (en)
Korean (ko)
Inventor
김기운
유혜동
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CHO DANG PHARM Co Ltd
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CHO DANG PHARM Co Ltd
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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a pharmaceutical formulation for treating chronic myelogenous leukemia, which contains the extract of the bark of the lily of the valley as an active ingredient. More specifically, in order to selectively inhibit the mutant T315I due to the BCR-ABL fusion gene mutation, which is the cause of chronic myeloid leukemia, poly ADP ribose polymerization related to the change of mitochondrial membrane potential (MMP) and apoptosis pathway in leukemia cells.
  • MMP mitochondrial membrane potential
  • a pharmaceutical formulation for the treatment of chronic myelogenous leukemia which contains an extract of the bark of cauliflower, which causes apoptosis through cleavage of enzyme (PARP) and caspase-3.
  • Liriodendron tulipifera L. (Yellow-poplar) is a deciduous broad-leaved arborescent belonging to the Magnoliaceae, and it has been reported that the extract of the bark of the lily contains various compounds such as alkaloids, sesquiterpins and lignans. .
  • Lily bark extracts include costunolide, tulipinolide, epi-tulipinolide, epi-tulipdienolide and gamma-ririodenola Sesquiterpin lactones such as gamma-liriodenolide and the like are included.
  • the parthenolides have been found to have anti-inflammatory or anti-cancer effects through the nuclear transcription factors NF- ⁇ B, p21 and cyclin D1, and especially LC-, a synthetic derivative of patenolide and patenolide.
  • 1 dimethylamino-parthenolide
  • AML acute myeloid leukemia
  • Leukemia is a type of blood tumor in which blood cells, especially white blood cells, multiply abnormally. Leukocytes that do not mature properly are a disease that exists in the blood in large quantities. Compared with the abnormal proliferation of leukocytes, the normal number of blood cells becomes extremely small, which means that they can't perform basic blood functions such as oxygen transport or nutrition, as well as immune function, and abnormal leukocytes cause similar reactions to autoimmune diseases. It can also destroy normal tissue.
  • Chronic myeloid leukemia is a myeloproliferative disease in which myeloid leukemia cells proliferate uncontrolled in the bone marrow and accumulate in the blood.
  • the types of leukemia are divided into acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
  • abnormal myeloid cells In chronic myelogenous leukemia, abnormal myeloid cells generally appear mature in appearance but fail to function properly. These chronic myeloid leukemias are associated with abnormal genetic markers in cells called the Philadelphia chromosome.
  • Chronic myeloid leukemia is different from other common leukemias, and in particular, the transition from the slow progress of the chronic multiplication stage of abnormal cells to the acute stage of proliferation occurs.
  • Chronic myeloid leukemia can remain chronic for three to four years, at which time it is more effective to suppress rather than cure the disease.
  • most of the patients who have a sudden transition is very difficult to treat.
  • Chronic myeloid leukemia is caused by the BCR-ABL fusion gene, a Philadelphia chromosome in which the ABL gene on chromosome 9 and the BCR gene on chromosome 22 are transcribed.
  • BCR-ABL fusion genes are involved in carcinogenic protein p210 biosynthesis by expressing fusion proteins with Tyrosine kinase activity, and the biosynthesized p210 protein inhibits cell death of myeloid progenitor cells, resulting in abnormal cell death. Leads to myeloproliferative diseases due to proliferation.
  • Imatinib brand name: Gleevec
  • Gleevec is a first-generation ⁇ BCR-ABL '' tyrosine kinase inhibitor that has been used for a long time as a primary treatment for myeloid leukemia, but patients with imatinib resistance develop. Was caused.
  • the second generation of therapies that overcome the resistance to imatinib, such as Dasatinib, Nilotinib, and Bosutinib have been developed to raise expectations for more effective and diverse drug treatments.
  • the present inventors attempted to extract and purify pharmacologically active ingredients such as epi-tulipinide and costunolide from the bark of lily tree, and then, in vitro, to treat the effects of chronic myelogenous leukemia on each active ingredient. It was measured through a growth inhibition experiment of the Korean Patent Application No. 10-2013-46506 'the pharmaceutical composition for treating chronic myelogenous leukemia containing lycopene extract'.
  • lily bark extract is poorly soluble, so that the bioavailability may be lowered because the solubility and dissolution rate in the digestive fluid is low during absorption into the body. Therefore, various formulation means should be devised to improve the solubilization or dissolution rate of poorly soluble drugs, including lily bark extract.
  • the present inventors continued the formulation study to maximize the therapeutic effect and minimize side effects in using the lily bark extract as a treatment for chronic myelogenous leukemia, and the pharmaceutical formulation showing excellent chronic myelogenous leukemia treatment effect from the bark of lily tree bark.
  • the present invention was completed by inventing a pharmaceutical formulation that can improve the solubilization or dissolution rate of the poorly water-soluble lily bark extract.
  • the problem to be solved by the present invention is to develop a pharmaceutical formulation for maximizing the therapeutic effect and minimizing side effects in using the bark extract as a treatment for chronic myelogenous leukemia.
  • a pharmaceutical formulation that can improve the solubilization or dissolution rate of the poorly water-soluble lily bark extract.
  • An object of the present invention is to 1) polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid based on 100 parts by weight of the extract of the bark of the bark which contains epi-tulipinlide and costunolide as active ingredients.
  • Esters polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene polyoxypropylene copolymers, reaction products of natural or hydrogenated vegetable oils with ethylene glycol, sodium dioctylsulfosuccinate, sodium lauryl sulfonate, phospholipids, propylene glycol fatty acids 5-100 parts by weight of at least one surfactant selected from esters, trans esterification products of natural vegetable oil triglycerides with polyalkylene polyols, mono-glycerides, di-glycerides or sterols; And 2) 50-400 parts by weight of one or more cosolvents selected from propylene carbonate, propylene glycol, ethanol, diethylene glycol monoethyl ether, glycofurol, polyethylene glycol, dimethyl isosorbide or N-methyl pyrrolidone;
  • the lily bark extract is characterized in that it may further comprise epitulipdienolide (Epitulipdienolide) or ridentin (Ridentin) or deacetyllipiferolide (Deacetyllipiferolide) as an active ingredient.
  • the non-aqueous pharmaceutical formulation is characterized in that it comprises 10 to 50 parts by weight of surfactant and 100 to 200 parts by weight of the cosolvent based on 100 parts by weight of the lily bark extract.
  • the surfactant is at least one selected from polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer or polyoxyethylene polyoxypropylene copolymer It is done.
  • the co-solvent is characterized in that at least one selected from propylene glycol, polyethylene glycol or diethylene glycol monoethyl ether.
  • the effect of the present invention is to provide a pharmaceutical formulation for maximizing the therapeutic effect and minimizing side effects in using the bark extract as a treatment for chronic myelogenous leukemia. It is to provide a pharmaceutical formulation that can improve the solubilization or dissolution rate of the poorly water-soluble lily bark extract.
  • the non-aqueous pharmaceutical formulation of the present invention comprises 10 to 50 parts by weight of the surfactant and 100 to 200 parts by weight of the cosolvent based on 100 parts by weight of the lily bark extract.
  • the surfactant is at least one member selected from polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer or polyoxyethylene polyoxypropylene copolymer.
  • the cosolvent is at least one member selected from propylene glycol, polyethylene glycol or diethylene glycol monoethyl ether.
  • the present invention is to provide a soft capsule useful for the treatment of chronic myeloid leukemia containing the non-aqueous pharmaceutical formulation as a solution and molded into a gelatin coating.
  • the present invention relates to a pharmaceutical composition of a lily extract useful for selectively inhibiting the mutation enzyme T315I caused by the BCR-ABL fusion gene, which is a cause of chronic myeloid leukemia, and its active ingredients, epi-tulipinoid and costunolide. It provides, and may contain one or more known active ingredients having the same effect as the pharmaceutical composition or extract.
  • the lily bark extract of the present invention may further comprise epitulipdienolide (Epitulipdienolide) or ridentin (Ridentin) or deacetyllipiferolide (Deacetyllipiferolide) as an active ingredient.
  • the non-aqueous pharmaceutical formulation of the present invention may be administered in the form of general pharmaceutical compositions such as tablets, granules, capsules, powders, syrups, ointments, suppositories, and subcutaneous, intramuscular, intravenous or injectable drops, as well as soft capsules, 1 10 to 500 mg per day can be taken once or several times.
  • general pharmaceutical compositions such as tablets, granules, capsules, powders, syrups, ointments, suppositories, and subcutaneous, intramuscular, intravenous or injectable drops, as well as soft capsules, 1 10 to 500 mg per day can be taken once or several times.
  • composition is eluted by increasing the solubility and absorption in the gastrointestinal tract of substances commonly used in pharmaceuticals, such as lily bark extract, within the range that does not adversely affect the drug efficacy, and dispersed and emulsified with water during oral administration
  • Additives such as acids, fatty acids or fatty alcohols, sugars such as white sugar, macion syrup, white sugar, gelatin, sugars and syrups, glidants such as magnesium stearate and talc, microcrystalline Excipients such as cellulose, calcium dihydrogen phosphate, starch, mannitol, antioxidants, flavoring agents, preservatives, fragrances, sweeteners, pigments, pH adjusting agents and viscosity adjusting agents, which prevent the formulation from oxidizing, which may be lilies It is preferred to add the bark extract in a commonly used amount.
  • Acids, fatty acids or fatty alcohols that may be used in the compositions of the present invention include citric acid, oleic acid, stearyl alcohol, myristic acid, linoleic or lauric acid, capric acid, caprylic acid, caproic acid (caproic acid) ) May be used, but is not limited thereto.
  • Antioxidants that can be used in the compositions of the present invention are butylated hydroxytoluene, sodium bisulfite, ⁇ -tocopherol, vitamin C, ⁇ -carotene, tocopherol acetate, fumaric acid, nalic acid Butylated hydroxyanisole, propyl galate, sodium ascorbate and the like may be used, but are not limited thereto.
  • Flavoring agents that can be used in the composition of the present invention may be mixed fruit flavor, apple flavor, strawberry flavor, cherry flavor, peppermint flavor, vanilla flavor, yogurt flavor, or drink flavor and the like, but are not limited thereto.
  • Preservatives that can be used in the composition of the present invention may be used, but is not limited to benzoic acid, sodium benzoate, ethyl paraben, methyl paraben or propyl paraben.
  • Perfume which can be used in the composition of the present invention may be used, but not limited to, peppermint brain, peppermint oil, orange oil, clove oil, cinnamon oil, strawberry essence and other common fruit or plant essence.
  • Sweeteners that can be used in the compositions of the present invention may be used, but are not limited to, white sugar, glucose, fructose, aspartame, stevioside, sorbitol, mannitol, oligosaccharide, syrup or macion syrup.
  • the pigments that can be used in the composition of the present invention are green No. 3, red No. 2, red No. 3, blue No. 1, blue No. 2, yellow No. 4, yellow No. 5, water-soluble mannitol, caramel, titanium oxide or ferric oxide Can be used, but is not limited to these.
  • PH adjusting agent that can be used in the composition of the present invention may be used, but is not limited to sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine or monoethanol amine.
  • Viscosity modifiers that may be used in the compositions of the present invention are hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose (CMC), acacia , Bentonite, alginic acid, propylene glycol alginate, polyvinylpyrrolidone, polyvinyl alcohol (PVC), carbopol, polycarbopil, tragacanth or xanthan gum ) May be used, but is not limited thereto.
  • the administration of the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient and diluent in addition to the active ingredient.
  • carriers, excipients and diluents that may be included include lactose, textose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose It may be at least one selected from microcrystalline cellulose, polyvinylpyrrolidone, purified water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, hard capsules, soft capsules, chewing tablets of caramel or jelly type, and such solid preparations include at least one excipient in the active ingredient.
  • it can be used by mixing starch, calcium carbonate, sucrose or lactose, gelatin and the like.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to purified water and liquid paraffin, which are commonly used simple diluents. have.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like, and non-aqueous solvents and suspending agents include vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, and ethylol. Injectable esters such as late and the like can be used.
  • aqueous solvents and suspending agents include vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, and ethylol.
  • Injectable esters such as late and the like can be used.
  • As the base of the suppository utopsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the lily bark extract of the present invention and its pharmaceutical composition may be administered by various routes according to the desired method in addition to the oral administration, oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections, etc. Include.
  • the extract contains epi-tulipinlide and costunolide as main components and is called CD-200.
  • CD-200 extract inhibits leukemia mutant gene cell proliferation by inducing cell death by inducing apolarization of mitochondrial membrane potential (MMP) against T315I, a mutation of the BCR-ABL fusion gene, a cause of chronic myeloid leukemia Tested.
  • MMP mitochondrial membrane potential
  • CD-200 was treated with 1, 5, 10 ⁇ g / ml in Bcr-Abl T315I Ba / F3 cell line (1 ⁇ 10 6 cells / 10ml) and incubated in a 37 ° C., 5% CO 2 incubator for 8 hours. It was.
  • CD-200 extract inhibited leukemia mutant gene cell proliferation by inducing apoptosis through induction of Caspase-3 activity against T315I, a mutation of BCR-ABL fusion gene, a cause of chronic myeloid leukemia.
  • CD-200 was treated with 1,5 ⁇ g / ml in a Bcr-AblT315IBa / F3 cell line (8 ⁇ 10 5 cells / 2ml / well) and cultured in a 37 ° C., 5% CO 2 incubator for 12 hours.
  • B-C-Abl T315I Ba / F3 cell line (2 ⁇ 10 6 / 10ml) was treated with CD-200 at a concentration of 1 ⁇ 10 ⁇ g / ml and 37 ° C for 14 hours, Incubated in a 5% CO 2 incubator.
  • Western blot experiments were carried out as follows. 30 ⁇ g of protein was added to 10% and 15% SDS polyacrylamide gels, followed by electrophoresis for 2 hours, then transferred to fullovinylidene fluoride (PVDF) and for 1 hour with 5% non-fat skim milk.
  • PVDF fullovinylidene fluoride
  • BCD-200 induces apoptosis in Bcr-Abl T315I Ba / F3 cell line unlike Imatinib by forming a truncated form of the protein PARP, Caspase-3, which is involved in the apoptosis pathway at 5 ⁇ g / ml.
  • composition 100 mg of the yellow bark extract obtained in Preparation Example 1 and 40 mg of polyoxyethylene sorbitan fatty acid ester were mixed. 20 mg of Cremopoa RH40 and 200 mg of diethylene glycol monoethyl ether were added to the mixed solution, and heated to 80 ° C. to dissolve until clear, thereby preparing a composition.
  • the composition was formulated by filling in soft capsules.
  • composition 100 mg of the lily bark extract obtained in Preparation Example 1, 30 mg of polyoxyethylene sorbitan fatty acid ester, and 10 mg of polyoxyethylene polyoxypropylene block copolymer were mixed. 20 mg of Cremopoa RH40 and 150 mg of diethylene glycol monoethyl ether were added to the mixed solution, and heated at 80 ° C. to dissolve until clear to prepare a composition. The composition was formulated by filling into soft capsules.
  • the experimental method is as follows.
  • oral preparations (test preparations) by the automatic micelle drug delivery system according to the present invention can be seen that the solubility is very high in the gastrointestinal small intestine and large intestine compared to the preparation prepared by the conventional method, and various pH It can be seen that even under conditions, it dissolves constantly.
  • the dissolution rate of the soft capsule containing the lily bark extract CD-200 by the automatic micelle drug delivery system of the present invention and the oral tablet of the lily bark extract CD-200 without such a system were measured and compared.
  • the experimental method is as follows.

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Abstract

La présente invention concerne une forme posologique pharmaceutique destinée au traitement d'une leucémie myéloïde chronique, contenant un extrait d'écorce de Liriodendron tulipifera L. comme principe actif, et plus spécifiquement une forme posologique pharmaceutique destinée au traitement d'une leucémie myéloïde chronique, contenant un extrait d'écorce de Liriodendron tulipifera L., qui entraîne la mort cellulaire par une modification du potentiel membranaire mitochondriale (MMP) dans des cellules leucémiques, et le clivage de la poly(ADP-ribose) polymérase (PARP) et de la caspase-3 associé à une voie de mort cellulaire, de façon à inhiber sélectivement l'enzyme mutante T315I générée par la mutation du gène de fusion BCR-ABL, qui est un gène provoquant la leucémie myéloïde chronique.
PCT/KR2014/011607 2013-12-03 2014-12-01 Forme posologique pharmaceutique destinée au traitement d'une leucémie myéloïde chronique, contenant un extrait d'écorce de liriodendron tulipifera l. comme principe actif Ceased WO2015083996A1 (fr)

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KR10-2013-0149033 2013-12-03
KR1020130149033A KR101564926B1 (ko) 2013-12-03 2013-12-03 백합나무 수피 추출물을 유효 성분으로 함유하는 만성 골수성 백혈병 치료용 의약 제형

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106987599A (zh) * 2017-03-28 2017-07-28 重庆医科大学 采用锌指核酸酶技术破坏人bcr‑abl融合基因以抑制CML细胞增殖和促使其凋亡
CN116265455A (zh) * 2021-12-16 2023-06-20 复旦大学 一类倍半萜-生物碱杂聚体及其制备方法和制药的用途

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KR101327282B1 (ko) * 2012-02-16 2013-11-08 초당약품공업 주식회사 백합나무 수피 추출물을 유효 성분으로 함유하는 개선된 의약 제형

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KR101327282B1 (ko) * 2012-02-16 2013-11-08 초당약품공업 주식회사 백합나무 수피 추출물을 유효 성분으로 함유하는 개선된 의약 제형

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MOON, M.K. ET AL.: "Famesyl Protein Transferase and Tumor Cell Growth Inhibitory Activities of Lipiferolide Isolated from Liriodendron tulipifera", ARCHIVES OF PHARMACAL RESEARCH, vol. 30, no. 3, 2007, pages 299 - 302 *
XU, MING-LU ET AL.: "The Antioxidant and Anticancer Effects of MeOH Extract of Liridendron tulipifera", KOREAN JOURNAL OF PLANT RESOURCES, vol. 24, no. 1, 2011, pages 23 - 29, XP053017561 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106987599A (zh) * 2017-03-28 2017-07-28 重庆医科大学 采用锌指核酸酶技术破坏人bcr‑abl融合基因以抑制CML细胞增殖和促使其凋亡
CN116265455A (zh) * 2021-12-16 2023-06-20 复旦大学 一类倍半萜-生物碱杂聚体及其制备方法和制药的用途

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