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WO2025230305A1 - Composition comprenant de l'acide biliaire ou un dérivé de celui-ci et emballage pharmaceutique la comprenant - Google Patents

Composition comprenant de l'acide biliaire ou un dérivé de celui-ci et emballage pharmaceutique la comprenant

Info

Publication number
WO2025230305A1
WO2025230305A1 PCT/KR2025/005848 KR2025005848W WO2025230305A1 WO 2025230305 A1 WO2025230305 A1 WO 2025230305A1 KR 2025005848 W KR2025005848 W KR 2025005848W WO 2025230305 A1 WO2025230305 A1 WO 2025230305A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
days
months
pharmaceutical package
paragraph
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/KR2025/005848
Other languages
English (en)
Korean (ko)
Inventor
조수진
유다정
송윤석
이재철
민재홍
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medy Tox Inc
Original Assignee
Medy Tox Inc
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 Medy Tox Inc filed Critical Medy Tox Inc
Priority claimed from KR1020250056786A external-priority patent/KR20250158693A/ko
Publication of WO2025230305A1 publication Critical patent/WO2025230305A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D39/00—Closures arranged within necks or pouring openings or in discharge apertures, e.g. stoppers

Definitions

  • the present invention includes a composition comprising bile acids and derivatives thereof and a pharmaceutical package comprising the same.
  • compositions must be stored in protective containers to minimize exposure to the external environment during storage and transport.
  • containers should be made of chemically stable materials, and the container caps should have an adequate seal to prevent the ingress of external contaminants and leakage of the internal ingredients.
  • Some light-sensitive pharmaceuticals may be manufactured with light-blocking materials to prevent exposure of the pharmaceutical formulation to light.
  • One object of the present invention is to provide a pharmaceutical package for stably storing a pharmaceutical composition containing bile acid.
  • a pharmaceutical package may include a pharmaceutical composition, a container containing the pharmaceutical composition, and a stopper for sealing the container.
  • the pharmaceutical composition may include a bile acid or a pharmaceutically acceptable salt thereof.
  • the stopper may be made of an elastomeric material.
  • the stopper may include a radical scavenger as an antioxidant. A portion of the stopper that comes into contact with the composition may be coated.
  • the composition may maintain stability when stored at 25°C for 18 months, at 40°C for 3 months, at 60°C for 20 days, or at 80°C for 10 days.
  • the radical scavenger may be a phenol-based additive
  • the phenol-based additive may be dibutylhydroxytoluene
  • the pharmaceutical composition may have a dibutylhydroxytoluene release amount of less than 0.5 ppm when stored at 25°C for 18 months, at 40°C for 3 months, at 60°C for 20 days, or at 80°C for 10 days.
  • the pharmaceutical composition may have a dibutylhydroxytoluene dimer content of less than 0.25 ppm when stored at 25°C for 18 months, at 40°C for 3 months, at 60°C for 20 days, or at 80°C for 10 days.
  • the pharmaceutical composition may have a UV absorbance at a wavelength of 425 nm of 0.03 or less when stored at 80°C for 14 days.
  • the above composition may further comprise an ionic compound.
  • the ionic compound may comprise a halide.
  • composition may comprise the bile acid or a pharmaceutically acceptable salt thereof at a concentration higher than the micelle critical concentration.
  • the bile acid may include at least one selected from the group consisting of cholic acid, deoxycholic acid, chenoteoxycholic acid, taurorosodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, taurine or glycine conjugates thereof, and pharmaceutically acceptable salts thereof.
  • composition may further comprise a buffer.
  • the above elastic polymer material may include at least one selected from isoprene rubber, butadiene rubber, butyl rubber, halogenated butyl rubber, ethylene propylene diene rubber, silicone rubber, natural rubber, and styrene-butadiene rubber.
  • the above plug may be in indirect contact with the composition.
  • the above composition may be a topical administration preparation for non-surgical removal of localized fat deposits in a subject.
  • a method for non-surgically removing localized fat deposits in a subject in need thereof may be provided by administering the aforementioned pharmaceutical package to the subject.
  • a pharmaceutical package comprising a container containing a pharmaceutical composition comprising a bile acid or a pharmaceutically acceptable salt thereof, and a stopper sealing the container and comprising an elastic polymer material and a radical scavenger as an antioxidant.
  • the above stopper can release the radical scavenger when in contact with the bile acid or a pharmaceutically acceptable salt thereof in an uncoated state.
  • the portion of the stopper that comes into contact with the composition may be coated.
  • the composition may be such that the radical scavenger does not release when stored at 25°C for 18 months, at 40°C for 3 months, at 60°C for 20 days, or at 80°C for 10 days.
  • a pharmaceutical package for stably storing a pharmaceutical composition comprising a bile acid is provided.
  • Figure 1 is a graph showing the results of absorbance measurements according to packaging materials and storage conditions of a pharmaceutical package of one embodiment.
  • Figure 2 is a graph showing the HPLC results for the substance causing discoloration.
  • Figures 3 and 4 are graphs showing the results of LC-MS measurements on substances causing discoloration.
  • Figure 5 shows the properties of a solution after storing the formulation of one example at 80°C for two weeks.
  • Figure 7 shows the HPLC results (80°C, 2 weeks storage) of an example formulation with 100 ppm BHT added.
  • Figures 8a and 8b are LC-MS results for peaks 1 and 2 shown in the HPLC results of the example formulation with 100 ppm BHT added.
  • the term “about” is used to encompass a typical tolerance in the relevant technical field.
  • the term “about” may mean that a tolerance of up to 5%, 10%, 15%, or 20% exists within a given value or range of values.
  • 'Treat', 'treating' or 'treatment' means the alleviation or reduction (including partial reduction, substantial reduction, almost complete reduction and complete reduction), resolution or prevention (whether temporary or permanent) of a disease, disorder or condition so as to achieve a desired therapeutic result, for example, by healing injured or damaged tissue, or by altering, changing, strengthening, improving, ameliorating and/or beautifying an existing or recognized disease, disorder or condition.
  • 'treatment' includes prevention.
  • 'Prevention' means the delay of the onset of a disease, disorder or condition. Prevention may be considered complete if the onset of the disease, disorder or condition is delayed for a predetermined period of time.
  • 'treatment' means treating a disease, disorder, or medical condition in a patient, such as a mammal (particularly a human), comprising one or more of the following:
  • composition refers to a dosage form containing an active ingredient.
  • composition or “pharmaceutical composition” may include at least one additional active ingredient or excipient in addition to the active ingredient (e.g., a bile acid).
  • the excipients may include carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition according to the present invention may further include an anesthetic.
  • the pharmaceutical composition of one embodiment may be prepared by further including an anesthetic such as lidocaine and/or benzyl alcohol, or may be prepared to be suitable for mixing with an anesthetic such as lidocaine and/or benzyl alcohol in the preparation stage prior to administration to a subject.
  • an anesthetic such as lidocaine and/or benzyl alcohol
  • the pharmaceutical composition included in the pharmaceutical package may be mixed with an anesthetic such as lidocaine and/or benzyl alcohol prior to administration to the subject.
  • an anesthetic such as lidocaine and/or benzyl alcohol
  • composition of one embodiment may further comprise a stabilizer and/or antioxidant.
  • the stabilizer and/or antioxidant may be benzyl alcohol.
  • the pharmaceutical composition is a formulation suitable for administration to a subject, such as a mammal, including a human.
  • the subject to which the composition is administered may include, without limitation, a human or an animal, such as a human, pig, dog, cat, cow, horse, or rat.
  • the pharmaceutical composition of one embodiment may be in a liquid formulation.
  • the composition of one embodiment may be administered in a therapeutically effective amount, and the terms "effective amount” or “therapeutically effective amount,” as used herein, refer to an amount sufficient to treat or prevent a disease at a reasonable benefit/risk ratio applicable to any medical treatment or prevention.
  • the effective dosage level may be determined depending on the severity of the disease, the activity of the drug, the patient's age, weight, health, and sex, the sensitivity to the drug, the timing of administration, the route of administration, and the rate of excretion of the composition of the present disclosure, the duration of treatment, drugs used concurrently or in combination with the composition of the present disclosure, and other factors known in the medical arts.
  • composition of one embodiment may be administered locally as a single or divided injection at the injection site.
  • the composition of one embodiment may be administered by injection as a divided injection at the site of localized fat deposition.
  • the injection may include, for example, a needle or cannula.
  • composition of one embodiment may be administered in a single or multiple treatment sessions.
  • the composition of one embodiment may be administered at intervals of 12 months, 6 months, 4 months, or 3 months or less.
  • the interval between administrations of the composition includes the first treatment and the second treatment, and the dosage of the second treatment may be less than, more than, or the same as the dosage of the first treatment.
  • a pharmaceutical package according to one embodiment of the present invention may include a pharmaceutical composition comprising a bile acid or a pharmaceutically acceptable salt thereof, a container, and a stopper for sealing the container.
  • the pharmaceutical composition of one embodiment may be contained in the container of one embodiment and sealed by the stopper of one embodiment.
  • the composition may comprise at least one selected from the group consisting of cholic acid, deoxycholic acid, chenoteoxycholic acid, taurorosodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, taurine or glycine conjugates thereof, and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts of the bile acids may be sodium salts or potassium salts.
  • the composition may comprise cholic acid, deoxycholic acid, and/or salts thereof as the bile acids.
  • the composition may include a bile acid at a concentration greater than or equal to the critical micelle concentration.
  • the concentration may be greater than or equal to about 0.4%, which is the critical micelle concentration.
  • composition of one embodiment may comprise cholic acid or a salt thereof in a concentration of 0.4% to 4.0%, 0.5% to 4.0%, 1.0% to 4.0%, 1.0% to 3.0%, 1.0% to 2.0%, or about 1.5%.
  • composition of one embodiment may comprise deoxycholic acid or a salt thereof in a concentration of from 0.4% to 4.0%, from 0.5% to 4.0%, from 0.5% to 3.0%, from 0.7% to 2.0%, from 0.7% to 1.5%, or about 1.0%.
  • the composition of one embodiment may further comprise a buffer.
  • buffer refers to an aqueous solution comprising a mixture of a weak acid and its conjugate base, or a weak base and its conjugate acid.
  • the pH of a solution containing a buffer changes only slightly when a given amount of acid or base is added to the solution. Buffer solutions are widely used as a means of maintaining the pH at a nearly constant value in a variety of chemical applications. Examples of suitable buffers include phosphate buffers such as PBS and those known in the literature.
  • the buffer may be at least one selected from the group consisting of sodium citrate, sodium hydroxide, adipic acid, citric acid, phosphoric acid, sodium phosphate, disodium phosphate, monosodium phosphate, anhydrous sodium biphosphate, calcium carbonate, calcium hydroxide, calcium lactate, maleic acid, malic acid, sodium glutamate, sodium acetate, sodium bicarbonate, trisodium citrate, sodium lactate, and triethanolamine.
  • the pH of the composition of one embodiment may be less than about 9, less than about 8.5, less than about 8, less than about 7.5, less than about 7, greater than or equal to about 6, and/or greater than or equal to about 6.5.
  • the pH of the composition of one embodiment may be greater than or equal to about 6 and less than or equal to 8, greater than or equal to about 6.5 and less than or equal to 7.5, greater than or equal to about 7 and less than or equal to 7.5, for example, about 7.4.
  • composition of one embodiment may further comprise an ionic compound.
  • the ionic compound may comprise a halide (e.g., fluoride, chloride, bromide, iodide, etc.), such as NaCl, NaBr, and/or KCl.
  • the ionic compound may be used as an isotonic solution to make the osmotic pressure of the formulation similar to the osmotic pressure in the body of the subject to be administered, thereby improving patient compliance.
  • the composition of one embodiment includes a halide
  • the intermediate radical generated during the synthesis of BHT into a dimer can be stabilized by the chloride ion. Therefore, when BHT is eluted from the formulation, the reaction that produces the BHT dimer can be accelerated.
  • the ionic compound of one embodiment may be a compound that accelerates the radical coupling reaction.
  • the composition of one embodiment may further comprise a basic compound.
  • the basic compound of one embodiment may comprise one or more of an alkali metal hydroxide (e.g., potassium hydroxide or sodium hydroxide), an alkaline earth metal hydroxide (e.g., calcium hydroxide, magnesium hydroxide, strontium hydroxide, or barium hydroxide), and an inorganic salt (e.g., sodium (hydrogen) carbonate or potassium (hydrogen) carbonate).
  • an alkali metal hydroxide e.g., potassium hydroxide or sodium hydroxide
  • an alkaline earth metal hydroxide e.g., calcium hydroxide, magnesium hydroxide, strontium hydroxide, or barium hydroxide
  • an inorganic salt e.g., sodium (hydrogen) carbonate or potassium (hydrogen) carbonate
  • the composition of one embodiment may further comprise NaOH.
  • composition of one embodiment may be an injectable formulation.
  • the composition of one embodiment may be an injectable formulation for fat dissolution.
  • composition of one embodiment may be a locally administered injectable formulation for non-surgically removing localized fat deposits in a patient with localized fat accumulation.
  • the localized fat accumulation may include at least one disease or condition selected from the group consisting of lower eyelid fat herniation, lipomas, lipodystrophy, and fat deposits associated with cellulite.
  • the fat deposits may be localized under the eyes, under the chin, under the arms, buttocks, calves, back, thighs, or ankles of the subject in need thereof.
  • the closure comprises an elastomeric material and may be made of an elastomeric material and may include a radical scavenger as a stabilizer or antioxidant.
  • the elastomeric material may be a rubber.
  • the elastomeric material may comprise at least one selected from isoprene rubber, butadiene rubber, butyl rubber, halogenated butyl rubber, and styrene-butadiene rubber.
  • the elastomeric material may comprise a halogenated butyl rubber, such as chlorobutyl rubber and/or bromobutyl rubber.
  • the radical scavenger may refer to a compound having a conjugated pi electron field. In one embodiment, the radical scavenger reacts first with free radicals generated when the elastomeric material is oxidized, thereby preventing the oxidation chain reaction from proceeding, thereby inhibiting the decomposition of a plug comprising the elastomeric material. In one embodiment, the radical scavenger may be a phenolic additive.
  • the phenolic additive may comprise at least one selected from the following compounds:
  • the phenolic additive may include, for example, butyl hydroxyanisole, tert-butylhydroquinone, or propyl gallate.
  • the phenolic additive may be dibutylhydroxytoluene (BHT).
  • a stopper comprising an elastic polymeric material of one embodiment may have the characteristic of causing the phenolic additive to leach out upon contact with the bile acid composition described above or below.
  • the aforementioned phenolic additives are eluted from the formulation, safety issues such as toxicity or stability issues such as changes in the properties of the formulation may arise.
  • the above phenolic additives with wide conjugated pi electron fields may elute from the formulation and change the properties (e.g., color) of the formulation by themselves or by forming dimers through coupling reactions, thereby causing problems with the stability and safety of the formulation.
  • the pharmaceutical package of one embodiment can prevent the eluted phenolic additives, thereby improving stability and safety.
  • antioxidants e.g., radical scavengers
  • antioxidants e.g., radical scavengers
  • the stopper of one embodiment may be at least partially coated.
  • the portion of the stopper that comes into contact with the composition may be coated, or the entire stopper may be coated.
  • contact in this specification includes both direct contact between components A and B and indirect contact between components B.
  • components A and B are defined as being in indirect contact.
  • the closure of one embodiment may be coated on a portion that may come into direct or indirect contact with the vaporized formulation of one embodiment (e.g., a portion that is exposed to the interior of the container when combined with the container to seal the container).
  • the closure may be coated at least in part with at least one coating selected from the group consisting of polypropylene, polyethylene, parylene, silicone (e.g., cross-linked silicone or a cured siloxane polymer such as polydimethylsiloxane), cyclic olefin copolymer, cyclic olefin polymer, silicon dioxide (e.g., applied by plasma deposition or liquid coating), and fluoropolymers (e.g., polytetrafluoroethylene, ethylene tetrafluoroethylene, fluorinated ethylene propylene, or perfluoroalkoxy alkanes).
  • the closure may be coated with a fluoropolymer.
  • the pharmaceutical package can reduce the amount of the aforementioned phenolic additive dissolved in the formulation. Accordingly, safety issues or formulation stability issues, such as changes in appearance, that may arise due to the dissolution of the phenolic additive can be avoided.
  • composition of one embodiment may be capable of maintaining stability without visible discoloration or precipitation when stored in the pharmaceutical package of one embodiment at about 25°C for about 3 months, about 6 months, about 12 months, about 18 months, about 20 months, about 22 or about 24 months, or at about 40°C for about 3 months, about 4 months, about 5 months or about 6 months.
  • composition of one embodiment may remain stable for 5 days, 7 days, 10 days, 13 days, 15 days, 18 days, or 20 days at about 60°C when stored in the pharmaceutical package of one embodiment.
  • composition of one embodiment may remain stable for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days at about 80°C when stored in the pharmaceutical package of one embodiment.
  • composition of one embodiment may remain stable when stored at about 25°C to about 40°C for 1 month, 2 months, 3 months, 4 months, 5 months, and/or 6 months.
  • composition of one embodiment may be stable when stored for 6 to 24 months at about 25°C; 1 to 6 months at about 40°C; 5 to 20 days at about 60°C; and 1 to 10 days at about 80°C.
  • the amount of dibutylhydroxytoluene released may be less than 0.3 ppm or 0.5 ppm when stored at about 25°C for about 3 months, about 6 months, about 12 months, about 18 months, about 20 months, about 22 months, or about 24 months; at about 40°C for about 3 months, about 4 months, about 5 months, or about 6 months; at about 60°C for 5 days, 7 days, 10 days, 13 days, 15 days, 18 days, or 20 days; or at about 80°C for 8 days, 10 days, 15 days, 20 days, 30 days, 1 month, 2 months, 3 months, or 4 months.
  • composition of one embodiment may have a dibutylhydroxytoluene dimer content of less than 0.15 ppm, 0.2 ppm, or 0.25 ppm when stored in the pharmaceutical package of one embodiment at about 25°C for about 3 months, about 6 months, about 12 months, about 18 months, about 20 months, about 22 months, or about 24 months; at about 40°C for about 3 months, about 4 months, about 5 months, or about 6 months; at about 60°C for 5 days, 7 days, 10 days, 13 days, 15 days, 18 days, or 20 days; or at about 80°C for 8 days, 10 days, 15 days, 20 days, 30 days, 1 month, 2 months, 3 months, or 4 months.
  • the dimer may comprise a compound of formula 1 as a main component and a compound of formula 2 and/or formula 3 as a secondary component.
  • the compound may further comprise an additional dibutylhydroxytoluene dimer as a secondary component in addition to the compounds of formula 2 and formula 3.
  • composition of one embodiment may have a UV absorbance of 0.05 or less, 0.04 or less, or 0.03 or less at a wavelength of 400 nm to 500 nm, for example, 425 nm, when stored at 80°C for 14 days.
  • composition of one embodiment may be stored in an upright state, either in direct contact with the stopper or not in direct contact with the stopper.
  • the composition of one embodiment may be stored in an upright state.
  • a bile acid formulation containing 1.5% (w/v) cholic acid, an appropriate amount of PBS (sodium biphosphate monohydrate and sodium chloride) to make a pH 7.4 composition, and an appropriate amount of sodium hydroxide was prepared.
  • Five vials of the above example formulation were prepared and stored at 25°C in a constant temperature and humidity chamber (3QT-022).
  • Ten vials of the same formulation (1.5% concentration CA formulation) were prepared and stored at 40°C in a constant temperature and humidity chamber.
  • cholic acid dissolves in the formulation as a sodium salt.
  • the cholic acid mentioned in this experimental example may refer to the sodium salt of cholic acid.
  • the vials were stored upright using Company B's catalog number 1666091 (glass) and Company A's catalog number 7001-8452 (silicone-coated chlorobutyl elastomer container and 13 mm diameter rubber stopper).
  • 22 samples were prepared by mixing appropriate amounts of cholic acid, sodium hydroxide, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride as shown in Table 1, and placed in vials. These were then maintained at 60°C in a constant temperature and humidity chamber to induce discoloration. If each sample did not contain the substance, it was marked as 0, and if it did, it was marked as +.
  • the vials were stored upright using B Company's catalog number 1666091 (glass) and WEST Company's catalog number 7001-8452 (silicone-coated chlorobutyl elastomer container and 13 mm diameter rubber stopper).
  • the common ingredients in the discolored vials were identified as cholic acid, sodium chloride, and sodium hydroxide.
  • cholic acid compositions were prepared using the same method as described in the 'Stability Evaluation of Bile Acid Compositions' section, and vials were stored in a thermo-hygrostat at 60°C and 80°C, respectively, and the properties were observed once a day to determine the presence or absence of discoloration.
  • thermo-hygrostat 60°C and 80°C, respectively.
  • the vial stored at 60°C showed a change in appearance from colorless to yellow on the 20th day, and the same change in appearance was observed on the 20th day in repeated tests.
  • the vial stored at 80°C showed a change in appearance on the 11th, 15th, and 17th days of each of the three tests.
  • Figure 1 is a graph showing the absorbance measurement results according to the packaging material and storage conditions of the pharmaceutical package of one example.
  • Figure 2 is a graph showing HPLC results for substances causing discoloration.
  • Figure 2 A shows the results analyzed under the conditions in Table 4 below, and
  • Figure 2 B shows the results analyzed under the HPLC conditions in Table 5.
  • HPLC parameters column YMC Triart ExRS (150x4.6 mml.D. s-3 ⁇ m, 8 nm) Auto sampler temperature 20°C Column temperature 40°C flux 0.8 mL/min Injection volume 100 ⁇ L Moving A: 0.1% FA in Water, v/v B: 0.1% FA in ACN, v/v Pump mode (Gradient) Time (minutes) A% B% 0 60 40 15 60 40 45 35 65 46 10 90 53 10 90 53.1 60 40 65 60 40 Operating time 65 min PDA detector UV wavelength 289 nm
  • Figures 3 and 4 are graphs showing the results of LC-MS measurements on the discoloration-causing substance.
  • the molecular weight of Peak 1 was confirmed using LC-MS.
  • the result of confirming the molecular weight showed an m/z value of 235.1688, which is a form with a single hydrogen ion attached in positive mode.
  • the structure was determined through comprehensive analysis with the 1 H-NMR results described later, and the measured molecular weight was consistent with the molecular weight of BHT aldehyde (C 15 H 22 O 2 ).
  • 0.1, 1, 10, and 100 ppm BHT were added to the example formulation (Fig. 5), stored at 80°C for 2 weeks, and then the properties were confirmed and HPLC analysis was performed.
  • Fig. 5 depicts the properties of the solution after storing the formulation of one example at 80°C for 2 weeks.
  • the appearance of the example formulation with 100 ppm of BHT added changed from colorless to yellow, and the example formulation with 10 ppm of BHT added changed to light yellow.
  • the example formulations with 0.1 and 1 ppm of BHT added were observed to be colorless and transparent without any change in appearance.
  • BHT dimer is insoluble in water, the peak of BHT dimer could not be confirmed when dissolved in excess in PBS (pH 7.4).
  • concentration of cholic acid was 0.4% or higher, the solubility of BHT dimer increased rapidly.
  • surfactants form micelle structures above the critical micelle concentration (CMC), it is believed that the solubility of BHT dimer increased rapidly in cholic acid formulations (pH 7.4) containing approximately 0.4% or more of the critical micelle concentration of cholic acid.
  • a deoxycholic acid (1.0%) composition was prepared. Specifically, a vial of a bile acid formulation containing deoxycholic acid was prepared, containing an appropriate amount of PBS (sodium biphosphate hydrate and sodium chloride in appropriate amounts) and an appropriate amount of sodium hydroxide. In addition, a vial of a deoxycholic acid (1.0%) formulation containing an additional appropriate amount of benzyl alcohol was prepared.
  • PBS sodium biphosphate hydrate and sodium chloride in appropriate amounts
  • the two manufactured DCA formulations were each placed in rubber stoppered (Normal) + Type 1 glass vials and maintained at 60°C in a constant temperature and humidity chamber to induce discoloration. Both DCA formulations were confirmed to have turned yellow after 22 days of storage. This confirmed that the discoloration phenomenon can be applied equally to other bile acid formulations, not just cholic acid.
  • phase change is accelerated when an ionic compound such as a halide is included in the formulation because it can stabilize the intermediate radical generated during the process of BHT forming a dimer.
  • the formulation contains bile acids at a concentration above the micelle critical concentration, so that the hydrophobic BHT dimer dissolves in the formulation and exhibits a phase change.
  • the pharmaceutical package can improve the stability and safety of the formulation by preventing BHT from dissolving into the formulation by coating the stopper.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un emballage pharmaceutique selon un mode de réalisation de la présente invention comprend : un récipient contenant une composition pharmaceutique comprenant de l'acide biliaire ou un sel pharmaceutiquement acceptable de celui-ci ; et un bouchon pour sceller le récipient. Le bouchon est constitué d'un matériau élastomère et comprend un additif phénolique, et une partie du bouchon en contact avec la composition est revêtue. La composition maintient la stabilité lorsqu'elle est stockée à 25°C pendant 18 mois, à 40°C pendant 3 mois, à 60°C pendant 20 jours, ou à 80°C pendant 10 jours. L'emballage pharmaceutique d'un mode de réalisation peut maintenir la stabilité sans changement de propriétés même pendant un stockage à long terme.
PCT/KR2025/005848 2024-04-30 2025-04-29 Composition comprenant de l'acide biliaire ou un dérivé de celui-ci et emballage pharmaceutique la comprenant Pending WO2025230305A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2024-0058063 2024-04-30
KR20240058063 2024-04-30
KR10-2025-0056786 2025-04-29
KR1020250056786A KR20250158693A (ko) 2024-04-30 2025-04-29 담즙산 또는 이의 유도체를 포함하는 조성물 및 이를 포함하는 약학 패키지

Publications (1)

Publication Number Publication Date
WO2025230305A1 true WO2025230305A1 (fr) 2025-11-06

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2025/005848 Pending WO2025230305A1 (fr) 2024-04-30 2025-04-29 Composition comprenant de l'acide biliaire ou un dérivé de celui-ci et emballage pharmaceutique la comprenant

Country Status (1)

Country Link
WO (1) WO2025230305A1 (fr)

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