WO2012074243A2 - Injectable liquid composition containing revaprazan or its salt - Google Patents

Injectable liquid composition containing revaprazan or its salt Download PDF

Info

Publication number
WO2012074243A2
WO2012074243A2 PCT/KR2011/009047 KR2011009047W WO2012074243A2 WO 2012074243 A2 WO2012074243 A2 WO 2012074243A2 KR 2011009047 W KR2011009047 W KR 2011009047W WO 2012074243 A2 WO2012074243 A2 WO 2012074243A2
Authority
WO
WIPO (PCT)
Prior art keywords
revaprazan
surfactant
injection
polyoxyethylene
liquid composition
Prior art date
Application number
PCT/KR2011/009047
Other languages
French (fr)
Other versions
WO2012074243A3 (en
Inventor
Ji-Heon Kim
Chang-Keun Hyun
Yoong-Sik Park
Original Assignee
Yuhan Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yuhan Corporation filed Critical Yuhan Corporation
Priority to CN201180057045.7A priority Critical patent/CN103228280B/en
Publication of WO2012074243A2 publication Critical patent/WO2012074243A2/en
Publication of WO2012074243A3 publication Critical patent/WO2012074243A3/en

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
    • A61K47/06—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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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

Definitions

  • the present invention relates to an injectable liquid composition comprising revaprazan or its salt, a process for preparing the same, and a dry powder for injection. More specifically, the present invention relates to a liquid composition for injection in which revaprazan or its salt is dissolved in the form of a micelle or a mixed micelle in an aqueous medium using a certain surfactant(s); and a process for preparing the same. In addition, the present invention relates to a dry powder for injection obtained by drying the liquid composition for injection.
  • Revaprazan whose chemical name is 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, is represented by the following Formula 1.
  • Revaprazan can be used in a form of an acid addition salt, including e.g., HCl salt (see International Publication No. WO 1996/05177).
  • Revaprazan or its salt is reversibly bound to a H + /K + exchange site of a proton pump (H + /K + ATPase) existing in a gastric parietal cell so that secretion of H + into the gastric lumen is competitively inhibited.
  • Revaprazan or its salt is also bound to a specific site of H + /K + ATPase, thereby inhibiting transport of H + and suppressing an acid secretion to the gastric lumen, which results in increasing the intragastric pH.
  • irreversible proton pump inhibitors e.g., omeprazole
  • revaprazan or its salt is not dependent upon acid activation of a drug in a stomach or secretion status of a proton pump. Therefore, based on the mechanism different from irreversible proton pump inhibitors, such as omeprazole, revaprazan or its salt is classified into an acid pump antagonist (APA).
  • APA acid pump antagonist
  • Revaprazan has very low water-solubility, i.e. less than 0.2 mg/mL, and due to such a low solubility, its dissolution in a gastrointestinal tract is low. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglutination properties.
  • WO 2008/078922 has disclosed a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
  • revaprazan in order to formulate revaprazan into parenteral liquid forms (e.g., an injection), revaprazan should be completely dissolved in an aqueous medium such as water for injection. Especially, a therapeutically effective amount (at least 10 mg) of revaprazan should be completely dissolved in an aqueous medium, without any physical or physicochemical changes for long duration.
  • revaprazan in case revaprazan is formulated into the form of an injection using the solid dispersion according to WO 2008/078922, revaprazan becomes to be precipitated in the aqueous medium with time being elapsed. And also, because of additionally performing the process for preparing the solid dispersion, the costs associated with preparing an injectable formulation are increased.
  • the present invention provides a stable injectable formulation obtained by completely dissolving revaprazan or its salt in an aqueous medium, the process of which can be easily performed avoiding complicated processes (e.g., such as processes for preparing a solid dispersion); and a process for preparing the same.
  • the present invention provides a dry powder for injection, which is reconstituted into an injectable solution before administering to a subject
  • a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; and a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester in an aqueous medium, wherein the revaprazan or its salt and the surfactant are dissolved in the form of a micelle in the aqueous medium.
  • a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester; and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester in an aqueous medium, wherein the revaprazan or its salt, the surfactant, and the co-surfactant are dissolved in the form of a mixed micelle in the aqueous medium.
  • a process for preparing a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt in the form of a micelle or a mixed micelle.
  • a dry powder for injection obtained by drying the liquid composition for injection.
  • revaprazan or its salt having very low water-solubility can be completely dissolved through formulating revaprazan or its salt into the form of a micelle or a mixed micelle using a certain surfactant or a certain combination of surfactants.
  • the resulting formulation has excellent stability for long duration, without any physical or physicochemical changes (e.g., precipitation). Therefore, the composition of the present invention is usefully applied to an injectable solution.
  • the liquid composition for injection of the present invention does not require performing complicated processes (e.g., such as processes for preparing a solid dispersion), it can be easily prepared.
  • the present invention provides a liquid composition for injection in which a therapeutically effective amount of revaprazan or its salt is dissolved in the form of a micelle or a mixed micelle in an aqueous medium, using a certain surfactant or a certain combination of surfactants.
  • the present inventors have tried various studies on injectable liquid formulations which comprise revaprazan or its salt having very low water-solubility.
  • the resulting liquid composition for injection in the form of micelles or mixed micelles has excellent stability for long duration, without any physical or physicochemical changes (e.g., precipitation).
  • the salt of revaprazan may be an acid addition salt, including revaprazan hydrochloride, revaprazan sulfate, revaprazan phosphate, revaprazan nitrate, revaprazan camphorsulfonate (i.e., revaprazan camsylate), revaprazan thiocyanate, and the like.
  • the salt of revaprazan is revaprazan hydrochloride.
  • a liquid composition for injection having a micelle form. That is, the present invention provides a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; and a certain surfactant, wherein the revaprazan or its salt and the surfactant are dissolved in the form of a micelle in the aqueous medium.
  • the surfactant may be selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil [for example, Cremophor TM EL (polyoxyl 35 castor oil), Cremophor TM ELP (polyoxyl 35 castor oil, purified), Cremophor TM RH 40 (polyoxyl 40 castor oil), Cremophor TM RH 60 (polyoxyl 60 castor oil), etc], polyoxyethylene alkyl ether [for example, Cremophor TM A 25 (polyoxyl 25 cetostearyl ether), etc], polyethylene glycol-15-hydroxystearate [for example, Solutol TM HS 15 (macrogol 15 Hydroxystearate), etc], polyoxyethylene sorbitan fatty acid ester [for example, Tween TM 80 (polyoxyethylene 20 sorbitan monooleate), Crillet TM 1 (polyoxyethylene 20 sorbitan monolaurate), Crillet TM 4 (
  • the surfactant may be present in an amount ranging from 800 to 2800 parts by weigh, based on 100 parts by weight of revaprazan.
  • a liquid composition for injection having a mixed micelle form. That is, the present invention provides a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; a certain surfactant; and a certain co-surfactant, wherein the revaprazan or its salt, the surfactant, and the co-surfactant are dissolved in the form of a mixed micelle in the aqueous medium.
  • the surfactant may be selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester.
  • the co-surfactant may be one or more selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer [for example, Poloxamer TM 407, Poloxamer TM 188, etc], polyoxyethylene glycol [for example, Lutrol TM E 400 (macrogol 400), etc], and sorbitan ester.
  • the surfactant may be polyethylene glycol-15-hydroxystearate and the co-surfactant may be polyoxyethylene-polyoxypropylene copolymer or polyoxyethylene glycol.
  • the surfactant may be present in an amount ranging from 800 to 2600 parts by weigh, based on 100 parts by weight of revaprazan; and the co-surfactant may be present in an amount ranging from 20 to 500 parts by weigh, based on 100 parts by weight of revaprazan.
  • the surfactant may be present in an amount ranging from 1400 to 2000 parts by weigh, based on 100 parts by weight of revaprazan; and the co-surfactant may be present in an amount ranging from 40 to 250 parts by weigh, based on 100 parts by weight of revaprazan.
  • the aqueous medium may be sterile water conventionally used for injectable solution, e.g., water for injection.
  • the aqueous medium may be a mixed solution of water for injection and ethanol. It is found that the mixed solution of water for injection and ethanol may more effectively increase the solubility of revaprazan in the liquid composition for injection having a micelle or mixed micelle form, thereby showing more excellent stability for long duration without any precipitation.
  • the mixed solution may be an ethanol solution having a concentration of 15 to 35 wt%.
  • the present invention includes, within its scope, a process for preparing a liquid composition for injection having a micelle or mixed micelle form.
  • the liquid composition for injection may be prepared by melting a surfactant or a combination of the surfactants (i.e., surfactant and co-surfactant); mixing revaprazan or its salt with the resulting melt; and then adding an aqueous medium to the mixture, followed by cooling to a room temperature.
  • the liquid composition for injection may be prepared by dissolving revaprazan or its salt and a surfactant or a combination of the surfactants (i.e., surfactant and co-surfactant) in an aqueous medium at an elevated temperature; and then cooling to a room temperature.
  • a process for preparing a liquid composition for injection in which revaprazan or its salt and a surfactant are dissolved in the form of a micelle in an aqueous medium comprising (a) melting a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester; (b) mixing a therapeutically effective amount of revaprazan or its salt with the melt obtained from the step (a); and (c) adding an aqueous medium to the mixture obtained from the step (b), followed by cooling to a room temperature.
  • a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester
  • a process for preparing a liquid composition for injection in which revaprazan or its salt and a surfactant are dissolved in the form of a micelle in an aqueous medium comprising (i) dissolving a therapeutically effective amount of revaprazan or its salt and a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester in an aqueous medium at 50 to 80 °C; and (ii) cooling the solution obtained from the step (i) to a room temperature.
  • a process for preparing a liquid composition for injection in which revaprazan or its salt, a surfactant, and a co-surfactant are dissolved in the form of a mixed micelle in an aqueous medium comprising (a') melting a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester; (b') mixing a therapeutically effective amount of revaprazan or its salt with the melt obtained from the step (a'); and (c') adding an aqueous medium to the mixture obtained from the step (b'), followed by cooling to a room temperature.
  • a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene al
  • a process for preparing a liquid composition for injection in which revaprazan or its salt, a surfactant, and a co-surfactant are dissolved in the form of a mixed micelle in an aqueous medium comprising (i') dissolving a therapeutically effective amount of revaprazan or its salt, a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester, and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester in an aqueous medium at 50 to 80 °C; and (ii') cooling the solution obtained from the step (i') to a room temperature.
  • a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene
  • room temperature refers to an ambient temperature without any heat treatment.
  • room temperature refers to a temperature of 20 to 27 °C, typically about 25 °C.
  • the aqueous medium may be water for injection or a mixed solution of water for injection and ethanol.
  • the mixed solution may be an ethanol solution having a concentration of 15 to 35 wt%.
  • a dry powder for injection obtained by drying the liquid composition for injection.
  • the dry powder may be reconstituted with water for injection, a physiological saline, a glucose solution, an amino acid solution, etc, before administering to a subject.
  • the drying may be performed using any conventional drying methods known in the pharmaceutical field, such as freeze-drying, rotary evaporation drying, spray-drying, or fluidized-bed drying.
  • the drying may be performed by freeze-drying (or lyophilizing).
  • Liquid compositions for injection in a micelle form were prepared according to the components and amounts shown in Table 1. Each surfactant was completely dissolved in 20 ml of water for injection, in 70°C water bath. Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour. The resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a micelle form.
  • Liquid compositions for injection in a mixed micelle form were prepared according to the components and amounts shown in Table 2. Each surfactant and co-surfactant were completely dissolved in 20 ml of water for injection, in 70°C water bath. Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour. The resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a mixed micelle form.
  • Liquid compositions for injection in a mixed micelle form were prepared, using Solutol TM HS 15 as a surfactant and Lutrol TM E 400 as a co-surfactant, according to Table 3.
  • the surfactant (Solutol TM HS 15) and co-surfactant (Lutrol TM E 400) were completely dissolved in 20 ml of water for injection, in 70°C water bath.
  • Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour.
  • the resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a mixed micelle form.
  • Example 40 Liquid compositions for injection in a mixed micelle form
  • Liquid compositions for injection in a mixed micelle form were prepared, using Solutol TM HS 15 as a surfactant and Lutrol TM E 400 as a co-surfactant, according to Table 4.
  • the surfactant (Solutol TM HS 15) and co-surfactant (Lutrol TM E 400) were completely dissolved in 20 ml of each ethanol solution, in 70°C water bath.
  • Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour.
  • the resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a mixed micelle form.
  • the amount corresponding to 100 mg of revaprazan was taken from the sample and then dissolved in 100 mL of methanol. The obtained solution was used as a test solution.
  • UV spectrophotometer (wavelength: 270 nm)
  • the physicochemical stability was evaluated by measuring appearance, endotoxin, amount of revaprazan (as well as amount of potential impurities), Foreign Insoluble Matter, and Insoluble Particulate Matter, while storing the injectable solution prepared in Example 33 at 25 °C and 60 % RH (Relative Humidity) for 6 months. And also, the physicochemical stability was evaluated by measuring appearance, endotoxin, amount of revaprazan (as well as amount of potential impurities), Foreign Insoluble Matter, and Insoluble Particulate Matter, while storing the injectable solution prepared in Example 33 at 4 °C of refrigerator for 6 months. The results are shown in Table 5.
  • the physicochemical stability was evaluated by measuring appearance, endotoxin, and amount of revaprazan (as well as amount of potential impurities), while storing the injectable solution prepared in Example 36 at 25 °C and 60 %RH for 1 month. And also, the physicochemical stability was evaluated by measuring appearance, endotoxin, and amount of revaprazan (as well as amount of potential impurities), while storing the injectable solution prepared in Example 36 at 4 °C of refrigerator for 1 month. The results are shown in Table 6.
  • the injectable solutions in the form of a micelle or a mixed micelle obtained according to the present invention have excellent physical and physicochemical stabilities under the conditions of refrigeration as well as a room temperature.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a liquid composition for injection in which a therapeutically effective amount of revaprazan or its salt is dissolved in the form of a micelle or a mixed micelle in an aqueous medium, using a certain surfactant or a certain combination of surfactants; a process for preparing the same; and a dry powder for injection obtained by drying the liquid composition for injection.

Description

INJECTABLE LIQUID COMPOSITION CONTAINING REVAPRAZAN OR ITS SALT
The present invention relates to an injectable liquid composition comprising revaprazan or its salt, a process for preparing the same, and a dry powder for injection. More specifically, the present invention relates to a liquid composition for injection in which revaprazan or its salt is dissolved in the form of a micelle or a mixed micelle in an aqueous medium using a certain surfactant(s); and a process for preparing the same. In addition, the present invention relates to a dry powder for injection obtained by drying the liquid composition for injection.
Revaprazan, whose chemical name is 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, is represented by the following Formula 1. Revaprazan can be used in a form of an acid addition salt, including e.g., HCl salt (see International Publication No. WO 1996/05177).
Formula 1
Figure PCTKR2011009047-appb-I000001
Revaprazan or its salt is reversibly bound to a H+/K+ exchange site of a proton pump (H+/K+ ATPase) existing in a gastric parietal cell so that secretion of H+ into the gastric lumen is competitively inhibited. Revaprazan or its salt is also bound to a specific site of H+/K+ ATPase, thereby inhibiting transport of H+ and suppressing an acid secretion to the gastric lumen, which results in increasing the intragastric pH. Unlike irreversible proton pump inhibitors, e.g., omeprazole, revaprazan or its salt is not dependent upon acid activation of a drug in a stomach or secretion status of a proton pump. Therefore, based on the mechanism different from irreversible proton pump inhibitors, such as omeprazole, revaprazan or its salt is classified into an acid pump antagonist (APA).
Revaprazan has very low water-solubility, i.e. less than 0.2 mg/mL, and due to such a low solubility, its dissolution in a gastrointestinal tract is low. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglutination properties. In order to address these problems, WO 2008/078922 has disclosed a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
Meanwhile, in order to formulate revaprazan into parenteral liquid forms (e.g., an injection), revaprazan should be completely dissolved in an aqueous medium such as water for injection. Especially, a therapeutically effective amount (at least 10 mg) of revaprazan should be completely dissolved in an aqueous medium, without any physical or physicochemical changes for long duration. However, in case revaprazan is formulated into the form of an injection using the solid dispersion according to WO 2008/078922, revaprazan becomes to be precipitated in the aqueous medium with time being elapsed. And also, because of additionally performing the process for preparing the solid dispersion, the costs associated with preparing an injectable formulation are increased.
The present invention provides a stable injectable formulation obtained by completely dissolving revaprazan or its salt in an aqueous medium, the process of which can be easily performed avoiding complicated processes (e.g., such as processes for preparing a solid dispersion); and a process for preparing the same. In addition, the present invention provides a dry powder for injection, which is reconstituted into an injectable solution before administering to a subject
Therefore, it is an object of the present invention to provide a liquid composition for injection in which a therapeutically effective amount of revaprazan or its salt is completely dissolved.
It is another object of the present invention to provide a process for preparing the liquid composition for injection.
It is still another object of the present invention to provide a dry powder for injection obtained by drying the liquid composition for injection.
In accordance with an aspect of the present invention, there is provided a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; and a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester in an aqueous medium, wherein the revaprazan or its salt and the surfactant are dissolved in the form of a micelle in the aqueous medium.
In accordance with another aspect of the present invention, there is provided a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester; and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester in an aqueous medium, wherein the revaprazan or its salt, the surfactant, and the co-surfactant are dissolved in the form of a mixed micelle in the aqueous medium.
In accordance with still another aspect of the present invention, there is provided a process for preparing a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt in the form of a micelle or a mixed micelle.
In accordance with still another aspect of the present invention, there is provided a dry powder for injection obtained by drying the liquid composition for injection.
It is found by the present invention that revaprazan or its salt having very low water-solubility can be completely dissolved through formulating revaprazan or its salt into the form of a micelle or a mixed micelle using a certain surfactant or a certain combination of surfactants. In addition, it is also found by the present invention that the resulting formulation has excellent stability for long duration, without any physical or physicochemical changes (e.g., precipitation). Therefore, the composition of the present invention is usefully applied to an injectable solution. Furthermore, since the liquid composition for injection of the present invention does not require performing complicated processes (e.g., such as processes for preparing a solid dispersion), it can be easily prepared.
The present invention provides a liquid composition for injection in which a therapeutically effective amount of revaprazan or its salt is dissolved in the form of a micelle or a mixed micelle in an aqueous medium, using a certain surfactant or a certain combination of surfactants.
The present inventors have tried various studies on injectable liquid formulations which comprise revaprazan or its salt having very low water-solubility. Among them, we designed various forms of micelle or mixed micelle as a system for effectively dissolving revaprazan or its salt, using various surfactants or their combinations. It is surprisingly found that, when a certain surfactant or a certain combination of surfactants is used, revaprazan or its salt forms micelles or mixed micelles, thereby existing in a stable solution. Especially, it is also found that the resulting liquid composition for injection in the form of micelles or mixed micelles has excellent stability for long duration, without any physical or physicochemical changes (e.g., precipitation).
In the present invention, the salt of revaprazan may be an acid addition salt, including revaprazan hydrochloride, revaprazan sulfate, revaprazan phosphate, revaprazan nitrate, revaprazan camphorsulfonate (i.e., revaprazan camsylate), revaprazan thiocyanate, and the like. Preferably, the salt of revaprazan is revaprazan hydrochloride.
In accordance with an embodiment, there is provided a liquid composition for injection having a micelle form. That is, the present invention provides a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; and a certain surfactant, wherein the revaprazan or its salt and the surfactant are dissolved in the form of a micelle in the aqueous medium.
In the liquid composition for injection having a micelle form, the surfactant may be selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil [for example, CremophorTM EL (polyoxyl 35 castor oil), CremophorTM ELP (polyoxyl 35 castor oil, purified), CremophorTM RH 40 (polyoxyl 40 castor oil), CremophorTM RH 60 (polyoxyl 60 castor oil), etc], polyoxyethylene alkyl ether [for example, CremophorTM A 25 (polyoxyl 25 cetostearyl ether), etc], polyethylene glycol-15-hydroxystearate [for example, SolutolTM HS 15 (macrogol 15 Hydroxystearate), etc], polyoxyethylene sorbitan fatty acid ester [for example, TweenTM 80 (polyoxyethylene 20 sorbitan monooleate), CrilletTM 1 (polyoxyethylene 20 sorbitan monolaurate), CrilletTM 4 (polyoxyethylene 20 sorbitan monooleate), etc], and sorbitan ester [for example, CrillTM 3 (sorbitan monostearate), CrillTM 4 (sorbitan monooleate), CrillTM 36 (sorbitan tristearate), CrillTM 43 (sorbitan sesquioleate), CrillTM 45 (sorbitan trioleate), etc]. Among them, polyoxyethylene natural or hydrogenated castor oil, polyethylene glycol-15-hydroxystearate, polyoxyethylene alkyl ether, or polyoxyethylene sorbitan fatty acid ester may be preferably used.
In the liquid composition for injection having a micelle form, the surfactant may be present in an amount ranging from 800 to 2800 parts by weigh, based on 100 parts by weight of revaprazan.
In accordance with another embodiment, there is provided a liquid composition for injection having a mixed micelle form. That is, the present invention provides a liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; a certain surfactant; and a certain co-surfactant, wherein the revaprazan or its salt, the surfactant, and the co-surfactant are dissolved in the form of a mixed micelle in the aqueous medium.
In the liquid composition for injection having a mixed micelle form, the surfactant may be selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester. And also, the co-surfactant may be one or more selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer [for example, PoloxamerTM 407, PoloxamerTM 188, etc], polyoxyethylene glycol [for example, LutrolTM E 400 (macrogol 400), etc], and sorbitan ester. Preferably, the surfactant may be polyethylene glycol-15-hydroxystearate and the co-surfactant may be polyoxyethylene-polyoxypropylene copolymer or polyoxyethylene glycol.
In the liquid composition for injection having a mixed micelle form, the surfactant may be present in an amount ranging from 800 to 2600 parts by weigh, based on 100 parts by weight of revaprazan; and the co-surfactant may be present in an amount ranging from 20 to 500 parts by weigh, based on 100 parts by weight of revaprazan. Preferably, the surfactant may be present in an amount ranging from 1400 to 2000 parts by weigh, based on 100 parts by weight of revaprazan; and the co-surfactant may be present in an amount ranging from 40 to 250 parts by weigh, based on 100 parts by weight of revaprazan.
In the liquid composition for injection having a micelle or mixed micelle form, the aqueous medium may be sterile water conventionally used for injectable solution, e.g., water for injection. Preferably, the aqueous medium may be a mixed solution of water for injection and ethanol. It is found that the mixed solution of water for injection and ethanol may more effectively increase the solubility of revaprazan in the liquid composition for injection having a micelle or mixed micelle form, thereby showing more excellent stability for long duration without any precipitation. The mixed solution may be an ethanol solution having a concentration of 15 to 35 wt%.
The present invention includes, within its scope, a process for preparing a liquid composition for injection having a micelle or mixed micelle form. The liquid composition for injection may be prepared by melting a surfactant or a combination of the surfactants (i.e., surfactant and co-surfactant); mixing revaprazan or its salt with the resulting melt; and then adding an aqueous medium to the mixture, followed by cooling to a room temperature. And also, the liquid composition for injection may be prepared by dissolving revaprazan or its salt and a surfactant or a combination of the surfactants (i.e., surfactant and co-surfactant) in an aqueous medium at an elevated temperature; and then cooling to a room temperature.
According to an embodiment, there is provided a process for preparing a liquid composition for injection in which revaprazan or its salt and a surfactant are dissolved in the form of a micelle in an aqueous medium, the process comprising (a) melting a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester; (b) mixing a therapeutically effective amount of revaprazan or its salt with the melt obtained from the step (a); and (c) adding an aqueous medium to the mixture obtained from the step (b), followed by cooling to a room temperature.
According to another embodiment, there is provided a process for preparing a liquid composition for injection in which revaprazan or its salt and a surfactant are dissolved in the form of a micelle in an aqueous medium, the process comprising (i) dissolving a therapeutically effective amount of revaprazan or its salt and a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester in an aqueous medium at 50 to 80 ℃; and (ii) cooling the solution obtained from the step (i) to a room temperature.
According to still another embodiment, there is provided a process for preparing a liquid composition for injection in which revaprazan or its salt, a surfactant, and a co-surfactant are dissolved in the form of a mixed micelle in an aqueous medium, the process comprising (a') melting a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester; (b') mixing a therapeutically effective amount of revaprazan or its salt with the melt obtained from the step (a'); and (c') adding an aqueous medium to the mixture obtained from the step (b'), followed by cooling to a room temperature.
According to still another embodiment, there is provided a process for preparing a liquid composition for injection in which revaprazan or its salt, a surfactant, and a co-surfactant are dissolved in the form of a mixed micelle in an aqueous medium, the process comprising (i') dissolving a therapeutically effective amount of revaprazan or its salt, a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester, and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester in an aqueous medium at 50 to 80 ℃; and (ii') cooling the solution obtained from the step (i') to a room temperature.
In the processes according to the present invention, the term "room temperature" refers to an ambient temperature without any heat treatment. For example, the term "room temperature" refers to a temperature of 20 to 27 ℃, typically about 25 ℃.
In the processes according to the present invention, the aqueous medium may be water for injection or a mixed solution of water for injection and ethanol. And, the mixed solution may be an ethanol solution having a concentration of 15 to 35 wt%.
In accordance with another aspect of the present invention, there is provided a dry powder for injection obtained by drying the liquid composition for injection. The dry powder may be reconstituted with water for injection, a physiological saline, a glucose solution, an amino acid solution, etc, before administering to a subject.
The drying may be performed using any conventional drying methods known in the pharmaceutical field, such as freeze-drying, rotary evaporation drying, spray-drying, or fluidized-bed drying. Preferably, the drying may be performed by freeze-drying (or lyophilizing).
The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Examples 1 to 21. Liquid compositions for injection in a micelle form
Liquid compositions for injection in a micelle form were prepared according to the components and amounts shown in Table 1. Each surfactant was completely dissolved in 20 ml of water for injection, in 70℃ water bath. Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour. The resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a micelle form.
Table 1
Example Revaprazan hydrochloride (mg) Surfactant
Component Amount (mg)
1 100 CremophorTM EL 1000
2 100 CremophorTM EL 1100
3 100 CremophorTM EL 1200
4 100 CremophorTM ELP 900
5 100 CremophorTM ELP 1100
6 100 CremophorTM ELP 1600
7 100 CremophorTM RH 40 1500
8 100 CremophorTM RH 60 1500
9 100 CremophorTM A 25 1000
10 100 SolutolTM HS 15 900
11 100 SolutolTM HS 15 1100
12 100 SolutolTM HS 15 1200
13 100 TweenTM 80 900
14 100 CrilletTM 1 900
15 100 CrilletTM 1 1100
16 100 CrilletTM 1 1400
17 100 CrilletTM 4 800
18 100 CrilletTM 4 1000
19 100 CrilletTM 4 1400
20 100 CrillTM 4 2600
21 100 CrillTM 43 2800
Examples 22 to 30. Liquid compositions for injection in a mixed micelle form
Liquid compositions for injection in a mixed micelle form were prepared according to the components and amounts shown in Table 2. Each surfactant and co-surfactant were completely dissolved in 20 ml of water for injection, in 70℃ water bath. Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour. The resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a mixed micelle form.
Table 2
Example Revaprazan hydrochloride (mg) Surfactant Co-surfactant
Component Amount (mg) Component Amount (mg)
22 100 CremophorTM EL 1500 PoloxamerTM 407 150
23 100 CremophorTM EL 1200 LutrolTM E 400 120
24 100 CremophorTM RH 40 1500 PoloxamerTM 407 150
25 100 CremophorTM RH 40 1500 LutrolTM E 400 150
26 100 CremophorTM A 25 1200 PoloxamerTM 407 120
27 100 CremophorTM A 25 1200 LutrolTM E 400 120
28 100 SolutolTM HS 15 1500 PoloxamerTM 407 150
29 100 TweenTM 80 1000 PoloxamerTM 407 100
30 100 TweenTM 80 1000 LutrolTM E 400 100
Examples 31 to 39. Liquid compositions for injection in a mixed micelle form
Liquid compositions for injection in a mixed micelle form were prepared, using SolutolTM HS 15 as a surfactant and LutrolTM E 400 as a co-surfactant, according to Table 3. The surfactant (SolutolTM HS 15) and co-surfactant (LutrolTM E 400) were completely dissolved in 20 ml of water for injection, in 70℃ water bath. Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour. The resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a mixed micelle form.
Table 3
Example Revaprazan hydrochloride (mg) Surfactant(SolutolTM HS 15, mg) Co-surfactant(LutrolTM E 400, mg)
31 100 1200 120
32 100 1800 80
33 100 2000 70
34 100 2100 250
35 100 2600 500
36 100 1500 50
37 100 1400 40
38 100 1400 50
39 100 1400 80
Example 40. Liquid compositions for injection in a mixed micelle form
The mixture of SolutolTM HS 15 (1,500 mg) and LutrolTM E 400 (50 mg) was melted by heat-treatment and then revaprazan hydrochloride (100 mg) was added thereto. The mixture was stirred at 70 ℃ for about 10 minutes and 20 ml of water for injection was added thereto. The mixture was slowly cooled to a room temperature under stirring at 800 rpm for 2 hours to obtain the injectable solution in a mixed micelle form.
Examples 41 and 42. Liquid compositions for injection in a mixed micelle form
Liquid compositions for injection in a mixed micelle form were prepared, using SolutolTM HS 15 as a surfactant and LutrolTM E 400 as a co-surfactant, according to Table 4. The surfactant (SolutolTM HS 15) and co-surfactant (LutrolTM E 400) were completely dissolved in 20 ml of each ethanol solution, in 70℃ water bath. Revaprazan hydrochloride was added to each solution, which was then stirred at 800 rpm for 1 hour. The resulting respective solution was slowly cooled to a room temperature under stirring for 1 hour to obtain the injectable solutions in a mixed micelle form.
Table 4
Example Revaprazan hydrochloride (mg) Surfactant(SolutolTM HS 15)(mg) Co-surfactant(LutrolTM E 400)(mg) Concentration of ethanol solution
41 100 1000 30 15 %
42 100 1000 20 35 %
Experimental Example. Stability Tests
In the stability tests, the appearance, endotoxin, amount of revaprazan (as well as amount of potential impurities), Foreign Insoluble Matter, and Insoluble Particulate Matter were measured with the following methods.
- Appearance: observed with naked eyes
- Endotoxin: measured by the section of 'Colorimetric Determination' in the 'Optical Measurement' among the 'Endotoxin Test Method' in the 'General Test Method' of the Korean Pharmacopeia
- Amounts of revaprazan and potential impurities:
<Preparation of standard solution >
50 mg of revaprazan standard was dissolved in 50 mL of methanol. The obtained solution was used as a standard solution.
<Preparation of test solution >
The amount corresponding to 100 mg of revaprazan was taken from the sample and then dissolved in 100 mL of methanol. The obtained solution was used as a test solution.
<Measurement >
Using 20 ㎕ of the standard solution and 20 ㎕ of the test solution, a HPLC analyses were performed under the following conditions to measure the peak areas of revaprazan and impurities originated from the standard solution and the test solution. From the peak areas, the amounts of revaprazan and impurities were calculated.
· Detector: UV spectrophotometer (wavelength: 270 nm)
· Column: Capcell-pak C18 (particle size: 5 ㎛, inner diameter: 4.6 mm, length: 250 mm)
- Foreign Insoluble Matter: measured by the section of 'Injection' in the 'Measurement of Foreign Insoluble Matter' among the 'General Test Method' of the Korean Pharmacopeia
- Insoluble Particulate Matter: measured by the section of 'Light obscuration particle count method' in the 'Insoluble Particulate Matter Test for Injection' among the 'General Test Method' of the Korean Pharmacopeia
(1) Evaluation of Physicochemical Stability 1
The physicochemical stability was evaluated by measuring appearance, endotoxin, amount of revaprazan (as well as amount of potential impurities), Foreign Insoluble Matter, and Insoluble Particulate Matter, while storing the injectable solution prepared in Example 33 at 25 ℃ and 60 % RH (Relative Humidity) for 6 months. And also, the physicochemical stability was evaluated by measuring appearance, endotoxin, amount of revaprazan (as well as amount of potential impurities), Foreign Insoluble Matter, and Insoluble Particulate Matter, while storing the injectable solution prepared in Example 33 at 4 ℃ of refrigerator for 6 months. The results are shown in Table 5.
Table 5 Physicochemical Stability (25 ℃/60 %RH and 4 ℃)
Storage Condition Test item Criterion Storage Duration
Initial 2months 4months 6months
25 ℃/60 %RH Appearance Transparent Transparent Transparent Transparent Transparent
Endotoxin Less than 4 EU/mL ND ND ND ND
Amount of revaprazan 95~105 % 100.0% 100.6% 102.1% 100.9%
Amount of impurities Less than 0.2% in total 0.00% 0.00% 0.02% 0.04%
Foreign Insoluble Matter Clear Clear Clear Clear Clear
Insoluble Particulate Matter (IPM) More than 10㎛ of IPM: less than 6000 823 164 79 158
More than 25㎛ of IPM: less than 600 4 4 2 4
4 ℃ Appearance Transparent Transparent Transparent Transparent Transparent
Endotoxin Less than 4 EU/mL ND ND ND ND
Amount of revaprazan 95~105 % 100.0% 101.3% 102.5% 101.4%
Amount of impurities Less than 0.2% in total 0.00% 0.00% 0.00% 0.01%
Foreign Insoluble Matter Clear Clear Clear Clear Clear
Insoluble Particulate Matter (IPM) More than 10㎛ of IPM: less than 6000 823 235 124 174
More than 25㎛ of IPM: less than 600 4 7 1 3
(2) Evaluation of Physicochemical Stability 2
The physicochemical stability was evaluated by measuring appearance, endotoxin, and amount of revaprazan (as well as amount of potential impurities), while storing the injectable solution prepared in Example 36 at 25 ℃ and 60 %RH for 1 month. And also, the physicochemical stability was evaluated by measuring appearance, endotoxin, and amount of revaprazan (as well as amount of potential impurities), while storing the injectable solution prepared in Example 36 at 4 ℃ of refrigerator for 1 month. The results are shown in Table 6.
Table 6 Physicochemical Stability (25 ℃/60 %RH and 4 ℃)
Storage Condition Test item Criterion Storage Duration
Initial 1 month
25 ℃/60 %RH Appearance Transparent Transparent Transparent
Endotoxin Less than 4 EU/mL ND ND
Amount of revaprazan 95~105 % 99.7 % 98.1 %
Amount of impurities Less than 0.2% in total 0.045 % 0.095 %
4 ℃ Appearance Transparent Transparent Transparent
Endotoxin Less than 4 EU/mL ND ND
Amount of revaprazan 95~105 % 99.7 % 97.9 %
Amount of impurities Less than 0.2% in total 0.045 % 0.042 %
(3) Evaluation of Physical Stability 1
The physical stability was evaluated by measuring appearance, while storing the injectable solution in a micelle form prepared in Example 12 at 25 ℃ and 60 %RH for 1 month. The results are shown in Table 7.
Table 7 Physical Stability (25 ℃/60 %RH)
Storage Duration
Initial 1 month
Example 12 (micelle) Transparent Transparent
(4) Evaluation of Physical Stability 2
The physical stability was evaluated by measuring appearance, while storing the injectable solution in a mixed micelle form prepared in Example 42 at 25 ℃ and 60 %RH for 6 months. The results are shown in Table 8.
Table 8 Physical Stability (25 ℃/60 %RH)
Storage Duration
Initial 1 month 2 months 6 months
Example 42 (mixed micelle) Transparent Transparent Transparent Transparent
From the results of Tables 5 to 8, the injectable solutions in the form of a micelle or a mixed micelle obtained according to the present invention have excellent physical and physicochemical stabilities under the conditions of refrigeration as well as a room temperature.

Claims (15)

  1. A liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; and a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester in an aqueous medium, wherein the revaprazan or its salt and the surfactant are dissolved in the form of a micelle in the aqueous medium.
  2. The liquid composition for injection of claim 1, wherein the surfactant is present in an amount ranging from 800 to 2800 parts by weigh, based on 100 parts by weight of revaprazan.
  3. A liquid composition for injection comprising a therapeutically effective amount of revaprazan or its salt; a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester; and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester in an aqueous medium, wherein the revaprazan or its salt, the surfactant, and the co-surfactant are dissolved in the form of a mixed micelle in the aqueous medium.
  4. The liquid composition for injection of claim 3, wherein the surfactant is polyethylene glycol-15-hydroxystearate and the co-surfactant is polyoxyethylene-polyoxypropylene copolymer or polyoxyethylene glycol.
  5. The liquid composition for injection of claim 3, wherein the surfactant is present in an amount ranging from 800 to 2600 parts by weigh, based on 100 parts by weight of revaprazan; and the co-surfactant is present in an amount ranging from 20 to 500 parts by weigh, based on 100 parts by weight of revaprazan.
  6. The liquid composition for injection of claim 5, wherein the surfactant is present in an amount ranging from 1400 to 2000 parts by weigh, based on 100 parts by weight of revaprazan; and the co-surfactant is present in an amount ranging from 40 to 250 parts by weigh, based on 100 parts by weight of revaprazan.
  7. The liquid composition for injection according to any one of claims 1 to 6, wherein the aqueous medium is water for injection or a mixed solution of water for injection and ethanol.
  8. The liquid composition for injection of claim 7, wherein the mixed solution is an ethanol solution having a concentration of 15 to 35 wt%.
  9. A process for preparing a liquid composition for injection in which revaprazan or its salt and a surfactant are dissolved in the form of a micelle in an aqueous medium, the process comprising (a) melting a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester; (b) mixing a therapeutically effective amount of revaprazan or its salt with the melt obtained from the step (a); and (c) adding an aqueous medium to the mixture obtained from the step (b), followed by cooling to a room temperature.
  10. A process for preparing a liquid composition for injection in which revaprazan or its salt and a surfactant are dissolved in the form of a micelle in an aqueous medium, the process comprising (i) dissolving a therapeutically effective amount of revaprazan or its salt and a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester in an aqueous medium at 50 to 80 ℃; and (ii) cooling the solution obtained from the step (i) to a room temperature.
  11. A process for preparing a liquid composition for injection in which revaprazan or its salt, a surfactant, and a co-surfactant are dissolved in the form of a mixed micelle in an aqueous medium, the process comprising (a') melting a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester; (b') mixing a therapeutically effective amount of revaprazan or its salt with the melt obtained from the step (a'); and (c') adding an aqueous medium to the mixture obtained from the step (b'), followed by cooling to a room temperature.
  12. A process for preparing a liquid composition for injection in which revaprazan or its salt, a surfactant, and a co-surfactant are dissolved in the form of a mixed micelle in an aqueous medium, the process comprising (i') dissolving a therapeutically effective amount of revaprazan or its salt, a surfactant selected from the group consisting of polyoxyethylene natural or hydrogenated castor oil, polyoxyethylene alkyl ether, polyethylene glycol-15-hydroxystearate, and polyoxyethylene sorbitan fatty acid ester, and one or more co-surfactant selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene glycol, and sorbitan ester in an aqueous medium at 50 to 80 ℃; and (ii') cooling the solution obtained from the step (i') to a room temperature.
  13. The process for preparing a liquid composition for injection according to any one of claims 9 to 12, wherein the aqueous medium is water for injection or a mixed solution of water for injection and ethanol.
  14. The process for preparing a liquid composition for injection of claim 13, wherein the mixed solution is an ethanol solution having a concentration of 15 to 35 wt%.
  15. A dry powder for injection obtained by drying the liquid composition for injection according to any one of claims 1 to 6.
PCT/KR2011/009047 2010-12-01 2011-11-25 Injectable liquid composition containing revaprazan or its salt WO2012074243A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201180057045.7A CN103228280B (en) 2010-12-01 2011-11-25 Comprise the injectable liquids compositions of Revaprazan or its salt

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020100121580A KR101739815B1 (en) 2010-12-01 2010-12-01 Injectable liquid composition containing revaprazan or its salt
KR10-2010-0121580 2010-12-01

Publications (2)

Publication Number Publication Date
WO2012074243A2 true WO2012074243A2 (en) 2012-06-07
WO2012074243A3 WO2012074243A3 (en) 2012-07-26

Family

ID=46172365

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2011/009047 WO2012074243A2 (en) 2010-12-01 2011-11-25 Injectable liquid composition containing revaprazan or its salt

Country Status (3)

Country Link
KR (1) KR101739815B1 (en)
CN (1) CN103228280B (en)
WO (1) WO2012074243A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101739820B1 (en) 2012-03-28 2017-05-25 주식회사유한양행 Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274609B1 (en) * 1997-07-23 2001-08-14 Ono Pharmaceutical Co., Ltd. Aqueous liquid pharmaceutical composition containing as main component benzopyran derivative
US20100041688A1 (en) * 2006-12-22 2010-02-18 Yuhan Corporation Revaprazan-containing solid dispersion and process for the preparation thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2197298C (en) 1994-08-13 1999-10-19 Jong Wook Lee Novel pyrimidine derivatives and processes for the preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274609B1 (en) * 1997-07-23 2001-08-14 Ono Pharmaceutical Co., Ltd. Aqueous liquid pharmaceutical composition containing as main component benzopyran derivative
US20100041688A1 (en) * 2006-12-22 2010-02-18 Yuhan Corporation Revaprazan-containing solid dispersion and process for the preparation thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RANGEL-YAGUI, C. O. ET AL.: 'Micellar solubilization of drugs' J. PHARM. PHARM. SCI. vol. 8, no. 2, 08 July 2005, pages 147 - 165 *
STRICKLEY, R. G.: 'Solubilizing excipients in oral and injectable formulations' PHARM. RES. vol. 21, no. 2, February 2004, pages 201 - 230 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101739820B1 (en) 2012-03-28 2017-05-25 주식회사유한양행 Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt

Also Published As

Publication number Publication date
CN103228280A (en) 2013-07-31
CN103228280B (en) 2015-11-25
WO2012074243A3 (en) 2012-07-26
KR20120060028A (en) 2012-06-11
KR101739815B1 (en) 2017-05-26

Similar Documents

Publication Publication Date Title
KR101887004B1 (en) Formulations of rifaximin and uses thereof
WO2014163400A1 (en) Pharmaceutical composition for parenteral administration, containing donepezil
WO2010074379A1 (en) Preparation method of polymeric micelles composition containing a poorly water-soluble drug
WO2012074244A2 (en) Injectable liquid composition or injectable dried powder containing revaprazan or its salt
WO2017196148A1 (en) Composite formulation of dutasteride and tadalafil comprising glycerol fatty acid ester derivative or propylene glycol fatty acid ester derivative and oral capsule formulation comprising the same
WO2019147094A1 (en) Pharmaceutical formulation comprising esomeprazole and sodium bicarbonate
WO2015141897A1 (en) Liquid pharmaceutical composition
WO2019138398A1 (en) Drug-layered silicate composite for enhancement of oral bioavailability, oral pharmaceutical composition comprising same, and method for manufacturing composite
CN112220748A (en) Desloratadine oral liquid preparation and preparation method thereof
WO2013147452A1 (en) Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt
CN110464846B (en) Meloxicam composition, preparation method and application thereof
WO2017043913A1 (en) Pharmaceutical composition including dutasteride and capsule formulation comprising the same
WO2012074243A2 (en) Injectable liquid composition containing revaprazan or its salt
WO2015194923A1 (en) Pharmaceutical preparation containing entecavir as active ingredient, and preparation method therefor
WO2016126058A2 (en) Solid dispersion containing dutasteride, and composition containing same
WO2017057973A1 (en) Novel ophthalmic composition comprising rebamipide and method for preparing the same
WO2015130110A1 (en) Solid dispersion composition with increased stability, containing amorphous solifenacin or salt thereof, and preparation method therefor
WO2017069533A1 (en) Oral liquid formulation of tadalafil
WO2018124363A1 (en) Ceria nanocomposite for biomedical treatment and pharmaceutical composition containing same
WO2017116031A1 (en) Pharmaceutical composition containing gefitinib, administrable to patients with lactose intolerance and having improved dosing convenience
WO2011031100A2 (en) Aripiprazole-bentonite-aea hybrid, pharmaceutical composition containing the same and method for preparing the same
WO2016072748A1 (en) Pharmaceutical compositions comprising lobeglitazone for oral administration
WO2019124789A1 (en) Pharmaceutical composition containing irinotecan or pharmaceutically acceptable salt thereof for oral administration
WO2018190451A1 (en) Pharmaceutical composition containing angiotensin receptor blocker
WO2022158893A2 (en) Ophthalmic composition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11845949

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11845949

Country of ref document: EP

Kind code of ref document: A2

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 13.12.2013)

122 Ep: pct application non-entry in european phase

Ref document number: 11845949

Country of ref document: EP

Kind code of ref document: A2