Composition comprising bile acid or derivative thereof and pharmaceutical package comprising same

Abstract

A pharmaceutical package according to an embodiment of the present invention comprises: a container containing a pharmaceutical composition comprising bile acid or a pharmaceutically acceptable salt thereof; and a stopper for sealing the container. The stopper is made of an elastomeric material and includes a phenolic additive, and a portion of the stopper in contact with the composition is coated. The composition maintains 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 pharmaceutical package of one embodiment can maintain stability without a change in properties even during long-term storage.

Description

Composition comprising bile acid or its derivative and pharmaceutical package comprising same

[0001] The present invention includes a composition comprising bile acids and derivatives thereof and a pharmaceutical package comprising the same.

[0002] Pharmaceutical compositions must be stored in protective containers to minimize exposure to the external environment during storage and transport. To ensure chemical stability, 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.

[0003] However, depending on the formulation, sufficient stability may not be guaranteed even if the protective container satisfies the general conditions for storing the pharmaceutical composition.

[0004] One object of the present invention is to provide a pharmaceutical package for stably storing a pharmaceutical composition containing bile acid.

[0005] A pharmaceutical package according to one embodiment of the present invention may include a pharmaceutical composition, a container containing the pharmaceutical composition, and a stopper for sealing the container. In one embodiment, 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.

[0006] In one embodiment, the radical scavenger may be a phenol-based additive, and the phenol-based additive may be dibutylhydroxytoluene.

[0007] 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.

[0008] The above composition may further comprise an ionic compound. The ionic compound may comprise a halide.

[0009] The composition may comprise the bile acid or a pharmaceutically acceptable salt thereof at a concentration higher than the micelle critical concentration.

[0010] 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.

[0011] The above composition may further comprise a buffer.

[0012] 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.

[0013] The above plug may be in indirect contact with the composition.

[0014] The portion of the above stopper that comes into contact with the composition may be coated with at least one coating agent selected from polypropylene, polyethylene, parylene, silicone, cyclic olefin copolymer, cyclic olefin polymer, silicon dioxide, and fluoropolymer.

[0015] The above composition may be a topical administration preparation for non-surgical removal of localized fat deposits in a subject.

[0016] According to one embodiment of the present invention, 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.

[0017] According to one embodiment of the present invention, a pharmaceutical package is provided, 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.

[0018] 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.

[0019] According to one embodiment of the present invention, a pharmaceutical package for stably storing a pharmaceutical composition comprising a bile acid is provided.

[0020] 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.

[0021] Figure 2 is a graph showing the HPLC results for the substance causing discoloration.

[0022] Figures 3 and 4 are graphs showing the results of LC-MS measurements on substances causing discoloration.

[0023] Figure 5 shows the properties of a solution after storing the formulation of one example at 80°C for two weeks.

[0024] Figures 6a to 6c illustrate the HPLC analysis results of example formulations with 0.1, 1, 10, and 100 ppm of BHT added.

[0025] Figure 7 shows the HPLC results (80°C, 2 weeks storage) of an example formulation with 100 ppm BHT added.

[0026] 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.

[0027] Unless otherwise defined, technical and scientific terms used herein have the same meanings commonly used in the art. To facilitate understanding of the present invention, the following definitions will apply, and singular expressions include plural expressions, and vice versa, unless the context clearly dictates otherwise.

[0028] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein.

[0029] The term "and / or" includes all combinations that the associated constructs may define.

[0030] When interpreting components, even if not explicitly stated otherwise, they are interpreted as including a tolerance. In this specification, the term "about" is used to encompass a typical tolerance in the relevant technical field. For example, 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.

[0031] "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. As used herein, "treatment" includes prevention. "Prevention" means delaying 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.

[0032] In one embodiment, '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:

[0033] (a) preventing the occurrence of said disease, disorder, or medical condition, i.e. preventing the recurrence of said disease or medical condition, or prophylactic treatment of a patient pre-disposed to said disease or medical condition;

[0034] (b) ameliorating the disease, disorder, or medical condition, i.e., eliminating or causing regression of the disease, disorder, or medical condition in a patient, including by antagonizing the effect of other treatments;

[0035] (c) suppressing said disease, disorder, or medical condition, i.e. slowing or arresting the development of said disease, disorder, or medical condition in the patient; or

[0036] (d) Alleviation of symptoms of the disease, disorder, or medical condition in the patient.

[0037] The term "pharmaceutical composition" refers to a dosage form containing an active ingredient. The term "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). For example, the excipients may include carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. For example, the pharmaceutical composition according to the present invention may further include an anesthetic.

[0038] 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.

[0039] In one embodiment, 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.

[0040] The composition of one embodiment may further comprise a stabilizer and / or antioxidant. For example, the stabilizer and / or antioxidant may be benzyl alcohol.

[0041] 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.

[0042] 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.

[0043] The 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.

[0044] The composition of one embodiment may be administered in a single or multiple treatment sessions. In 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. In multiple treatment sessions, 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.

[0045] 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.

[0046] In 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. For example, in one embodiment, the composition may comprise cholic acid, deoxycholic acid, and / or salts thereof as the bile acids.

[0047] In one embodiment, the composition may include a bile acid at a concentration greater than or equal to the critical micelle concentration. For example, if the bile acid is cholic acid or deoxycholic acid, the concentration may be greater than or equal to about 0.4%, which is the critical micelle concentration.

[0048] For example, the composition of one embodiment may comprise a bile acid (e.g., cholic acid, deoxycholic acid, or a salt thereof) in a concentration of 0.4% to 5.0%, 0.5% to 5.0%, 1.0% to 5.0%, 1.0% to 4.0%, or 1.5% to 3.0%. Here, the concentration of the bile acid may be w / v%.

[0049] For example, the 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%.

[0050] For example, the 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%.

[0051] The composition of one embodiment may further comprise a buffer. The term "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. When a given amount of acid or base is added to a solution containing a buffer, the pH of the solution changes only slightly. 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. For example, 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.

[0052] 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. For example, 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.

[0053] The composition of one embodiment may further comprise an ionic compound. For example, the ionic compound may comprise a halide (e.g., fluoride, chloride, bromide, iodide, etc.), such as NaCl, NaBr, and / or KCl. In one embodiment, 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.

[0054] Because the composition of one embodiment includes a halide, when BHT is eluted from the formulation, 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. In other words, the ionic compound of one embodiment may be a compound that accelerates the radical coupling reaction.

[0055] 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). For example, the composition of one embodiment may further comprise NaOH.

[0056] The composition of one embodiment may be an injectable formulation. For example, the composition of one embodiment may be an injectable formulation for fat dissolution.

[0057] The 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.

[0058] In one embodiment, 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.

[0059] The composition of one embodiment may be formulated for direct injection into a treatment area of ​​a patient in need of fat reduction without the need for surgical intervention.

[0060] In one embodiment, 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. For example, the elastomeric material may comprise at least one selected from isoprene rubber, butadiene rubber, butyl rubber, halogenated butyl rubber, and styrene-butadiene rubber. For example, the elastomeric material may comprise a halogenated butyl rubber, such as chlorobutyl rubber and / or bromobutyl rubber.

[0061] In one embodiment, 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.

[0062] In one embodiment, the phenolic additive may comprise at least one selected from the following compounds:

[0063]

[0064] In one embodiment, the phenolic additive may include, for example, butyl hydroxyanisole, tert-butylhydroquinone, or propyl gallate.

[0065] For example, the phenolic additive may be dibutylhydroxytoluene (BHT).

[0066] 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.

[0067] If 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. For example, 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. However, the pharmaceutical package of one embodiment can prevent the eluted phenolic additives, thereby improving stability and safety.

[0068] In this specification, even if trace amounts of antioxidants (e.g., radical scavengers) are eluted to a degree that is difficult to detect with an analytical instrument or does not cause problems with pharmaceutical approval, it is expressed as “antioxidants (including radical scavengers) are not eluted.”

[0069] The stopper of one embodiment may be at least partially coated. For example, the portion of the stopper that comes into contact with the composition may be coated, or the entire stopper may be coated.

[0070] The term “contact” in this specification includes both direct contact between components A and B and indirect contact between components B. For example, when liquid component B vaporizes and contacts component A, components A and B are defined as being in indirect contact.

[0071] 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).

[0072] Any pharmaceutically acceptable material may be used, but in one embodiment 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). For example, in one embodiment the closure may be coated with a fluoropolymer.

[0073] In one embodiment, 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.

[0074] The 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.

[0075] The 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.

[0076] The 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.

[0077] For example, the 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.

[0078] The 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.

[0079] When the composition of one embodiment is stored in the pharmaceutical package of one embodiment, 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.

[0080] The 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.

[0081] In one embodiment, 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. In one embodiment, the compound may further comprise an additional dibutylhydroxytoluene dimer as a secondary component in addition to the compounds of formula 2 and formula 3.

[0082]

[0083] The 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.

[0084] The 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. For example, the composition of one embodiment may be stored in an upright state.

[0085] Experimental example

[0086] 1. Stability evaluation of bile acid composition

[0087] To evaluate the long-term stability of bile acid compositions, 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.

[0088] Meanwhile, when an appropriate amount of cholic acid and sodium hydroxide are mixed, 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.

[0089] 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).

[0090] No discoloration was observed after 18 months of storage at 25°C, but yellow discoloration was observed in one of the five vials after 24 months, and yellow discoloration was observed in all 10 vials after 6 months of storage at 40°C.

[0091] 2. Analysis of the substance causing the discoloration

[0092] In order to identify substances affecting discoloration of the formulation, 22 samples were prepared by combining appropriate amounts of cholic acid, sodium hydroxide, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride as shown in Table 1, placed in vials, and 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 +.

[0093] 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).

[0094] No. Mixing Sodium sulfate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, sodium chloride, sodium hydroxide 1 Single ingredient 0+000200+003000+040000+52 Mixing +000+60+00+70++0080+0+0900++01000+0+11000++123 Mixing++00+13+0+0+14+00++150+0++160+++0170++0+1800+++194 Mixing+++0+20++0++21+0+++220++++

[0095] For specimens 1-3, 5-9, 12, 13, 16, and 19, no sedimentation or discoloration was observed until the 61st day, the end of observation.

[0096] Samples No. 4, 10, 11, 15, 17, 18, and 22, which did not contain cholic acid but contained sodium hydroxide, showed sedimentation and no color change during the test period.

[0097] Samples 14 (cholic acid, sodium chloride, sodium hydroxide) and 21 (cholic acid, sodium chloride, sodium hydroxide, sodium dihydrogen phosphate) changed from colorless to yellow on the 18th day, and sample 20 (cholic acid, sodium chloride, sodium hydroxide, sodium dihydrogen phosphate) changed to yellow on the 35th day.

[0098] The common ingredients in the discolored vials were identified as cholic acid, sodium chloride, and sodium hydroxide.

[0099] Through this, it was confirmed that the appearance changed to yellow when bile acids, ionic compounds, and basic compounds were included in the formulation.

[0100] 3. Evaluation of the effect of discoloration according to storage temperature

[0101] To determine the effect of storage temperature on discoloration, 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. To determine the reproducibility of discoloration, storage at 60°C was tested twice in total, and storage at 80°C was tested three times in total to determine the properties.

[0102] 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.

[0103] 4. Stability evaluation according to packaging materials and storage conditions

[0104] In order to determine the effect of primary packaging material on vial discoloration, the rubber stoppers and vials in Table 2 were combined and packaged under four conditions, and the properties were observed visually for 21 days under upright and inverted storage conditions at 80 ℃, and the absorbance was measured at 425 nm once a week.

[0105] Stopper Vial Material Manufacturer 13 mm Rubber Stopper (Normal) Chlorobutyl Elastomer / Silicone Coating A 13 mm Teflon Coated Rubber Stopper Chlorobutyl Elastomer / Teflon Coating A 2 mL Type 1 Glass Vial Borosilicate (Type I Glass) B 2 mL Type I Plus Glass Vial Borosilicate (Type I plus Glass) B 13 mm Flip Off Blue Seal Aluminum Seal / Polypropylene Flip Off-Tear Off Cap A

[0106] The absorbance measurement results are shown in Table 3 and Figure 1. 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.

[0107] Day Type 1 Glass Vial Type I Plus Glass Vial Distilled Water Rubber Stopper (Normal) Teflon Coated Rubber Stopper Rubber Stopper (Normal) Teflon Coated Rubber Stopper 00.00530.00530.00530.00530.009370.01420.02040.01820.00360.0030140.06340.01540.05660.02300.0078210.03800.01780.03360.02780.0058

[0108] The specimens in the rubber stopper (Normal) + Type 1 glass vial group and the rubber stopper (Normal) + Type 1 plus glass vial group were observed to change in appearance from colorless to yellow on the 11th day.

[0109] The specimens from the coated rubber stopper + type 1 glass vial group and the coated rubber stopper + type 1 plus glass vial group were observed to be colorless with no change in appearance for 21 days.

[0110] The absorbance of the rubber stopper (Normal) + Type 1 glass vial group and the rubber stopper (Normal) + Type 1 plus glass vial group, in which discoloration was observed with the naked eye, was measured at 0.0634 and 0.0566 on the 14th day, respectively, confirming that they had high absorbance, while the remaining sample groups were confirmed to have absorbances of less than 0.03 until the 21st day.

[0111] That is, in the case of the coated rubber stopper (Mormal) packaging material, no change in the properties of the formulation occurred, and in the case of the uncoated rubber stopper packaging material, a change in the properties of the formulation occurred.

[0112] 5. Identification of discoloring substances

[0113] Extraction and separation of discoloring substances

[0114] Approximately 200 mL of the example formulation that changed color from colorless to yellow (same formulation as the example formulation prepared in Experimental Example 1 above) was collected and placed in a separatory funnel, 100 mL of diethyl ether was added, the lid was closed, and the mixture was shaken well.

[0115] After the organic and aqueous layers were completely separated, yellow diethyl ether (organic layer) was separated to remove the main components and excipients of the aqueous layer. Diethyl ether was removed using a rotary evaporator.

[0116] After adding 20 mL of acetonitrile (ACN), the mixture was mixed well using a vortex mixer. The remaining main ingredients and excipients of the example formulation that were not soluble in ACN were removed by filtration through a 0.22 μm pore size filter, and the ACN was removed using a rotary concentrator. This step was repeated 2 to 3 times, and the substance causing the discoloration was identified using HPLC. The HPLC results are shown in Figures 2A and B.

[0117] 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.

[0118] HPLC parameters Column YMC Triart ExRS (150 x 4.6 mml. D. s-3 μm, 8 nm) Autosampler temperature 20 °C Column temperature 40 °C Flow rate 0.8 mL / min Injection volume 100 μL Mobile phase A: 0.1 % FA in Water, v / v B: 0.1 % FA in ACN, v / v Pump mode (Gradient) Time (min) A%B% 0 6 0 4 0 1 5 6 0 4 0 4 5 3 5 6 5 4 6 1 0 9 0 5 3 1 0 9 0 5 3. 1 6 0 4 0 6 5 6 0 4 0 Operating time 65 min PDA detector UV wavelength 289 nm

[0119] HPLC parameters: Column YMC Triart ExRS (150 x 4.6 mml. D. s-3 μm, 8 nm) Autosampler temperature 20 °C Column temperature 40 °C Flow rate 0.9 mL / min Injection volume 100 μL Mobile phase 0.1 % FA in 90 % ACN, v / v Pump mode Isocratic mode Operating time 90 min PDA detector UV wavelength 420 nm

[0120] Through the HPLC analysis results of Figure 2, peak 1 and peak 2, which are the substances causing discoloration, were detected, and after confirming that the yellow substance was peak 2, it was separated using HPLC and analyzed with LC-MS as described below. 1 The structure was predicted by measuring H-NMR.

[0121] Structural identification of the substance causing discoloration

[0122] Figures 3 and 4 are graphs showing the results of LC-MS measurements on the discoloration-causing substance. As shown in Figure 3, the molecular weight of peak 1 was confirmed using LC-MS. As a result of confirming the molecular weight, an m / z value of 235.1688 was obtained, which is a form in which one hydrogen ion is attached in positive mode. As described later, 1 The structure was determined by comprehensive analysis with the H-NMR results, and the measured molecular weight was BHT aldehyde (C 15 H 22 It matched the molecular weight of O2).

[0123] As shown in Fig. 4, the molecular weight of peak 2 was confirmed using LC-MS equipment, and the m / z value was 409.3088, which is a form with one hydrogen ion attached in positive mode. As described later, 1 The structure was determined by comprehensive analysis with H-NMR results, and the measured molecular weight was BHT dimer (C 28 H 40 It matched the molecular weight of O2).

[0124] For Peak 2 material, use VANCE NEO 500M Hz instrument 1 H-NMR analysis was performed. The structure of the substance causing the discoloration was confirmed through the analysis results as shown in Table 6, and the substance in peak 2 was confirmed as the BHT dimer below.

[0125] Chemical shift (ppm)Structure confirmationNumber of hydrogens1.37CH3(1)367.71CH(2)4

[0126] BHT dimer (C 28 H 40 Chemical structure of O2)

[0127] Verifying the cause of discoloration

[0128] In order to verify whether the BHT dimer confirmed above is the substance causing the discoloration, 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.

[0129] After two 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.

[0130] Figures 6a to 6c illustrate the HPLC analysis results of example formulations containing 0.1, 1, 10, and 100 ppm of BHT. As can be seen in Figures 6a to 6c, as time elapses, BHT is consumed and the amounts of BHT aldehyde and BHT dimer increase. It was also confirmed that the amount of BHT added tends to increase the amount of BHT dimer produced. Through this, it was confirmed that BHT is eluted from the rubber stopper, and the eluted BHT forms a dimer via aldehyde, thereby changing the properties of the finished pharmaceutical product.

[0131] Additional structure of the discoloration-causing substance

[0132] When BHT was added at a high concentration (100 ppm) to the example formulation, two new peaks were identified and LC-MS analysis was performed. Figure 7 shows the HPLC results (80°C, 2 weeks storage) of the example formulation with 100 ppm BHT added. Figures 8a and 8b show the LC-MS results for peaks 1 and 2 shown in the HPLC results of the example formulation with 100 ppm BHT added. The molecular weight of peak 1 was confirmed using LC-MS equipment and was found to be an m / z value of 423.32, which is a form with one hydrogen ion attached in positive mode, and peak 2 had an m / z value of 435.32, which matched the molecular weight of the BHT dimer represented by the chemical structure below, respectively.

[0133]

[0134] Confirmation of BHT dimer dissolution conditions

[0135] As described above, common raw materials affecting the discoloration of the example formulations were bile acids, sodium chloride, and sodium hydroxide. To determine the effect of bile acids on the discoloration of the example formulations, the example formulation and formulations with cholic acid contents of 0.2%, 0.4%, 0.8%, 1.0%, and 1.5% were prepared, and an excess of BHT dimer was added to each sample, stirred, and then filtered. The filtered solutions were analyzed by HPLC, and the degree of BHT dimer dissolution was confirmed by plotting in Figures 8a and 8b.

[0136] Since BHT dimer is insoluble in water, the peak of BHT dimer could not be confirmed when dissolved in excess in PBS (pH 7.4). When the concentration of cholic acid was 0.4% or higher, the solubility of BHT dimer increased rapidly. Since 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.

[0137] 5. Check for discoloration in deoxycholic acid formulations

[0138] To evaluate whether discoloration occurs in the case of deoxycholic 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.

[0139] 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.

[0140] 6. Summary

[0141] After synthesizing all of the above data, it was confirmed that the properties of the example formulation changed as BHT contained in the rubber stopper was dissolved and formed a dimer.

[0142] It is believed that the 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.

[0143] In one embodiment, 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.

[0144] In one embodiment, the pharmaceutical package can improve the stability and safety of the formulation by preventing BHT from dissolving into the formulation by coating the stopper.

Claims

1. A container containing a pharmaceutical composition comprising a bile acid or a pharmaceutically acceptable salt thereof; and a stopper for sealing the container, The above stopper is made of an elastic polymer material and contains a radical scavenger as an antioxidant, and the portion of the stopper that comes into contact with the composition is coated. A pharmaceutical package wherein the composition remains stable 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.

2. In paragraph 1, A pharmaceutical package wherein the above radical scavenger is a phenol-based additive.

3. In paragraph 2, The above phenolic additive contains dibutylhydroxytoluene, A pharmaceutical package, wherein the pharmaceutical composition has a release amount of dibutylhydroxytoluene 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.

4. In paragraph 2, The above phenolic additive contains dibutylhydroxytoluene, A pharmaceutical package, wherein the pharmaceutical composition has 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.

5. In paragraph 1, A pharmaceutical package, wherein the pharmaceutical composition has a UV absorbance at a wavelength of 425 nm of 0.03 or less when stored at 80°C for 14 days.

6. In paragraph 1, A pharmaceutical package, wherein the composition further comprises an ionic compound.

7. In paragraph 6, A pharmaceutical package wherein the ionic compound comprises a halide.

8. In paragraph 1, A pharmaceutical package, wherein the composition comprises the bile acid or a pharmaceutically acceptable salt thereof at a concentration higher than the micelle critical concentration.

9. In paragraph 1, A pharmaceutical package comprising 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.

10. In paragraph 1, A pharmaceutical package, wherein the composition further comprises a buffer.

11. In paragraph 1, A pharmaceutical package, wherein the elastic polymer material comprises 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.

12. In paragraph 1, A pharmaceutical package wherein the stopper is in indirect contact with the composition.

13. In paragraph 1, A pharmaceutical package, wherein the portion of the stopper that comes into contact with the composition is coated with at least one coating agent selected from polypropylene, polyethylene, parylene, silicone, cyclic olefin copolymer, cyclic olefin polymer, silicon dioxide, and fluoropolymer.

14. In paragraph 1, A pharmaceutical package wherein the composition is a topical administration preparation for non-surgical removal of localized fat deposits of a subject.

15. 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, when in an uncoated state, comes into contact with the bile acid or a pharmaceutically acceptable salt thereof to elute the radical scavenger, The portion of the above plug that comes into contact with the composition is coated, A pharmaceutical package wherein the radical scavenger is not eluted when the composition is 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.

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