WO2016153304A1 - 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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WO2016153304A1
WO2016153304A1 PCT/KR2016/003019 KR2016003019W WO2016153304A1 WO 2016153304 A1 WO2016153304 A1 WO 2016153304A1 KR 2016003019 W KR2016003019 W KR 2016003019W WO 2016153304 A1 WO2016153304 A1 WO 2016153304A1
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pharmaceutical preparation
weight
cyclodextrin
solution
preparation according
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PCT/KR2016/003019
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French (fr)
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Geun Tae Kim
Kang Min Kim
Ki Sook Park
So La PARK
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Lg Life Sciences Ltd.
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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

Definitions

  • the present invention relates to a novel preparation comprising an indole compound or a pharmaceutically acceptable derivative thereof and a cyclodextrin derivative, and a method for preparing the same.
  • PCI Percutaneous coronary intervention
  • Korean Patent Application Publication No. 10-2012-0013266 discloses indole and indazole derivatives which can efficiently prevent cellular necrosis induced under pathological circumstances, as a potent antioxidant having a mechanism of action different from conventional antioxidants ⁇ i.e., having an activity for removing ROS/RNS (Reactive Oxygen Species/Reactive Nitrogen Species) and specifically acting on mitochondria of cells.
  • ROS/RNS Reactive Oxygen Species/Reactive Nitrogen Species
  • PCI operation via the pre-treatment of indole compound which can strongly inhibit cellular necrosis by specifically acting on mitochondria and has preventive efficacy on ischemia/reperfusion injury on the various organs, fatal reperfusion cardiac injury by PCI operation can be basically prevented or treated.
  • Such medicaments must be developed as an injection in view of the urgency and convenience of patients.
  • problems in developing them as an injection because not only does indole compound have low solubility of 5 ⁇ g/ml or less in an aqueous solution but also it is not stable in an aqueous solution. Therefore, there is a need to develop a stable formulation which can be administered as an injection by overcoming such problems of indole compound.
  • the object of the present invention is the provision of a pharmaceutical preparation in which transparency is maintained regardless of temperature change during storage periods, and the problems of low solubility and stability in the aqueous solution phase are resolved, at the time of the provision of a composition comprising an indole compound which can efficiently prevent cellular necrosis induced under pathological circumstances as an active ingredient.
  • the present invention provides a pharmaceutical preparation comprising an indole compound or a pharmaceutically acceptable derivative thereof, a cyclodextrin derivative and an antioxidant.
  • the indole compound is preferably [5-(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-ylmethyl)-2-phenyl-1 H -indol-7-yl]-(tetrahydropyran-4-yl)-amine) of the following Formula (1).
  • the cyclodextrin derivative is preferably ß-cyclodextrin, specifically hydroxypropyl ß-cyclodextrin (HP-ß-CD), and is preferably comprised in the preparation in an amount of 0.1 to 30% by weight.
  • HP-ß-CD hydroxypropyl ß-cyclodextrin
  • the antioxidant is, for example, but is not limited to, thioglycerol or L-cysteine hydrochloride, and is preferably comprised in the preparation in an amount of 0.1 to 2.0% by weight.
  • the pharmaceutical preparation according to the present invention may further comprise propylene glycol to improve solubility and a chelating agent to improve stability.
  • Propylene glycol is preferably comprised in the preparation in an amount of 0.1 to 1.0% by weight
  • the chelating agent is preferably edetate (ethylene diamine triacetic acid) and comprised in the preparation in an amount of 0.001 to 0.01% by weight.
  • Such a pharmaceutical preparation of the present invention can be used for inhibiting cellular necrosis and preventing ischemia/reperfusion injury, is suitable for parenteral administration, and includes a liquid or freeze-dried formulation.
  • a pharmaceutical preparation having improved stability in solution in which the solubility of indole compound is improved by forming indole compound having the solubility of 5 ⁇ g/ml or less in an aqueous solution as an inclusion complex of cyclodextrin derivative.
  • Cyclodextrins are structurally composed of 6, 7 or 8 units of D-glucopyranosyl linked by ⁇ (1-4) glycosidic linkage, and they are called ⁇ (alpha)-cyclodextrin, ß (beta)-cyclodextrin and ⁇ (gamma)-cyclodextrin, respectively. They are the most stable three-dimensional structures among oligosaccharides.
  • Cyclodextrin derivatives are understood as cyclodextrins or mixtures thereof, and some or all hydrogen atom(s) at the 2-, 3- and 6-positions of glucose is (are) substituted with another functional group(s) such as dihydroxyalkyl group, saccharide residue, hydroxyalkyl group, sulfonate group, sulfoalkyl group, alkyl group, alkanoyl group, acetyl group and benzoyl group.
  • another functional group(s) such as dihydroxyalkyl group, saccharide residue, hydroxyalkyl group, sulfonate group, sulfoalkyl group, alkyl group, alkanoyl group, acetyl group and benzoyl group.
  • Cyclodextrins or derivatives thereof used in the present invention are commercially available or may be synthesized according to the methods known in this field.
  • Examples of cyclodextrins or derivatives thereof include, but are not limited to, natural cyclodextrin (alpha, beta or gamma), hydroxypropylcyclodextrin, carboxymethylcyclodextrin, sulfobutylcyclodextrin, aminocyclodextrin, dimethylcyclodextrin, cyclodextrinphosphate, hydroxyethylcyclodextrin, acetyl-cyclodextrin, ethylcyclodextrin, trimethylcyclodextrin, carboxyethylcyclodextrin, glucosylcyclodextrin, 6-O- ⁇ -maltosylcyclodextrin, butyl-cyclodextrin, sulfate cyclodextrin,
  • cyclodextrins include hydroxypropyl ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin, sulfobutylethyl- ⁇ -cyclodextrin or a mixture thereof.
  • an antioxidant is necessary for the improvement of stability in a solution state and the prevention of discoloration.
  • antioxidants include, but are not limited to, retinol, tocopherol, sodium ascorbate, ascorbic acid, sulfite compounds, L-cysteine, thioglycerol, thiodipropionic acid, thiolactic acid or monothioglycerol.
  • cysteine hydrochloride or thioglycerol stability can be maintained during the storage period by inhibiting oxidation reaction of indole compounds.
  • the antioxidant such as cysteine hydrochloride or thioglycerol may be used in an amount of 0.1 to 2% by weight.
  • the pharmaceutical preparation according to the present invention may further comprise a pH control agent such as phosphate buffer or citric acid/sodium hydroxide buffer solution in order to adjust pH to between 3.0 and 4.0, if necessary.
  • a pH control agent such as phosphate buffer or citric acid/sodium hydroxide buffer solution in order to adjust pH to between 3.0 and 4.0, if necessary.
  • Available phosphate salt may be in the form of sodium salt or potassium salt, or anhydride or hydrate, and citric acid is also used in the form of anhydride or hydrate.
  • phosphate buffer solution of potassium dihydrogen phosphate and sodium monohydrogen phosphate, sodium dihydrogen phosphate-citric acid buffer solution, and phosphate buffer solution of potassium dihydrogen phosphate and sodium hydroxide may be used.
  • the pH control agent may be used in an amount necessary for adjusting the pH of the pharmaceutical preparation according to the present invention to 3.0 to 4.0.
  • the pharmaceutical preparation of the present invention may further comprise propylene glycol to improve solubility and a chelating agent such as edetate to improve stability.
  • a chelating agent such as edetate
  • the use of an antioxidant and nitrogen gas may overcome pharmaceutical instability caused by 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 them may be used in the system according to the present invention.
  • Indole compounds or derivatives thereof used in the present invention may be synthesized according to the method disclosed in Korean Patent Application Publication No. 10-2012-0013266.
  • Available derivatives of indole compounds include salts such as hydrochloride, sulfate, mesylate, malate and the like.
  • an injectable composition comprises 1 to 20% by weight of indole compound, 0.1 to 30% by weight of hydroxypropyl ß-cyclodextrin, 0.1 to 2.0% by weight of an antioxidant, 0.1 to 1.0% by weight of propylene glycol and 0.001 to 0.01% by weight of edetate.
  • the antioxidant is preferably thioglycerol or L-cysteine hydrochloride.
  • a method for preparing an 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 hydrochloric acid solution; adding 1 to 20% by weight of indole compound and agitating; adding 0.1 to 2.0% by weight of an antioxidant and 0.001 to 0.01% by weight of edetate; and adjusting pH to about 3.0 to 4.0.
  • the pharmaceutical preparation according to the present invention may be for parenteral administration, and includes a liquid or freeze-dried formulation.
  • Dosage form may be a solution in oil or aqueous media, suspension or emulsion, and may comprise a conventional dispersing agent, suspending agent or stabilizer.
  • the pharmaceutical preparation may be a dried powder form which is used by being dissolved in pyrogen-free, sterile water.
  • a pharmaceutical preparation according to the present invention 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 according to the present invention may preferably be 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.
  • PCI percutaneous coronary intervention
  • Figures 1 and 2 are DSC and XRD charts, respectively, showing whether inclusion complexes of indole compound/cyclodextrin are formed when a solution preparation for injection is prepared according to Example 4.
  • 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 ⁇ m PES filter and a 0.5/0.2 ⁇ m bilayer filter, and the filtered solution was collected.
  • the pH of the solution was about 3.0-3.5.
  • the solution was filtered via a sterile 0.2 ⁇ m PVDF filter to a vessel.
  • Aim concentration 20 mg/ml
  • UV absorption spectrophotometer (wavelength: 254 nm)
  • the solution (b) was mixed with the solution (a), and monothioglycerol was added thereto and dissolved.
  • the pH of the solution was about 3.0-3.5.
  • Figures 1 and 2 are DSC and XRD charts, respectively, showing whether inclusion complexes of indole compound/cyclodextrin are formed when a solution preparation for injection is prepared according to Example 4.
  • Preparations for injection in the solution formulation were prepared with the same compositions as in Example 4 except that 2%, 1% and 0.1% by weight of L-cysteine hydrochloride instead of monothioglycerol were used (see Table 5), and by the same process as in Example 4.
  • Preparations for injection in the solution formulation were prepared with the same compositions as in Example 4 except for the use of 1.0% or 0.1% by weight of propylene glycol and 0.01% or 0.001% by weight of disodium edetate (see Table 6), and by the same process as in Example 4. This time, propylene glycol was added to the solution (b), and disodium edetate was added at the time of mixing the solutions (a) and (b).
  • Preparations for injection in the solution formulation were prepared with the same compositions as in Example 4 except that 1% by weight of propylene glycol was additionally comprised (see Table 7), and by the same process as in Example 4.
  • Preparations for injection in the solution formulation were prepared with the same compositions as in Example 7 except that 1% by weight of propylene glycol was additionally comprised (see Table 8), and by the same process as in Example 7.
  • Indole compound solution injections comprising the compositions of Table 1 were prepared. At this time, nitrogen purging was not carried out.
  • Solution formulations of indole compound have the problems of precipitation of indole compound in a solution and low stability such as color change. Therefore, after one-month storage in an amber glass vial under acceleration (40°C), room temperature (25°C) and cold storage (4°C) conditions, precipitation of indole compound and color change were observed with the naked eye by the foreign insoluble matter test. The results are represented in Table 11.
  • Example 6 The preparation of Example 6 in which 0.1% by weight of antioxidant (monothioglycerol) is comprised was stable only under the condition of cold storage. Meanwhile, the preparations of Examples 4 and 5 ⁇ which comprise 2.0% by weight and 1.0% by weight of monothioglycerol, respectively ⁇ showed stability under the conditions of room temperature and cold storage. Such results indicate that the stability at room temperature is increased as the concentration of the antioxidant is higher.
  • the preparations of Examples 7 and 8 ⁇ which comprise 2.0% by weight and 1.0% by weight of L-cysteine hydrochloride as an antioxidant, respectively ⁇ also showed stability under the conditions of room temperature and cold storage, and the preparation of Example 9 in which 0.1% by weight is comprised was stable only under the condition of cold storage. That is, it can be known that the addition of antioxidant plays an important role in the stability of preparations.
  • Example 10 the preparations comprising 1.0% by weight or 0.1% by weight of propylene glycol or 0.01% by weight or 0.001% by weight of edetate were stable under the conditions of room temperature and cold storage, only when 1.0% by weight or 2.0% by weight of monothioglycerol is comprised.
  • the preparation of Example 12 comprising 0.1% by weight of monothioglycerol showed stability only under the condition of cold storage, as did that of Example 6.

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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

PREPARATION COMPRISING INDOLE COMPOUND AND PROCESS FOR PREPARING THE SAME
The present invention relates to a novel preparation comprising an indole compound or a pharmaceutically acceptable derivative thereof and a cyclodextrin derivative, and a method for preparing the same.
Necrosis―which is a major mechanism of cell death under pathological circumstances―is a clinically major cause of ischemic and reperfusion injury, and causes very important pathological phenomena such as myocardial infarction and stroke. Percutaneous coronary intervention (PCI), which operates on myocardial infarction patients, may induce fatal reperfusion injury, thereby leaving the myocardial infarction site unhealed which results in increased mortality. Although there is an urgent need for developing a medicament for decreasing infarction site remained due to reperfusion injury after PCI operation, no medicament has yet been developed for basically preventing such ischemia/reperfusion injury of myocardial tissue until now.
Korean Patent Application Publication No. 10-2012-0013266 discloses indole and indazole derivatives which can efficiently prevent cellular necrosis induced under pathological circumstances, as a potent antioxidant having a mechanism of action different from conventional antioxidants―i.e., having an activity for removing ROS/RNS (Reactive Oxygen Species/Reactive Nitrogen Species) and specifically acting on mitochondria of cells. As such, via the pre-treatment of indole compound which can strongly inhibit cellular necrosis by specifically acting on mitochondria and has preventive efficacy on ischemia/reperfusion injury on the various organs, fatal reperfusion cardiac injury by PCI operation can be basically prevented or treated.
Such medicaments must be developed as an injection in view of the urgency and convenience of patients. However, there are problems in developing them as an injection because not only does indole compound have low solubility of 5 μg/ml or less in an aqueous solution but also it is not stable in an aqueous solution. Therefore, there is a need to develop a stable formulation which can be administered as an injection by overcoming such problems of indole compound.
The object of the present invention is the provision of a pharmaceutical preparation in which transparency is maintained regardless of temperature change during storage periods, and the problems of low solubility and stability in the aqueous solution phase are resolved, at the time of the provision of a composition comprising an indole compound which can efficiently prevent cellular necrosis induced under pathological circumstances as an active ingredient.
To accomplish the above object, the present invention provides a pharmaceutical preparation comprising an indole compound or a pharmaceutically acceptable derivative thereof, a cyclodextrin derivative and an antioxidant.
Here, the indole compound is preferably [5-(1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-yl)-amine) of the following Formula (1).
Figure PCTKR2016003019-appb-I000001
(1)
In addition, in the present invention the cyclodextrin derivative is preferably ß-cyclodextrin, specifically hydroxypropyl ß-cyclodextrin (HP-ß-CD), and is preferably comprised in the preparation in an amount of 0.1 to 30% by weight.
Furthermore, in the pharmaceutical preparation according to the present invention, the antioxidant is, for example, but is not limited to, thioglycerol or L-cysteine hydrochloride, and is preferably comprised in the preparation in an amount of 0.1 to 2.0% by weight.
The pharmaceutical preparation according to the present invention may further comprise propylene glycol to improve solubility and a chelating agent to improve stability. Propylene glycol is preferably comprised in the preparation in an amount of 0.1 to 1.0% by weight, and the chelating agent is preferably edetate (ethylene diamine triacetic acid) and comprised in the preparation in an amount of 0.001 to 0.01% by weight.
Such a pharmaceutical preparation of the present invention can be used for inhibiting cellular necrosis and preventing ischemia/reperfusion injury, is suitable for parenteral administration, and includes a liquid or freeze-dried formulation.
Hereinafter, the present invention is explained in more detail.
In the present invention, a pharmaceutical preparation having improved stability in solution is provided in which the solubility of indole compound is improved by forming indole compound having the solubility of 5 μg/ml or less in an aqueous solution as an inclusion complex of cyclodextrin derivative.
Cyclodextrins are structurally composed of 6, 7 or 8 units of D-glucopyranosyl linked by α(1-4) glycosidic linkage, and they are called α (alpha)-cyclodextrin, ß (beta)-cyclodextrin and γ (gamma)-cyclodextrin, respectively. They are the most stable three-dimensional structures among oligosaccharides. Cyclodextrin derivatives are understood as cyclodextrins or mixtures thereof, and some or all hydrogen atom(s) at the 2-, 3- and 6-positions of glucose is (are) substituted with another functional group(s) such as dihydroxyalkyl group, saccharide residue, hydroxyalkyl group, sulfonate group, sulfoalkyl group, alkyl group, alkanoyl group, acetyl group and benzoyl group.
Cyclodextrins or derivatives thereof used in the present invention are commercially available or may be synthesized according to the methods known in this field. Examples of cyclodextrins or derivatives thereof include, but are not limited to, natural cyclodextrin (alpha, beta or gamma), hydroxypropylcyclodextrin, carboxymethylcyclodextrin, sulfobutylcyclodextrin, aminocyclodextrin, dimethylcyclodextrin, cyclodextrinphosphate, hydroxyethylcyclodextrin, acetyl-cyclodextrin, ethylcyclodextrin, trimethylcyclodextrin, carboxyethylcyclodextrin, glucosylcyclodextrin, 6-O-α-maltosylcyclodextrin, butyl-cyclodextrin, sulfate cyclodextrin, N,N-diethylaminoethylcyclodextrin, tert-butylsilylcyclodextrin, silyl[(6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-cyclodextrin, succinyl-(2-hydroxypropyl)-cyclodextrin, succinyl-cyclodextrin, sulfopropyl-cyclodextrin and polycyclodextrin. In a specific embodiment of the present invention, cyclodextrins include hydroxypropyl α-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylethyl-β-cyclodextrin or a mixture thereof.
Meanwhile, in the pharmaceutical preparation according to the present invention, an antioxidant is necessary for the improvement of stability in a solution state and the prevention of discoloration. Examples of available antioxidants include, but are not limited to, retinol, tocopherol, sodium ascorbate, ascorbic acid, sulfite compounds, L-cysteine, thioglycerol, thiodipropionic acid, thiolactic acid or monothioglycerol. Specifically, in the case of using cysteine hydrochloride or thioglycerol, stability can be maintained during the storage period by inhibiting oxidation reaction of indole compounds. The antioxidant such as cysteine hydrochloride or thioglycerol may be used in an amount of 0.1 to 2% by weight.
In a preferred embodiment of the present invention, the pharmaceutical preparation according to the present invention may further comprise a pH control agent such as phosphate buffer or citric acid/sodium hydroxide buffer solution in order to adjust pH to between 3.0 and 4.0, if necessary. Available phosphate salt may be in the form of sodium salt or potassium salt, or anhydride or hydrate, and citric acid is also used in the form of anhydride or hydrate. For example, phosphate buffer solution of potassium dihydrogen phosphate and sodium monohydrogen phosphate, sodium dihydrogen phosphate-citric acid buffer solution, and phosphate buffer solution of potassium dihydrogen phosphate and sodium hydroxide may be used. The pH control agent may be used in an amount necessary for adjusting the pH of the pharmaceutical preparation according to the present invention to 3.0 to 4.0.
As a preferred embodiment, the pharmaceutical preparation of the present invention may further comprise propylene glycol to improve solubility and a chelating agent such as edetate to improve stability. In addition, the use of an antioxidant and nitrogen gas may overcome pharmaceutical instability caused by 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 them may be used in the system according to the present invention.
Indole compounds or derivatives thereof used in the present invention may be synthesized according to the method disclosed in Korean Patent Application Publication No. 10-2012-0013266. Available derivatives of indole compounds include salts such as hydrochloride, sulfate, mesylate, malate and the like.
As a preferred embodiment of the pharmaceutical preparation according to the present invention, an injectable composition comprises 1 to 20% by weight of indole compound, 0.1 to 30% by weight of hydroxypropyl ß-cyclodextrin, 0.1 to 2.0% by weight of 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.
As a preferred embodiment of the pharmaceutical preparation according to the present invention, a method for preparing an 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 hydrochloric acid solution; adding 1 to 20% by weight of indole compound and agitating; adding 0.1 to 2.0% by weight of an antioxidant and 0.001 to 0.01% by weight of edetate; and adjusting pH to about 3.0 to 4.0.
In addition, the pharmaceutical preparation according to the present invention may be for parenteral administration, and includes a liquid or freeze-dried formulation. Dosage form may be a solution in oil or aqueous media, suspension or emulsion, and may comprise a conventional dispersing agent, suspending agent or stabilizer. Furthermore, for example, the pharmaceutical preparation may be a dried powder form which is used by being dissolved in pyrogen-free, sterile water.
A pharmaceutical preparation according to the present invention 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 according to the present invention may preferably be 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.
Figures 1 and 2 are DSC and XRD charts, respectively, showing whether inclusion complexes of indole compound/cyclodextrin are formed when a solution preparation for injection is prepared according to Example 4.
Hereinafter, the present invention is explained in more detail with the following examples. However, it must be understood that the protection scope of the present invention is not limited to the examples.
Examples 1 to 4: Determination of cyclodextrin content (based on 100 ml)
As shown in Table 1, the solubility of hydroxypropyl ß-cyclodextrin and indole compound in a solution formulation for injection was tested. All process steps were carried out under nitrogen purging.
(a) After dissolving hydroxypropyl ß-cyclodextrin in 0.1 N hydrochloric acid, 1% by volume of propylene glycol was added thereto and dissolved, and indole compound was then added thereto and dissolved for about 20 minutes.
(b) 0.9% by volume of anhydrous citric acid was added to 9% by volume of 1 N sodium hydroxide solution in a beaker and dissolved for about 10 minutes, and water for injection was then added thereto.
And then, 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 bilayer filter, and the filtered solution was collected. The pH of the solution was about 3.0-3.5. Finally, for HPLC analysis the solution was filtered via a sterile 0.2 μm PVDF filter to a vessel.
Figure PCTKR2016003019-appb-T000001
Aim concentration: 20 mg/ml
<Analysis condition>
Column: Capcell pak UG120 (4.6 × 150 mm, 5 mm, Shiseido)
Column temperature: 40°C
Mobile phase A: acetonitrile/water/trifluoroacetic acid = 30/70/0.1 (v/v/v)
Mobile phase B: acetonitrile/water/trifluoroacetic acid = 80/20/0.1 (v/v/v)
Flow rate: 1 ml/min
Detector: UV absorption spectrophotometer (wavelength: 254 nm)
Injection amount: 10 ml
Figure PCTKR2016003019-appb-T000002
As can be seen from Table 3, it was confirmed that the solubility of indole compound which has the solubility of 0.10 mg/ml or below in an aqueous solution is dramatically increased by forming inclusion complexes of indole compound/ hydroxypropyl ß-cyclodextrin of Examples 1 to 3.
Figure PCTKR2016003019-appb-T000003
Examples 4 to 6: Preparation of solution formulations (1)
Preparations for injection in the solution formulation comprising 43.3 mg of indole compound were prepared with the compositions of Table 4 (based on 22 g). All process steps were carried out under nitrogen purging.
(a) Hydroxypropyl ß-cyclodextrin was dissolved in 0.1 N hydrochloric acid, and indole compound was then added thereto and dissolved for about 20 minutes.
(b) Anhydrous citric acid was added to 1 N sodium hydroxide solution in a beaker and dissolved for about 10 minutes, and water for injection was then added thereto.
And then, the solution (b) was mixed with the solution (a), and monothioglycerol was added thereto and dissolved. The pH of the solution was about 3.0-3.5.
Figures 1 and 2 are DSC and XRD charts, respectively, showing whether inclusion complexes of indole compound/cyclodextrin are formed when a solution preparation for injection is prepared according to Example 4.
Figure PCTKR2016003019-appb-T000004
Examples 7 to 9: Preparation of solution formulations (2)
Preparations for injection in the solution formulation were prepared with the same compositions as in Example 4 except that 2%, 1% and 0.1% by weight of L-cysteine hydrochloride instead of monothioglycerol were used (see Table 5), and by the same process as in Example 4.
Figure PCTKR2016003019-appb-T000005
Examples 10 to 14: Preparation of solution formulations (3)
Preparations for injection in the solution formulation were prepared with the same compositions as in Example 4 except for the use of 1.0% or 0.1% by weight of propylene glycol and 0.01% or 0.001% by weight of disodium edetate (see Table 6), and by the same process as in Example 4. This time, propylene glycol was added to the solution (b), and disodium edetate was added at the time of mixing the solutions (a) and (b).
Figure PCTKR2016003019-appb-T000006
Examples 15 to 17: Preparation of solution formulations (4)
Preparations for injection in the solution formulation were prepared with the same compositions as in Example 4 except that 1% by weight of propylene glycol was additionally comprised (see Table 7), and by the same process as in Example 4.
Figure PCTKR2016003019-appb-T000007
Examples 18 to 20: Preparation of solution formulations (5)
Preparations for injection in the solution formulation were prepared with the same compositions as in Example 7 except that 1% by weight of propylene glycol was additionally comprised (see Table 8), and by the same process as in Example 7.
Figure PCTKR2016003019-appb-T000008
Comparative Examples 1 and 2: Preparation of comparative solution formulations (1)
Preparations for injection in the solution formulation were prepared with the compositions of Table 9.
Figure PCTKR2016003019-appb-T000009
Comparative Examples 3 and 4: Preparation of comparative solution formulations (2)
Indole compound solution injections comprising the compositions of Table 1 were prepared. At this time, nitrogen purging was not carried out.
Figure PCTKR2016003019-appb-T000010
Experimental Example: Test for property change according to storage condition
Solution formulations of indole compound have the problems of precipitation of indole compound in a solution and low stability such as color change. Therefore, after one-month storage in an amber glass vial under acceleration (40°C), room temperature (25°C) and cold storage (4°C) conditions, precipitation of indole compound and color change were observed with the naked eye by the foreign insoluble matter test. The results are represented in Table 11.
Figure PCTKR2016003019-appb-T000011
From Table 11, it can be known that all preparations were unstable under the condition of acceleration (40°C) and 75% humidity. In the preparations of Comparative Examples 1 to 4 which do not comprise an antioxidant, color change and precipitation were observed under all conditions of acceleration, room temperature and cold storage.
The preparation of Example 6 in which 0.1% by weight of antioxidant (monothioglycerol) is comprised was stable only under the condition of cold storage. Meanwhile, the preparations of Examples 4 and 5―which comprise 2.0% by weight and 1.0% by weight of monothioglycerol, respectively―showed stability under the conditions of room temperature and cold storage. Such results indicate that the stability at room temperature is increased as the concentration of the antioxidant is higher. The preparations of Examples 7 and 8―which comprise 2.0% by weight and 1.0% by weight of L-cysteine hydrochloride as an antioxidant, respectively―also showed stability under the conditions of room temperature and cold storage, and the preparation of Example 9 in which 0.1% by weight is comprised was stable only under the condition of cold storage. That is, it can be known that the addition of antioxidant plays an important role in the stability of preparations.
In addition, as can be seen from Examples 10, 11, 13 and 14, the preparations comprising 1.0% by weight or 0.1% by weight of propylene glycol or 0.01% by weight or 0.001% by weight of edetate were stable under the conditions of room temperature and cold storage, only when 1.0% by weight or 2.0% by weight of monothioglycerol is comprised. The preparation of Example 12 comprising 0.1% by weight of monothioglycerol showed stability only under the condition of cold storage, as did that of Example 6. In the same manner, in the case of the preparation comprising 1.0% by weight of propylene glycol (Examples 15 to 20), the preparations comprising 0.1% by weight of monothioglycerol and 0.1% by weight of L-cysteine hydrochloride (Examples 17 and 20) showed stability only under the condition of cold storage, and the preparations comprising 1% by weight and 2% by weight of monothioglycerol or L-cysteine hydrochloride (Examples 15, 16, 18 and 19) showed stability under the conditions of room temperature and cold storage.

Claims (12)

  1. A pharmaceutical preparation comprising an indole compound or a pharmaceutically acceptable derivative thereof, a cyclodextrin derivative and an antioxidant.
  2. The pharmaceutical preparation according to Claim 1, wherein the indole compound is a compound of the following Formula (1):
    Figure PCTKR2016003019-appb-I000002
    (1)
  3. The pharmaceutical preparation according to Claim 1, wherein the cyclodextrin derivative is ß-cyclodextrin or a derivative thereof.
  4. The pharmaceutical preparation according to Claim 1, which comprises 0.1 to 30% by weight of the cyclodextrin derivative.
  5. The pharmaceutical preparation according to Claim 1, wherein the antioxidant is thioglycerol or L-cysteine hydrochloride.
  6. The pharmaceutical preparation according to Claim 1, which comprises 0.1 to 2.0% by weight of the antioxidant.
  7. The pharmaceutical preparation according to Claim 1, which further comprises 0.1 to 1.0% by weight of propylene glycol.
  8. The pharmaceutical preparation according to Claim 1, which further comprises 0.001 to 0.01% by weight of edetate.
  9. The pharmaceutical preparation according to Claim 1, which comprises 1 to 20% by weight of indole compound, 0.1 to 30% by weight of hydroxypropyl ß-cyclodextrin, 0.1 to 2.0% by weight of thioglycerol or L-cysteine hydrochloride, 0.1 to 1.0% by weight of propylene glycol and 0.001 to 0.01% by weight of edetate.
  10. The pharmaceutical preparation according to Claim 1, which is for inhibiting cellular necrosis and preventing ischemia/reperfusion injury.
  11. The pharmaceutical preparation according to Claim 1, which is for parenteral administration.
  12. The pharmaceutical preparation according to Claim 1, which is a liquid or freeze-dried formulation.
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