TW201707707A - Preparation comprising indole compound and process for preparing the same - Google Patents

Preparation comprising indole compound and process for preparing the same Download PDF

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TW201707707A
TW201707707A TW105108958A TW105108958A TW201707707A TW 201707707 A TW201707707 A TW 201707707A TW 105108958 A TW105108958 A TW 105108958A TW 105108958 A TW105108958 A TW 105108958A TW 201707707 A TW201707707 A TW 201707707A
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pharmaceutical preparation
cyclodextrin
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金根泰
金剛民
朴基淑
朴索拉
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Ｌｇ生命科學股份有限公司
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    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Abstract

The present invention relates to the provision of a pharmaceutical preparation having improved stability in solution by improving the solubility of indole compound. A pharmaceutical preparation comprising an indole compound or a pharmaceutically acceptable derivative thereof, a cyclodextrin derivative and an antioxidant renders indole compounds-which have low aqueous solubility and are unstable in water capable of parenteral administration via the improvement of the solubility and stability in solution of indole compounds by forming as an inclusion complex of cyclodextrin derivative. The pharmaceutical preparation may be preferably used for inhibiting cellular necrosis and preventing ischemia/reperfusion injury. Specifically, fatal reperfusion cardiac injury by percutaneous coronary intervention (PCI) operation can be basically prevented or treated by the pre-treatment.

Description

包含吲哚化合物之製劑及其製備方法 Preparation containing bismuth compound and preparation method thereof

本發明係關於包含吲哚化合物或其醫藥上可接受之衍生物以及環糊精衍生物之新穎的製劑、以及其製備方法。 The present invention relates to novel formulations comprising an anthraquinone compound or a pharmaceutically acceptable derivative thereof, and a cyclodextrin derivative, and a process for the preparation thereof.

壞死-其係在病理情況下細胞死亡之主要機制-係缺血及再灌流損傷之臨床上主要成因，且會引起非常重要的病理現象，諸如心肌梗塞及中風。對心肌梗塞患者所執行之經皮冠狀動脈介入(percutaneous coronary intervention,PCI)可能會誘發致命性再灌流損傷，從而使心肌梗塞位置不發生癒合，其會導致死亡率增加。雖然對於開發用於減少因PCI手術後之再灌流損傷而殘留下梗塞位置之藥劑係有迫切的需求，但直至目前為止仍未開發出用於在根本上預防該種心肌組織的局部缺血/再灌流損傷之藥劑。 Necrosis - the main mechanism of cell death in pathological conditions - is the main clinical cause of ischemia and reperfusion injury, and can cause very important pathological phenomena, such as myocardial infarction and stroke. Percutaneous coronary intervention (PCI) performed in patients with myocardial infarction may induce fatal reperfusion injury, so that the location of myocardial infarction does not heal, which leads to increased mortality. Although there is an urgent need to develop a drug system for reducing the position of the infarct due to reperfusion injury after PCI surgery, it has not been developed until now to fundamentally prevent ischemia of the myocardial tissue. Reperfusion of the agent for injury.

韓國專利申請公開案第10-2012-0013266號係揭示吲哚及吲唑衍生物，其可作為具有與習知抗氧化劑不同的作用機制之強力抗氧化劑-即，具有去除ROS/RNS (活性氧類/活性氮類(Reactive Oxygen Species/Reactive Nitrogen Species))之活性且專一性地作用於細胞之粒線體，而有效地預防在病理情況下所誘發之細胞壞死。如此，透過可藉由專一性地作用於粒線體而強烈抑制細胞壞死且於各種器官對局部缺血/再灌流損傷具有預防功效之吲哚化合物的預處理，可在根本上預防或治療PCI手術所造成之致命性再灌流心臟損傷。 Korean Patent Application Publication No. 10-2012-0013266 discloses an anthraquinone and a carbazole derivative which can act as a strong antioxidant having a different mechanism of action than a conventional antioxidant - that is, having a ROS/RNS removal (Reactive Oxygen Species/Reactive Nitrogen Species) is active and specifically acts on the mitochondria of cells to effectively prevent cell necrosis induced under pathological conditions. In this way, the pretreatment of a sputum compound that can strongly inhibit cell necrosis by specifically acting on the mitochondria and having preventive effects on ischemia/reperfusion injury in various organs can fundamentally prevent or treat PCI. Fatal reperfusion of heart damage caused by surgery.

就患者的迫切性及便利性而言，該種藥劑必須開發成注射劑。然而，由於吲哚化合物不僅在水溶液中具有5μg/ml或更低的低溶解性，且其在水溶液中並不安定，因而在將其開發成注射劑上係存在有問題。因此，有需要藉由克服吲哚化合物之該種問題而開發出可以注射劑之形式進行投予之安定的調配物。 In terms of patient urgency and convenience, the agent must be developed into an injection. However, since the cerium compound has not only low solubility of 5 μg/ml or less in an aqueous solution, and it is not stable in an aqueous solution, there is a problem in developing it into an injection. Therefore, there is a need to develop a formulation which can be administered in the form of an injectable preparation by overcoming the problem of the quinone compound.

本發明之目的為在提供包含可有效地預防在病理情況下所誘發之細胞壞死之吲哚化合物作為活性成分之組成物的同時，提供在儲存期間無論溫度變化皆維持澄清度，並解決在水溶液相中之低溶解性及安定性的問題之醫藥製劑。 An object of the present invention is to provide a composition comprising an anthraquinone compound which is effective for preventing cell necrosis induced under pathological conditions as an active ingredient, while maintaining a clearness regardless of temperature change during storage, and solving the problem in aqueous solution A pharmaceutical preparation having problems of low solubility and stability in the phase.

為了達成上述目的，本發明係提供一種醫藥製劑，其係包含吲哚化合物或其醫藥上可接受之衍生物、環糊精衍生物以及抗氧化劑。 In order to achieve the above object, the present invention provides a pharmaceutical preparation comprising a guanidine compound or a pharmaceutically acceptable derivative thereof, a cyclodextrin derivative, and an antioxidant.

此處，該吲哚化合物較佳為下式(1)之[5-(1,1-二側氧基-1 λ6-硫代嗎啉-4-基甲基)-2-苯基-1H-吲哚-7-基]-(四氫哌喃-4-基)-胺)。 Here, the hydrazine compound is preferably [5-(1,1-di- oxy-1 λ 6 -thiomorpholin-4-ylmethyl)-2-phenyl- of the following formula (1)- 1 H -吲哚-7-yl]-(tetrahydropyran-4-yl)-amine).

此外，在本發明中，該環糊精衍生物較佳為β-環糊精，特別是，羥丙基β-環糊精(HP-β-CD)，且較佳係以0.1至30重量%之量包含在該製劑中。 Further, in the present invention, the cyclodextrin derivative is preferably β-cyclodextrin, particularly, hydroxypropyl β-cyclodextrin (HP-β-CD), and preferably 0.1 to 30 by weight. The amount of % is included in the formulation.

再者，在根據本發明之醫藥製劑中，該抗氧化劑係例如但不限於硫代甘油或L-半胱胺酸鹽酸鹽，且較佳係以0.1至2.0重量%之量包含在該製劑中。 Further, in the pharmaceutical preparation according to the present invention, the antioxidant is, for example but not limited to, thioglycerol or L-cysteine hydrochloride, and is preferably contained in the preparation in an amount of 0.1 to 2.0% by weight. in.

根據本發明之醫藥製劑可進一步包含用以改善溶解性之丙二醇以及用以改善安定性之螯合劑。丙二醇較佳係以0.1至1.0重量%之量包含在該製劑中，而該螯合劑較佳為依地酸鹽(edetate)(乙二胺三醋酸)且以0.001至0.01重量%之量包含在該製劑中。 The pharmaceutical preparation according to the present invention may further comprise propylene glycol for improving solubility and a chelating agent for improving stability. The propylene glycol is preferably contained in the preparation in an amount of 0.1 to 1.0% by weight, and the chelating agent is preferably edetate (ethylenediaminetriacetic acid) and is contained in an amount of 0.001 to 0.01% by weight. In the preparation.

該種本發明之醫藥製劑可用於抑制細胞壞死及預防局部缺血/再灌流損傷，適合非經口投予，且包括液體或冷凍乾燥調配物。 The pharmaceutical preparation of the present invention can be used for inhibiting cell necrosis and preventing ischemia/reperfusion injury, suitable for parenteral administration, and includes liquid or freeze-dried formulations.

以下，對本發明更詳細地進行說明。 Hereinafter, the present invention will be described in more detail.

在本發明中，係提供具有經改善的溶液中之安定性之醫藥製劑，其中，吲哚化合物的溶解性係藉由 使在水溶液中具有5μg/ml或更低的溶解性之吲哚化合物形成為環糊精衍生物的包容錯合物而獲得改善。 In the present invention, there is provided a pharmaceutical preparation having an improved stability in a solution, wherein the solubility of the ruthenium compound is An improvement is obtained by forming a ruthenium compound having a solubility of 5 μg/ml or less in an aqueous solution into a tolerant complex of a cyclodextrin derivative.

環糊精係結構上由α(1-4)醣苷鍵聯所連結之6、7或8個單元的D-葡萄哌喃糖基所構成，且其分別稱為α(alpha)-環糊精、β(beta)-環糊精及γ(gamma)-環糊精。該等係寡糖之中最安定的三維結構。環糊精衍生物係理解為環糊精或其混合物，且在葡萄糖的2-、3-及6-位之某些或所有氫原子係經另一官能基(諸如二羥烷基、醣殘基、羥烷基、磺酸酯基、磺烷基、烷基、烷醯基、乙醯基以及苯甲醯基)取代。 The cyclodextrin structure is composed of 6, 7 or 8 units of D-glucopyranose groups linked by α(1-4) glycosidic linkages, and is referred to as α(alpha)-cyclodextrin, respectively. , β(beta)-cyclodextrin and gamma (gamma)-cyclodextrin. The most stable three-dimensional structure among these oligosaccharides. A cyclodextrin derivative is understood to be a cyclodextrin or a mixture thereof, and some or all of the hydrogen atoms at the 2-, 3- and 6-positions of glucose are via another functional group (such as a dihydroxyalkyl group, a sugar residue). Substituents of hydroxy, alkyl, sulfonate, sulfoalkyl, alkyl, alkanoyl, ethenyl and benzhydryl groups.

本發明中所使用之環糊精或其衍生物係市面上可取得或可根據此領域中已知的方法予以合成。環糊精或其衍生物之實例包括但不限於天然環糊精(α、β或γ)、羥丙基環糊精、羧甲基環糊精、磺丁基環糊精、胺基環糊精、二甲基環糊精、環糊精磷酸酯、羥乙基環糊精、乙醯基-環糊精、乙基環糊精、三甲基環糊精、羧乙基環糊精、葡萄糖基環糊精、6-O-α-麥芽糖基環糊精、丁基-環糊精、硫酸環糊精、N,N-二乙基胺基乙基環糊精、第三丁基矽烷基環糊精、矽烷基[(6-O-第三丁基二甲基)-2,3,-二-O-乙醯基)-環糊精、琥珀醯基-(2-羥丙基)-環糊精、琥珀醯基-環糊精、磺丙基-環糊精及聚環糊精。在本發明之特定具體例中，環糊精包括羥丙基α-環糊精、羥丙基β-環糊精、磺丁基乙基-β-環糊精或其混合物。 The cyclodextrin or its derivative used in the present invention is commercially available or can be synthesized according to methods known in the art. Examples of cyclodextrins or derivatives thereof include, but are not limited to, natural cyclodextrins (α, β or γ), hydroxypropyl cyclodextrin, carboxymethyl cyclodextrin, sulfobutylcyclodextrin, amine cyclodextrin Refined, dimethyl cyclodextrin, cyclodextrin phosphate, hydroxyethyl cyclodextrin, ethionyl-cyclodextrin, ethyl cyclodextrin, trimethylcyclodextrin, carboxyethyl cyclodextrin, Glucosyl cyclodextrin, 6-O-α-maltosyl cyclodextrin, butyl-cyclodextrin, cyclodextrin sulfate, N,N-diethylaminoethylcyclodextrin, tert-butyldecane Cyclodextrin, decylalkyl [(6-O-tert-butyldimethyl)-2,3,-di-O-ethinyl)-cyclodextrin, amber thiol-(2-hydroxypropyl) ) - cyclodextrin, amber thiol-cyclodextrin, sulfopropyl-cyclodextrin and polycyclodextrin. In a particular embodiment of the invention, the cyclodextrin comprises hydroxypropyl alpha-cyclodextrin, hydroxypropyl beta-cyclodextrin, sulfobutylethyl-beta-cyclodextrin or a mixture thereof.

同時，在根據本發明之醫藥製劑中，為了 改善溶液狀態中之安定性及預防變色，係需要抗氧化劑。可取得之抗氧化劑之實例包括但不限於視黃醇、生育醇、抗壞血酸鈉、抗壞血酸、亞硫酸鹽化合物、L-半胱胺酸、硫代甘油、硫代二丙酸、硫代乳酸或單硫代甘油。具體而言，在使用半胱胺酸鹽酸鹽或硫代甘油之情況，可藉由抑制吲哚化合物之氧化反應而在儲存期間維持安定性。抗氧化劑(諸如半胱胺酸鹽酸鹽或硫代甘油)可以0.1至2重量%之量使用。 Meanwhile, in the pharmaceutical preparation according to the present invention, Antioxidants are required to improve the stability and prevent discoloration in solution conditions. Examples of antioxidants that may be obtained include, but are not limited to, retinol, tocopherol, sodium ascorbate, ascorbic acid, sulfite compounds, L-cysteine, thioglycerol, thiodipropionic acid, thiolactic acid or a single Thioglycerol. Specifically, in the case of using cysteamine hydrochloride or thioglycerol, stability can be maintained during storage by inhibiting the oxidation reaction of the ruthenium compound. An antioxidant such as cysteamine hydrochloride or thioglycerol may be used in an amount of 0.1 to 2% by weight.

在本發明之較佳實施例中，必要時，根據本發明之醫藥製劑可進一步包含pH控制劑，諸如磷酸鹽緩衝溶液或檸檬酸/氫氧化鈉緩衝溶液，以便將pH值調節至3.0與4.0之間。可取得之磷酸鹽可呈鈉鹽或鉀鹽、或酸酐或水合物之形式，而檸檬酸亦以酸酐或水合物之形式使用。舉例而言，可使用磷酸二氫鉀及磷酸一氫鈉之磷酸鹽緩衝溶液、磷酸二氫鈉-檸檬酸緩衝溶液、以及磷酸二氫鉀及氫氧化鈉之磷酸鹽緩衝溶液。pH控制劑可以將根據本發明之醫藥製劑的pH值調節至3.0至4.0所需之量使用。 In a preferred embodiment of the present invention, the pharmaceutical preparation according to the present invention may further comprise a pH controlling agent such as a phosphate buffer solution or a citric acid/sodium hydroxide buffer solution to adjust the pH to 3.0 and 4.0, if necessary. between. The phosphate which can be obtained can be in the form of a sodium or potassium salt, or an anhydride or a hydrate, and citric acid is also used in the form of an acid anhydride or a hydrate. For example, a phosphate buffer solution of potassium dihydrogen phosphate and sodium monohydrogen phosphate, a sodium dihydrogen phosphate-citric acid buffer solution, and a phosphate buffer solution of potassium dihydrogen phosphate and sodium hydroxide can be used. The pH controlling agent can be used in an amount required to adjust the pH of the pharmaceutical preparation according to the present invention to 3.0 to 4.0.

作為較佳實施例，本發明之醫藥製劑可進一步包含用以改善溶解性之丙二醇以及用以改善安定性之螯合劑(諸如依地酸鹽)。此外，使用抗氧化劑及氮氣可克服氧化反應所引起之醫藥不安定性。螯合劑(諸如依地酸鹽)可以0.001至0.01重量%之量使用，而丙二醇可以0.1至1.0重量%之量使用。可在根據本發明之系統中使用該等之任一者。 As a preferred embodiment, the pharmaceutical preparation of the present invention may further comprise propylene glycol for improving solubility and a chelating agent (such as edetate) for improving stability. In addition, the use of antioxidants and nitrogen can overcome the medical instability caused by the oxidation reaction. A chelating agent such as edetate may be used in an amount of 0.001 to 0.01% by weight, and propylene glycol may be used in an amount of 0.1 to 1.0% by weight. Any of these may be used in the system according to the invention.

本發明中所使用之吲哚化合物或其衍生物可根據韓國專利申請公開案第10-2012-0013266號中所揭示之方法予以合成。可取得之吲哚化合物之衍生物包括鹽類，諸如鹽酸鹽、硫酸鹽、甲磺酸鹽、蘋果酸鹽等。 The hydrazine compound or a derivative thereof used in the present invention can be synthesized according to the method disclosed in Korean Patent Application Laid-Open No. 10-2012-0013266. Derivatives of the ruthenium compound obtainable include salts such as hydrochlorides, sulfates, methanesulfonates, malates, and the like.

作為根據本發明之醫藥製劑之較佳具體例，可注射之組成物係包含1至20重量%的吲哚化合物、0.1至30重量%的羥丙基β-環糊精、0.1至2.0重量%的抗氧化劑、0.1至1.0重量%的丙二醇以及0.001至0.01重量%的依地酸鹽。此處，抗氧化劑較佳為硫代甘油或L-半胱胺酸鹽酸鹽。 As a preferred embodiment of the pharmaceutical preparation according to the present invention, the injectable composition contains 1 to 20% by weight of a hydrazine compound, 0.1 to 30% by weight of hydroxypropyl β-cyclodextrin, 0.1 to 2.0% by weight. An antioxidant, 0.1 to 1.0% by weight of propylene glycol and 0.001 to 0.01% by weight of edetate. Here, the antioxidant is preferably thioglycerol or L-cysteine hydrochloride.

作為根據本發明之醫藥製劑之較佳實施例，可注射之組成物之製備方法係包含下列步驟：將0.1至30重量%的環糊精及0.1至1.0重量%的丙二醇溶解於鹽酸溶液中；添加1至20重量%的吲哚化合物並進行攪拌；添加0.1至2.0重量%的抗氧化劑及0.001至0.01重量%的依地酸鹽；以及將pH值調節至約3.0至4.0。 As a preferred embodiment of the pharmaceutical preparation according to the present invention, the preparation method of the injectable composition comprises the steps of: dissolving 0.1 to 30% by weight of cyclodextrin and 0.1 to 1.0% by weight of propylene glycol in a hydrochloric acid solution; 1 to 20% by weight of a hydrazine compound is added and stirred; 0.1 to 2.0% by weight of an antioxidant and 0.001 to 0.01% by weight of edetate are added; and the pH is adjusted to about 3.0 to 4.0.

此外，根據本發明之醫藥製劑可用於非經口投予，且包括液體或冷凍乾燥調配物。劑型可為在油或水性介質中之溶液、懸浮液或乳液，且可包含習知的分散劑、懸浮劑或安定劑。再者，舉例而言，該醫藥製劑可呈乾燥粉末形式，其係藉由溶解於不含熱原之無菌水中而使用。 Furthermore, the pharmaceutical preparations according to the invention can be used for parenteral administration and include liquid or freeze-dried formulations. The dosage form can be a solution, suspension or emulsion in an oil or aqueous medium, and can contain conventional dispersing, suspending or stabilizing agents. Further, for example, the pharmaceutical preparation may be in the form of a dry powder which is used by dissolving in sterile water containing no pyrogen.

根據本發明之醫藥製劑係透過藉由形成為 環糊精衍生物的包容錯合物來改善吲哚化合物的溶液中之溶解性及安定性而使吲哚化合物-其具有低水溶解性且在水中不安定-能夠進行非經口投予。根據本發明之醫藥製劑可較佳地用於抑制細胞壞死及預防局部缺血/再灌流損傷。具體而言，藉由預處理，可在根本上預防或治療由經皮冠狀動脈介入(PCI)手術所造成之致命性再灌流心臟損傷。 The pharmaceutical preparation according to the present invention is formed by The inclusion of the cyclodextrin derivative to improve the solubility and stability in the solution of the hydrazine compound allows the hydrazine compound, which has low water solubility and is unstable in water, can be administered parenterally. The pharmaceutical preparation according to the present invention can be preferably used for inhibiting cell necrosis and preventing ischemia/reperfusion injury. In particular, by pretreatment, a fatal reperfusion heart injury caused by percutaneous coronary intervention (PCI) surgery can be fundamentally prevented or treated.

第1圖及第2圖係分別為DSC及XRD圖表，其係顯示當根據實施例4製備注射用溶液製劑時，是否形成吲哚化合物/環糊精的包容錯合物。 Fig. 1 and Fig. 2 are DSC and XRD charts, respectively, showing whether or not the inclusion compound of the oxime compound/cyclodextrin is formed when the preparation for injection solution is prepared according to Example 4.

以下，利用下列示例更詳細說明本發明。然而，必須瞭解本發明之保護範疇並不限於該等示例。 Hereinafter, the present invention will be described in more detail by way of the following examples. However, it must be understood that the scope of protection of the present invention is not limited to such examples.

[示例1至4：環糊精含量之測定(以100ml為基準)] [Examples 1 to 4: Determination of cyclodextrin content (based on 100 ml)]

如表1所示，對羥丙基β-環糊精及吲哚化合物在注射用溶液調配物中之溶解性進行試驗。所有製程步驟皆在氮吹掃下施行。 As shown in Table 1, the solubility of the hydroxypropyl β-cyclodextrin and the hydrazine compound in the solution for injection solution was tested. All process steps are performed under a nitrogen purge.

(a)將羥丙基β-環糊精溶解於0.1N鹽酸中後，對其添加1體積%的丙二醇並進行溶解，接著對其添加吲哚化合物並進行溶解約20分鐘。 (a) After dissolving hydroxypropyl β-cyclodextrin in 0.1 N hydrochloric acid, 1 vol% of propylene glycol was added thereto and dissolved, and then a hydrazine compound was added thereto and dissolved for about 20 minutes.

(b)在燒杯中將0.9體積%的無水檸檬酸添加至9體積% 的1N氫氧化鈉溶液中並進行溶解約10分鐘，接著對其添加注射用水。 (b) Adding 0.9% by volume of anhydrous citric acid to 9 vol% in a beaker The solution was dissolved in a 1 N sodium hydroxide solution for about 10 minutes, and then water for injection was added thereto.

接著，將溶液(b)與溶液(a)進行混合，對其添加1體積%的單硫代甘油及0.01體積%的依地酸二鈉並進行溶解。使所獲得之溶液依序通過1μm PES過濾器及0.5/0.2μm雙層過濾器，並收集所濾出之溶液。溶液的pH值為約3.0至3.5。最後，為了進行HPLC分析，透過無菌0.2μm PVDF過濾器將溶液過濾至容器中。 Next, the solution (b) was mixed with the solution (a), and 1% by volume of monothioglycerol and 0.01% by volume of disodium edetate were added thereto and dissolved. The obtained solution was sequentially passed through a 1 μm PES filter and a 0.5/0.2 μm double-layer filter, and the filtered solution was collected. The pH of the solution is between about 3.0 and 3.5. Finally, for HPLC analysis, the solution was filtered into a container through a sterile 0.2 [mu]m PVDF filter.

目標濃度：20mg/ml Target concentration: 20mg/ml

<分析條件> <Analysis conditions>

管柱：Capcell pak UG120(4.6×150mm，5μm，Shiseido) Column: Capcell pak UG120 (4.6×150mm, 5μm, Shiseido)

管柱溫度：40℃ Column temperature: 40 ° C

移動相A：乙腈/水/三氟醋酸=30/70/0.1(體積/體積/體積) Mobile phase A: acetonitrile / water / trifluoroacetic acid = 30 / 70 / 0.1 (vol / volume / volume)

移動相B：乙腈/水/三氟醋酸=80/20/0.1(體積/體積/體積) Mobile phase B: acetonitrile / water / trifluoroacetic acid = 80 / 20 / 0.1 (vol / volume / volume)

流動速率：1ml/分鐘 Flow rate: 1ml/min

檢測器：紫外吸收分光光度計(波長：254nm) Detector: UV absorption spectrophotometer (wavelength: 254 nm)

注入量：10ml Injection volume: 10ml

如表3可見，證實在水溶液具有0.10mg/ml或更低的溶解性之吲哚化合物的溶解性係藉由形成示例1至3之吲哚化合物/羥丙基β-環糊精的包容錯合物而急遽增加。 As can be seen from Table 3, it was confirmed that the solubility of the ruthenium compound having an solubility in an aqueous solution of 0.10 mg/ml or less was caused by the formation of the enthalpy compound of Example 1 to 3/hydroxypropyl β-cyclodextrin. The compound is rushing to increase.

[示例4至6：溶液調配物之製備(1)] [Examples 4 to 6: Preparation of Solution Formulation (1)]

以表4之組成(以22g為基準)製備包含43.3mg的吲哚化合物之溶液調配物中之注射用製劑。所有製程步驟皆在氮吹掃下施行。 An injection preparation containing a solution of 43.3 mg of an anthraquinone compound was prepared in the composition of Table 4 (on a basis of 22 g). All process steps are performed under a nitrogen purge.

(a)將羥丙基β-環糊精溶解於0.1N鹽酸中，接著對其 添加吲哚化合物並進行溶解約20分鐘。 (a) dissolving hydroxypropyl β-cyclodextrin in 0.1 N hydrochloric acid, followed by The hydrazine compound was added and dissolved for about 20 minutes.

(b)在燒杯中將無水檸檬酸添加至1N氫氧化鈉溶液中並進行溶解約10分鐘，接著對其添加注射用水。 (b) Anhydrous citric acid was added to a 1 N sodium hydroxide solution in a beaker and dissolved for about 10 minutes, followed by the addition of water for injection.

接著，將溶液(b)與溶液(a)進行混合，對其添加單硫代甘油並進行溶解。溶液的pH值為約3.0至3.5。 Next, the solution (b) is mixed with the solution (a), and monothioglycerol is added thereto and dissolved. The pH of the solution is between about 3.0 and 3.5.

第1圖及第2圖係分別為DSC及XRD圖表，其係顯示當根據示例4製備注射用溶液製劑時，是否形成吲哚化合物/環糊精的包容錯合物。 Fig. 1 and Fig. 2 are DSC and XRD charts, respectively, showing whether or not the inclusion complex of the quinone compound/cyclodextrin is formed when the preparation for injection solution is prepared according to Example 4.

[示例7至9：溶液調配物之製備(2)] [Examples 7 to 9: Preparation of Solution Formulation (2)]

除了使用2重量%、1重量%及0.1重量%的L-半胱胺酸鹽酸鹽代替單硫代甘油以外(參見表5)，以與示例4中相 同的組成，並藉由與示例4中相同的製程，製備溶液調配物中之注射用製劑。 In addition to using 2% by weight, 1% by weight, and 0.1% by weight of L-cysteamine hydrochloride instead of monothioglycerol (see Table 5), in comparison with Example 4 The same composition and the preparation for injection in the solution formulation were prepared by the same procedure as in Example 4.

[示例10至14：溶液調配物之製備(3)] [Examples 10 to 14: Preparation of Solution Formulation (3)]

除了使用1.0重量%或0.1重量%的丙二醇及0.01重量%或0.001重量%的依地酸二鈉以外(參見表6)，以與示例4中相同的組成，並藉由與示例4中相同的製程，製備溶液調配物中之注射用製劑。此時，將丙二醇添加至溶液(b)中，並在將溶液(a)及(b)進行混合時添加依地酸二鈉。 Except that 1.0% by weight or 0.1% by weight of propylene glycol and 0.01% by weight or 0.001% by weight of disodium edetate (see Table 6), the same composition as in Example 4, and by the same as in Example 4 The preparation process for the preparation of the solution is prepared. At this time, propylene glycol was added to the solution (b), and disodium edetate was added while mixing the solutions (a) and (b).

[示例15至17：溶液調配物之製備(4)] [Examples 15 to 17: Preparation of Solution Formulation (4)]

除了額外包含1重量%的丙二醇以外，以與示例4中相同的組成(參見表7)，並藉由與示例4中相同的製程，製備溶液調配物中之注射用製劑。 The preparation for injection in the solution formulation was prepared by the same composition as in Example 4 except that 1% by weight of propylene glycol was additionally contained (see Table 7), and by the same procedure as in Example 4.

[示例18至20：溶液調配物之製備(5)] [Examples 18 to 20: Preparation of Solution Formulation (5)]

除了額外包含1重量%的丙二醇以外，以與實施例7中相同的組成(參見表8)，並藉由與實施例7中相同的製程，製備溶液調配物中之注射用製劑。 The preparation for injection was prepared in the solution formulation by the same composition as in Example 7 except that 1% by weight of propylene glycol was additionally contained (see Table 8), and by the same procedure as in Example 7.

[比較例1及2：比較溶液調配物之製備(1)] [Comparative Examples 1 and 2: Preparation of Comparative Solution Formulations (1)]

以表9之組成製備溶液調配物中之注射用製劑。 The preparation for injection in the solution formulation was prepared in the composition of Table 9.

[比較例3及4：比較溶液調配物之製備(2)] [Comparative Examples 3 and 4: Preparation of Comparative Solution Formulations (2)]

製備包含表1之組成之吲哚化合物溶液注射劑。在此時，不施行氮吹掃。 An injection of a bismuth compound solution containing the composition of Table 1 was prepared. At this time, no nitrogen purge is performed.

由表11，可知所有製劑於加速(40℃)及75%濕度之條件下皆不安定。在不包含抗氧化劑之比較例1至4之製劑中，於加速、室溫及冷藏之所有條件下皆觀察到 變色及沉澱。 From Table 11, it can be seen that all the formulations were unstable under conditions of acceleration (40 ° C) and 75% humidity. In the preparations of Comparative Examples 1 to 4 which did not contain an antioxidant, it was observed under all conditions of acceleration, room temperature and refrigeration. Discoloration and precipitation.

其中包含0.1重量%的抗氧化劑(單硫代甘油)之示例6之製劑僅於冷藏條件下呈安定。同時，示例4及5之製劑-其分別包含2.0重量%及1.0重量%的單硫代甘油-係於室溫及冷藏條件下皆顯示出安定性。該等結果係表明隨著抗氧化劑的濃度越高，於室溫之安定性係增加。示例7及8之製劑-其分別包含2.0重量%及1.0重量%的L-半胱胺酸鹽酸鹽作為抗氧化劑-亦於室溫及冷藏條件下皆顯示出安定性，而其中包含0.1重量%者之示例9之製劑僅於冷藏條件下呈安定。亦即，可知抗氧化劑的添加係在製劑的安定性上扮演重要的角色。 The formulation of Example 6 in which 0.1% by weight of an antioxidant (monothioglycerol) was contained was only stable under refrigeration. Meanwhile, the formulations of Examples 4 and 5, which contained 2.0% by weight and 1.0% by weight of monothioglycerol, respectively, showed stability at room temperature and under refrigeration. These results indicate that as the concentration of the antioxidant increases, the stability at room temperature increases. The formulations of Examples 7 and 8 which contained 2.0% by weight and 1.0% by weight of L-cysteamine hydrochloride, respectively, as antioxidants - also showed stability at room temperature and under refrigeration, and contained 0.1 weight. The formulation of Example 9 of % was only stable under refrigeration. That is, it is known that the addition of an antioxidant plays an important role in the stability of the formulation.

此外，如示例10、11、13及14可見，包含1.0重量%或0.1重量%的丙二醇或0.01重量%或0.001重量%的依地酸鹽之製劑係僅在包含1.0重量%或2.0重量%的單硫代甘油時，於室溫及冷藏條件下皆呈安定。包含0.1重量%的單硫代甘油之示例12之製劑係如同示例6般僅於冷藏條件下顯示出安定性。同樣地，在包含1.0重量%的丙二醇之製劑之情況(示例15至20)，包含0.1重量%的單硫代甘油及0.1重量%的L-半胱胺酸鹽酸鹽之製劑(示例17及20)僅於冷藏條件下顯示出安定性，而包含1重量%及2重量%的單硫代甘油或L-半胱胺酸鹽酸鹽之製劑(示例15、16、18及19)則於室溫及冷藏條件下皆顯示出安定性。 Further, as seen in Examples 10, 11, 13, and 14, the formulation containing 1.0% by weight or 0.1% by weight of propylene glycol or 0.01% by weight or 0.001% by weight of edetate was only contained in 1.0% by weight or 2.0% by weight. Monothioglycerol is stable at room temperature and under refrigeration. The formulation of Example 12 containing 0.1% by weight of monothioglycerol showed stability as in Example 6 only under refrigeration conditions. Similarly, in the case of a formulation containing 1.0% by weight of propylene glycol (Examples 15 to 20), a formulation comprising 0.1% by weight of monothioglycerol and 0.1% by weight of L-cysteamine hydrochloride (Example 17 and 20) exhibiting stability only under refrigerated conditions, while formulations containing 1% by weight and 2% by weight of monothioglycerol or L-cysteamine hydrochloride (Examples 15, 16, 18 and 19) are Stability is shown at room temperature and under refrigerated conditions.

Claims (12)

一種醫藥製劑，係包含吲哚化合物或其醫藥上可接受之衍生物、環糊精衍生物以及抗氧化劑。 A pharmaceutical preparation comprising a guanidine compound or a pharmaceutically acceptable derivative thereof, a cyclodextrin derivative, and an antioxidant. 如申請專利範圍第1項所述之醫藥製劑，其中，該吲哚化合物為下式(1)之化合物： The pharmaceutical preparation according to claim 1, wherein the hydrazine compound is a compound of the following formula (1): 如申請專利範圍第1項所述之醫藥製劑，其中，該環糊精衍生物為β-環糊精或其衍生物。 The pharmaceutical preparation according to claim 1, wherein the cyclodextrin derivative is β-cyclodextrin or a derivative thereof. 如申請專利範圍第1項所述之醫藥製劑，係包含0.1至30重量%的該環糊精衍生物。 The pharmaceutical preparation according to claim 1, which comprises 0.1 to 30% by weight of the cyclodextrin derivative. 如申請專利範圍第1項所述之醫藥製劑，其中，該抗氧化劑為硫代甘油或L-半胱胺酸鹽酸鹽。 The pharmaceutical preparation according to claim 1, wherein the antioxidant is thioglycerol or L-cysteine hydrochloride. 如申請專利範圍第1項所述之醫藥製劑，係包含0.1至2.0重量%的該抗氧化劑。 The pharmaceutical preparation according to claim 1, which comprises 0.1 to 2.0% by weight of the antioxidant. 如申請專利範圍第1項所述之醫藥製劑，係進一步包含0.1至1.0重量%的丙二醇。 The pharmaceutical preparation according to claim 1, further comprising 0.1 to 1.0% by weight of propylene glycol. 如申請專利範圍第1項所述之醫藥製劑，係進一步包含0.001至0.01重量%的依地酸鹽(edetate)。 The pharmaceutical preparation according to claim 1, further comprising 0.001 to 0.01% by weight of edetate. 如申請專利範圍第1項所述之醫藥製劑，係包含1至20重量%的吲哚化合物、0.1至30重量%的羥丙基β-環糊精、0.1至2.0重量%的硫代甘油或L-半胱胺酸鹽 酸鹽、0.1至1.0重量%的丙二醇以及0.001至0.01重量%的依地酸鹽。 The pharmaceutical preparation according to claim 1, comprising 1 to 20% by weight of a hydrazine compound, 0.1 to 30% by weight of hydroxypropyl β-cyclodextrin, 0.1 to 2.0% by weight of thioglycerol or L-cysteine The acid salt, 0.1 to 1.0% by weight of propylene glycol and 0.001 to 0.01% by weight of edetate. 如申請專利範圍第1項所述之醫藥製劑，係用於抑制細胞壞死及預防局部缺血/再灌流損傷。 The pharmaceutical preparation according to claim 1 is for inhibiting cell necrosis and preventing ischemia/reperfusion injury. 如申請專利範圍第1項所述之醫藥製劑，係用於非經口投予。 The pharmaceutical preparation according to item 1 of the patent application is for parenteral administration. 如申請專利範圍第1項所述之醫藥製劑，係液體或冷凍乾燥調配物。 The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is a liquid or a freeze-dried preparation.
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