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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K47/30—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
  • 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
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • 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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to an injectable composition including an imidazo[l,2- a]pyridine compound or a salt thereof, a pharmaceutical formulation including the same, and a method for preparing the same.
• a candidate substance (drug) needs to have not only desirable biological properties but also physical properties which enable a pharmaceutical use so that the it may be considered to be developed as a medication.
• the drug often hardly applies to industrialization due to its low stability in a viewpoint of pharmaceutics.
• an injectable formulation is injected into the body in a liquid state, and thus is required to have high solubility for injection solvent.
• many drugs are poorly soluble or have low solubility or stability depending on pH conditions, and thus are difficult to be prepared into an injectable formulation.
• an appropriate injection solvent needs to be selected along with a sufficient amount of additives such as a solubilizer, a stabilizer, and the like.
• a large amount of the additives may decrease stability, productivity, and the like, or may cause pain when injected into the body.
• an imidazo[l,2-a]pyridine compound or a pharmaceutically acceptable salt thereof is a medicinal raw material for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastroduodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), etc.
• the present inventors have made extensive efforts to develop a very stable injectable formulation having excellent solubility and stability for the imidazo[l,2-a]pyridine compound or the pharmaceutically acceptable salt thereof, thereby completing the present invention.
• Patent Document 1 Korean Registered Patent Publication No. 10-1777971
• One object of the present invention is to provide an injectable composition having excellent solubility and/or stability, including an imidazo[l,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient.
• Another object of the present invention is to provide a pharmaceutical formulation including the injectable composition.
• Still another object of the present invention is to provide a kit including the pharmaceutical formulation.
• Still another object of the present invention is to provide a method for preparing the injectable composition or the pharmaceutical formulation.
• An injectable composition for one object of the present invention includes azetidin-1- yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyridin-6-yl (methanone citrate as an active ingredient; and sulfobutylether-beta-cyclodextrin (hereinafter, SBE-P-CD).
• azetidin-l-yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[l,2-a]pyridin-6-yl ⁇ methanone is Compound 1 represented by chemical formula 1 below:
• the active ingredient in the present invention is citrate of Compound 1 represented by chemical formula 1, and hereinafter, "azetidin-l-yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[l,2-a]pyridin-6-yl ⁇ methanone citrate” and "citrate of Compound 1" is referred to as the same thing as each other.
• the citrate of Compound 1 may be represented by chemical formula 2 below. ⁇ Chemical Formula 2>
• n may be 0.3 to 1.3, for example, 0.5 to 1.
• the citrate of Compound 1, which is an active ingredient of the present invention shows far superior bioavailability compared to Compound 1, which is a free base, and is a drug showing a very excellent effect in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.
• citrate of Compound 1 reaches a highest blood concentration within a short time compared to Compound 1, which is a free base, Cmax is 11 times or more remarkably higher, and AUC may be also at least five times or more excellent compared thereto.
• the citrate of Compound 1 shows very excellent solubility at below pH 3, but shows remarkably low solubility at a level of less than 1.5 mg/mL at pH 3 or higher, particularly at pH 3.3 or higher.
• the injectable composition according to the present invention may improve the solubility and stability of citrate of Compound 1 even at pH 3 or higher by using SBE-P-CD together with citrate of Compound 1
• the injectable composition according to the present invention may include SBE-P-CD to improve the solubility and stability of citrate of Compound 1 at pH 3 or higher.
• a content of citrate of Compound 1 is less than 1 mg/mL, a large volume of injectable solution may need to be injected in order to exhibit a sufficient therapeutic effect, which may cause difficulty in administration.
• citrate of Compound 1 may be included in an amount of 1 to 10 wt% based on 100 wt% of the total solid content of the injectable composition.
• 100 wt% of the solid content may refer to a case in which the sum of the weights of the components excluding the injection solvent is 100%.
• 100 wt% of the solid content may refer to a case in which a total weight of the injectable composition is 100%.
• citrate of Compound 1 When an amount of citrate of Compound 1 is less than 1 wt% based on 100 wt% of the total solid content of the injectable composition, a large amount of injectable solution may need to be injected in order to exhibit a sufficient therapeutic effect, which may cause difficulty in administration. In addition, when citrate of Compound 1 is more than 10 wt % based on 100 wt% of the total solid content of the injectable composition, it may be difficult to sufficiently dissolve citrate of Compound 1, which may be easily precipitated.
• citrate of Compound 1 may be included in an amount of 1 mg or more and 30 mg or less, for example, 5 mg or more and 30 mg or less, per unit formulation of the injectable composition.
• SBE-P-CD may be a dissolution aid for improving the solubility of citrate of Compound 1 at pH 3 or higher and/or a stabilizer for preventing citrate of Compound 1 from being precipitated.
• SBE-P-CD may be a compound (sodium sulfobutylether-beta- cyclodextrin) represented by chemical formula 3 below having a form in which sodium is added to sulfobutylether-P-cyclodextrin.
• a weight ratio of citrate of Compound 1 and SBE-P-CD may be 1 :5 to 1 :60 or 1 : 10 to 1 :60.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; and a pH adjuster.
• the pH adjuster may be used without limitation as long as it is a conventional pH adjuster to control pH in the preparation of an injectable composition such as sodium hydroxide.
• the injectable composition including citrate of Compound 1 and SBE-P-CD may not need to include other additives in addition to the pH adjuster, but may further optionally include, without limitation, isotonic agents, buffers, osmotic agents, and the like commonly used in the art.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; and albumin.
• albumin when used with citrate of Compound 1 and SBE-P-CD, albumin may improve the solubility and stability of citrate of Compound 1 even at pH 3 or higher.
• Albumin in the present invention may include recombinant albumin or albumin purified from human plasma.
• albumin may be in an amount of 1 mg or more and 60 mg or less per unit formulation of the injectable composition.
• albumin may be in an amount of 0.1 to 10 wt%, for example, 0.2 to 7 wt%, 0.25 to 7 wt%, 0.28 to 6.9 wt%, or 0.29 to 6.8 wt% based on 100 wt% of the total solid content of the injectable composition.
• an amount of albumin may be 105 mg to 1560 mg, specifically 106 mg to 1553 mg per 100 mL of the injectable composition, when a dosage form of the injectable composition is a liquid injectable formulation including an injection solvent.
• a weight ratio of SBE-P-CD and albumin may be 7: 1 to 300: 1.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; and two or more selected from albumin, lysine, and arginine. In one embodiment, the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; and lyophilizer.
• lyophilizer examples include mannitol, trehalose, and the like, which may be used alone or in combination.
• the lyophilizer may further improve the stability of citrate of Compound 1 together with SBE-P-CD, and thus may improve the stability of the solid content or the freeze-dried product of the injectable composition.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; and at least one or more of mannitol and trehalose.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; albumin; and lyophilizer.
• the lyophilizer, together with SBE-P-CD and albumin, may further improve the stability of citrate of Compound 1.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; albumin; and at least one or more of mannitol and trehalose.
• a weight ratio of citrate of Compound 1 and lyophilizer may be 1 :5 to 1 : 10.
• a weight ratio of citrate of Compound 1 and lyophilizer may be 1:7 to 1 :8.
• the injectable composition according to the present invention may be in a liquid phase or in a solid phase.
• the injectable composition according to the present invention may include citrate of Compound 1; SBE-P-CD; and an aqueous medium.
• the aqueous medium may be an injection solvent, and examples of the injection solvent may include, but are not particularly limited to, water for injection, physiological saline injectable solution, Ringer's solution, etc., and specifically, water for injection.
• the injectable composition according to the present invention may be colorless and transparent.
• a pH of the injectable composition according to the present invention may be 3 or higher.
• An injectable formulation having pH of less than 3 may cause pain at the time of administration and increase a decomposition product from citrate of Compound 1, which is an active ingredient, and thus it may be preferable that at least the pH is 3 or more when considering safety and stability.
• the pH of the injectable composition according to the present invention may be 3 or more and 4.9 or less, may be 3 or more, 3.5 or more, 3.7 or more, 3.75 or more, 3.8 or more, 3.95 or more, or 4 or more, and may be 4.9 or less, 4.7 or less, or 4 or less.
• the pH of the injectable composition according to the present invention may be 3 to 4.7, 3.5 to 4.9, 3.5 to 4.7, 3.5 to 4, 3.7 to 4, 3.75 to 4.7, 3.75 to 3.95, 4 to 4.7, 4 to 4.9, 3.75 to 4.9, or 3.75 to 4.
• the injectable composition according to the present invention may be a liquid formulation including citrate of Compound 1 and SBE-P-CD.
• the injectable composition according to the present invention may be a liquid formulation including citrate of Compound 1, SBE-P-CD and albumin.
• the injectable composition according to the present invention may be a colorless and transparent liquid formulation which includes citrate of Compound 1, SBE- P-CD and an aqueous medium, and has pH of 3 or more and 4.9 or less.
• the injectable composition according to the present invention may be a colorless and transparent liquid formation which includes citrate of Compound 1, SBE-P- CD, albumin, and an injection solvent, and has pH of 3 or more and 4.9 or less, for example, pH of 3.75 to 4.9.
• the injectable composition according to the present invention may be in a solid phase in the form of powder.
• the injectable composition in a liquid phase may be dried to be obtained in a powder form. Drying may be performed by a conventional drying process, for example, freeze drying, rotary evaporation drying, spray drying, fluid bed drying, or the like.
• the injectable composition according to the present invention may be a freeze-dried product.
• the injectable composition according to the present invention may be a dried product including citrate of Compound 1 and SBE-P-CD.
• the injectable composition according to the present invention may be a dried product including citrate of Compound 1, SBE-P-CD, and lyophilizer.
• the injectable composition according to the present invention may be a dried product including citrate of Compound 1, SBE-P-CD and albumin.
• the injectable composition according to the present invention may be a dried product including citrate of Compound 1, SBE-P-CD, albumin and lyophilizer.
• a pharmaceutical formulation for another object of the present invention may include citrate of Compound 1 and SBE-P-CD.
• the pharmaceutical formulation according to the present invention may be an injectable formulation including citrate of Compound 1 and SBE-P-CD.
• the injectable formulation may include an injection solvent.
• the injectable formulation according to the present invention may have excellent solubility for active ingredients and have excellent stability against temperature and/or humidity.
• the pharmaceutical formulation according to the present invention may be an injectable formulation including citrate of Compound 1, SBE-P-CD and albumin.
• the injectable formulation may include an injection solvent.
• the pH of the injectable formulation including citrate of Compound 1 and SBE-P-CD may be 3 or higher and 4.9 or less.
• the pH of the injectable formulation including citrate of Compound 1 and SBE-P-CD may be 3.75 or higher and less than 4, or 4 or higher and 4.9 or less.
• the pharmaceutical formulation according to the present invention may be a freeze-dried product including citrate of Compound 1 and SBE-P-CD.
• the freeze-dried product may include mannitol and/or trehalose.
• the pharmaceutical formulation according to the present invention may be a freeze-dried product including citrate of Compound 1, SBE-P-CD and albumin.
• the freeze-dried product may include mannitol and/or trehalose.
• the freeze-dried product according to the present invention may be stored for a long period of time by securing excellent stability against temperature and/or humidity, and may be easily formulated into an injectable formulation by being dissolving in the injection solvent as an aqueous medium.
• the pH of the obtained injectable formulation may be 3 or more and 4.9 or less, 3 or more and 4.7 or less, 3.75 or more and 4.9 or less, or 3.75 or more and 4.7 or less.
• a method for preparing an injectable composition according to the present invention may include mixing citrate of Compound 1; SBE-P-CD; and an aqueous medium.
• the step may be performed by adding SBE-P-CD to an aqueous medium, and then mixing citrate of Compound 1 in an aqueous SBE-P-CD solution.
• the pH of the solution obtained by mixing citrate of Compound 1, SBE-P-CD, and the aqueous medium may be 3 to 4.9, specifically 3.5 to 4, or 3.75 to 3.95.
• a liquid mixture including citrate of Compound 1 and SBE-P-CD may be an injectable formulation according to the present invention.
• the pH of the injectable formulation may be 3 to 4.9, specifically 3.5 to 4, or 3.75 to 3.95.
• a process of freeze-drying the liquid mixture may be performed, and then the freeze- dried product according to the present invention may be prepared.
• a method for preparing an injectable composition according to the present invention may include mixing citrate of Compound 1, SBE-P-CD, albumin, and an aqueous medium.
• the step may include: mixing citrate of Compound 1 and SBE- P-CD in an aqueous medium; and adding albumin to a mixed solution including citrate of Compound 1 and SBE-P-CD.
• the pH of the solution obtained by mixing citrate of Compound 1, SBE-P-CD, albumin and the aqueous medium may be 3 to 4.9, specifically 4 to 4.9, or 4 to 4.7.
• the liquid mixture including citrate of Compound 1, SBE-P-CD and albumin, or the liquid mixture further including the pH adjuster therein may be the injectable formulation according to the present invention.
• the pH of the injectable formulation may be 3 to 4.7, specifically 4 to 4.9, or 4 to 4.7.
• the preparation method may further include adding mannitol and/or trehalose to the liquid mixture.
• the preparation method may further include drying the liquid mixture to which mannitol and/or trehalose is added.
• the drying may be performed through a freeze-drying process.
• the freeze-dried product according to the present invention may be prepared.
• the freeze-dried product may be dissolved again in an aqueous medium such as an injection solvent, etc., to constitute a liquid injectable formulation.
• the freeze-dried product may be dissolved again to obtain a colorless and transparent property even when constituting a liquid injectable formulation.
• the pH of the liquid injectable formulation may be 3 to 4.9.
• a kit according to the present invention may include: a freeze-dried product including azetidin- 1 -yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyri din-6- yl [methanone citrate as active ingredient; and sulfobutylether-beta-cyclodextrin (SBE-P-CD) ; and an injection solvent.
• a freeze-dried product including azetidin- 1 -yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyri din-6- yl [methanone citrate as active ingredient; and sulfobutylether-beta-cyclodextrin (SBE-P-CD) ; and an injection solvent.
• freeze-dried product in the kit is substantially the same as described above, and thus a repeated detailed description thereof will be omitted.
• the injection solvent in the kit may be substantially the same as the aqueous medium described above. Thus, a repeated detailed description thereof will be omitted.
• the freeze-dried product and the injection solvent agent may be separately accommodated in each container to constitute one kit.
• the injectable composition according to the present invention includes: azetidin-1- yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyridin-6-yl (methanone citrate as an active ingredient; and sulfobutylether-beta-cyclodextrin (SBE-P-CD).
• the injectable composition according to above (1) may further include albumin.
• the injectable composition according to above (1) or (2) may further include mannitol or trehalose as lyophilizer.
• the injectable composition according to any one of above (1) to (3) may further include albumin as a dissolution aid; and mannitol or trehalose as lyophilizer.
• the injectable composition according to any one of above (1) to (4) may be in a liquid phase with pH of 3 or more and 4.9 or less.
• the injectable composition according to any one of above (1) to (5) may be in a colorless and transparent liquid phase with pH of 3 to 3.95.
• the injectable composition according to any one of above (1) to (6) may be in a colorless and transparent liquid phase with pH of 4 to 4.9.
• the injectable composition according to any one of above (1) to (4) may be in a solid phase as a freeze-dried product.
• the pharmaceutical formulation according to the present invention includes: azetidin- 1 -yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyridin-6- yl [methanone citrate as an active ingredient; and sulfobutylether-beta-cyclodextrin (SBE-P- CD).
• the pharmaceutical formulation according to above (9) may further include albumin.
• the pharmaceutical formulation according to above (9) or (10) may further include mannitol or trehalose as lyophilizer.
• the pharmaceutical formulation according to any one of above (9) to (11) may further include albumin; and mannitol or trehalose as lyophilizer.
• the pharmaceutical formulation according to any one of above (9) to (12) may be an injectable formulation or a freeze-dried product.
• the method for preparing the injectable composition according to the present invention includes: preparing an SBE-P-CD solution by mixing sulfobutylether-P-cyclodextrin (SBE-P-CD) and an aqueous medium; and mixing azetidin-l-yl ⁇ 8-[(2,6- dimethylbenzyl)amino]-2, 3 -dimethylimidazof l,2-a]pyridin-6-yl (methanone citrate in the SBE-P-CD solution.
• SBE-P-CD sulfobutylether-P-cyclodextrin
• a solution having a colorless and transparent property may be obtained from the mixing of azetidin-l-yl ⁇ 8-[(2,6- dimethylbenzyl)amino]-2, 3 -dimethylimidazof l,2-a]pyridin-6-yl (methanone citrate.
• the preparation method according to above (14) or (15) may further include: mixing albumin, after mixing azetidin-l-yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[l,2-a]pyridin-6-yl(methanone citrate.
• the preparation method according to above (16) may further include: drying a solution in which albumin is mixed.
• the preparation method according to above (16) or (17) may further include: adding mannitol or trehalose to a solution in which albumin is mixed; and drying the solution to which mannitol or trehalose is added.
• the pH of the solution obtained from the mixing of azetidin-l-yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[l,2-a]pyridin-6-yl ⁇ methanone citrate may be 3 to 4.9.
• the pH of the solution in which albumin is mixed may be 4 to 4.7.
• the pH of the solution in which albumin is mixed may be 4 to 4.9, and the preparation method may further include: drying the solution in which albumin is mixed.
• the injectable composition according to any one of above (1) to (8) may be a pharmaceutical composition for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.
• the present invention provides a method for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases, the method comprising a therapeutically effective amount of the injectable composition according to any one of above (1) to (8).
• the present invention provides a use of the injectable composition according to any one of above (1) to (8) for preparing a medication for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.
• the present invention provides a use of the injectable composition according to any one of above (1) to (8) for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.
• the injectable composition according to the present invention can secure excellent solubility and stability of azetidin- 1 -yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyridin-6- yl [methanone citrate.
• the injectable composition including azetidin- l-yl ⁇ 8-[(2, 6- dimethylbenzyl)amino]-2, 3 -dimethylimidazof l,2-a]pyridin-6-yl ⁇ methanone citrate with remarkably excellent bioavailability as an active ingredient can also have an excellent effect of preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.
• FIG. l is a view showing pictures capable of confirming the properties of a freeze-dried product according to embodiments of the present invention.
• Azetidin- 1 -yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2, 3 -dimethylimidazof 1 ,2-a]pyridin-6- yljmethanone citrate was obtained according to a process below. Specifically, azetidin-l-yl ⁇ 8- f(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl ⁇ methanone was obtained as described in Korean Registered Patent Publication No. 10-1777971.
• azetidin-l-yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[l,2-a]pyridin-6-yl ⁇ methanone was mixed in an alcohol solvent (isopropyl alcohol, IPA) and stirred, and then dried under vacuum at about 30°C to 35°C to obtain a dried product, about 10 g of which was taken and stirred together with about 167 g of acetone.
• a solution obtained by dissolving citric acid (about 5 g) in acetone (about 33 g) was slowly added dropwise thereto for 60 minutes or more, and stirred at the same temperature for one hour.
• the resulting mixture was cooled to about 20°C to 25°C and further stirred for about one hour, after which the resulting solid was filtered, washed with acetone, and vacuum dried to obtain azetidin- 1 -yl ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3 -dimethylimidazof 1 ,2-a]pyridin-6- yljmethanone citrate.
• the results of NMR analysis on the obtained azetidin-l-yl ⁇ 8-[(2,6- dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl ⁇ methanone citrate may be as follows.
• the citrate of Compound 1 may be used to obtain a transparent solution without SBE- P-CD under conditions of less than pH 3, but the solubility may rapidly decrease at pH 3 or higher, and citrate of Compound 1 may show excellent solubility at pH 3 to 4.7 due to SBE-P- CD. It can be confirmed that even if various known dissolution aids are used, the solubility of citrate of Compound 1 may not be improved in the range of pH 3 or higher, but solubility may be improved only due to SBE-P-CD by further including albumin and/or mannitol.
• the obtained solution was filtered through a 0.22 pm membrane filter, and the resulting solution was filled in a washed and sterilized sealable vial. After that, the vial was freeze-dried to prepare freeze-dried products according to Examples 36 to 43 of the present invention.
• liquid injectable compositions (Examples 2 to 5, 8 to 11, and 35) prepared according to above Tables 1 to 4 were freeze-dried by substantially the same process as described above, such as filtration, washing, etc., thereby preparing the freeze-dried products according to Examples 44 to 52 of the present invention.
• FIG. 1 Pictures of FIG. 1 show properties of each freeze-dried product after being prepared according to Examples 36 to 52 of the present invention. Referring to FIG. 1, it can be confirmed that the freeze-dried products according to Examples 36 to 52 of the present invention were stably obtained as a white solid in a sufficient amount. Evaluation 1: Stability of solution
• HPLC conditions may be as follows.
• the injectable formulations according to Examples 3, 4, 12, 13, 17 to 19, 23 to 25, 28, and 7 of the present invention have no change in properties under refrigerated/room temperature/high temperature conditions even after at least five days.
• HPLC analysis results after seven days of the injectable formulations according to Examples 1, 2, 3, 4, 5, 6, and 35 of the present invention showed at least 99.5% or more, and thus it was confirmed that the injectable formulations are not actually decomposed but stably maintained.
• freeze-dried products according to the embodiments of the present invention may be stably obtained as a white solid, and are maintained as they are even after four weeks without discoloration or change in properties.
• HPLC analysis results show 99% or more, respectively, and thus the products are not actually decomposed, but stably maintained. Accordingly, it can be confirmed that the freeze- dried product according to the present invention has excellent stability.
• freeze-dried products stored at 60°C and having properties and stability confirmed after four weeks were re-dissolved in 1 mL of distilled water after four weeks, and as a result, it was confirmed that a solution having a colorless and transparent property is obtained. In this case, it can be confirmed that the pH of the obtained solution is in the range of 3 to 4.9.
• Example 41 when the freeze-dried product of Example 41, which was stored at 4°C and had its properties and stability confirmed after four weeks, was re-dissolved in 1 mL of distilled water, a solution having a colorless and transparent property was obtained.

Landscapes

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

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=92024104

Family Applications (1)

Country Status (15)

Families Citing this family (1)

Citations (5)

• 2023
  • 2023-11-20 TW TW112144715A patent/TW202432120A/zh unknown
  • 2023-11-29 CN CN202311609051.XA patent/CN118415999A/zh active Pending
• 2024
  • 2024-01-23 AR ARP240100149A patent/AR131668A1/es unknown
  • 2024-01-31 PE PE2025001666A patent/PE20252396A1/es unknown
  • 2024-01-31 AU AU2024215883A patent/AU2024215883A1/en active Pending
  • 2024-01-31 KR KR1020240014951A patent/KR20240121186A/ko active Pending
  • 2024-01-31 IL IL322431A patent/IL322431A/en unknown
  • 2024-01-31 EP EP24749813.2A patent/EP4658244A1/en active Pending
  • 2024-01-31 WO PCT/IB2024/050869 patent/WO2024161316A1/en not_active Ceased
  • 2024-01-31 JP JP2025544851A patent/JP2026505092A/ja active Pending
• 2025
  • 2025-07-25 MX MX2025008735A patent/MX2025008735A/es unknown
  • 2025-07-28 JO JOJO/P/2025/0189A patent/JOP20250189A1/ar unknown
  • 2025-07-30 CL CL2025002270A patent/CL2025002270A1/es unknown
  • 2025-07-31 DO DO2025000185A patent/DOP2025000185A/es unknown
  • 2025-08-22 CO CONC2025/0011347A patent/CO2025011347A2/es unknown

Patent Citations (5)

Also Published As

Similar Documents

Legal Events