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

A composition comprising a bile acid or a derivative thereof and a pharmaceutical package comprising the same

[0001] The present invention comprises a composition comprising bile acid and a derivative thereof, and a pharmaceutical package comprising the same.

[0002] Pharmaceutical compositions must be stored in protective containers to minimize contact with the external environment during storage and transport. To ensure chemical stability, containers are made of chemically stable materials, and the caps of the containers must have an appropriate seal to prevent the intrusion of external contaminants and the leakage of internal components. Some light-sensitive pharmaceuticals may be made of materials with a light-blocking effect to prevent the pharmaceutical formulation from being exposed 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 objective 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 holding the same, and a stopper sealing the container. The pharmaceutical composition of one embodiment 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. The portion of the stopper in contact with the composition may be coated. The composition may maintain stability when stored for 18 months at 25°C, 3 months at 40°C, 20 days at 60°C, or 10 days at 80°C.

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

[0007] The above pharmaceutical composition may have a dissolution 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. The above pharmaceutical composition may have a content of dibutylhydroxytoluene dimer 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 above pharmaceutical composition may have a UV absorbance of 425 nm of 0.03 or less when stored at 80°C for 14 days.

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

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

[0010] The bile acid may comprise at least one selected from cholic acid, deoxycholic acid, chenoteoxycholic acid, taurorosodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, their taurine or glycine conjugates, and pharmaceutically acceptable salts thereof.

[0011] The above composition may further include a buffer solution.

[0012] The above elastomeric material may comprise at least one selected from isoprene rubber, butadiene rubber, butyl rubber, butyl halogenated rubber, ethylene propylene diene rubber, silicone rubber, natural rubber, and styrene-butadiene rubber.

[0013] The above stopper may be in indirect contact with the above 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 locally administered preparation for the 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 by administering the aforementioned pharmaceutical package to a subject in need thereof may be provided.

[0017] According to one embodiment of the present invention, a pharmaceutical package is provided that includes a container for holding a pharmaceutical composition comprising a bile acid or a pharmaceutically acceptable salt thereof, and a stopper that seals the container and comprises an elastomeric material and a radical scavenger as an antioxidant.

[0018] The above stopper may elute the radical scavenger by contacting the bile acid or a pharmaceutically acceptable salt thereof in an uncoated state. The portion of the above stopper that contacts the composition may be coated. The composition may not elute the radical scavenger 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 containing bile acid is provided.

[0020] Figure 1 is a graph showing the absorbance measurement results according to the packaging material and storage conditions of a pharmaceutical package of one embodiment.

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

[0022] Figures 3 and 4 are graphs showing the LC-MS measurement results for the discoloration-causing substance.

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

[0024] Figures 6a to 6c show 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, stored for 2 weeks) of the example formulation with 100 ppm BHT added.

[0026] Figures 8a and 8b are LC-MS results for peaks 1 and 2 that appeared 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 meaning as commonly used in the field to which this technology belongs. For the understanding of the invention, the following definitions shall apply, wherein the singular expression includes the plural expression unless the context clearly indicates otherwise, and vice versa.

[0028] Any method and material similar to or equivalent to that described in this specification may be used in the practice or testing of the present invention, but preferred methods and materials are described in this specification.

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

[0030] In interpreting the components, they are interpreted to include a margin of error even without separate explicit indication. In this specification, the term “about” is used to include a customary margin of error in the art. For example, the term “about” may mean that there is a margin of error of up to 5%, 10%, 15%, or 20% in the said number or numerical range.

[0031] "To treat," "treating," or "treatment" means the alleviation or reduction (including partial reduction, substantial reduction, near-complete reduction, and complete reduction), resolution, or prevention (temporary or permanent) of a disease, disorder, or abnormality, thereby achieving a desired therapeutic outcome, for example, by healing injured or damaged tissue, or by altering, changing, reinforcing, improving, refining, and / or beautifying an existing or perceived disease, disorder, or abnormality. In this specification, "treatment" is a concept that includes prevention. "Prevention" means the delay of the onset of a disease, disorder, or condition. Prevention may be considered complete if the onset of a disease, disorder, or condition is delayed for a scheduled period.

[0032] In one embodiment, 'treatment' means the treatment of a disease, disorder, or medical condition in a patient such as a mammal (particularly, human), comprising one or more of the following:

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

[0034] (b) improvement (ameliorating) of the said disease, disorder, or medical condition, including antagonizing the effect of other therapeutic agents, i.e., removal or regression of the said disease, disorder, or medical condition in the patient;

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

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

[0037] "Pharmaceutical composition" refers to a formulation containing an active ingredient. The terms "composition" or "pharmaceutical composition" may include at least one additional active ingredient or additive in addition to the active ingredient (e.g., bile acid). For example, additives 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 to further include 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 during the administration preparation stage before administration to a subject.

[0039] A pharmaceutical composition included in a pharmaceutical package according to one embodiment may be mixed with an anesthetic such as lidocaine and / or benzyl alcohol before administration to a subject.

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

[0041] The pharmaceutical composition is a formulation suitable for administration to subjects such as mammals, including humans. Subjects to which the composition of the present invention is administered may include humans or animals, such as humans, pigs, dogs, cats, cattle, horses, rats, etc., without limitation.

[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 as used herein, the terms “effective amount” or “therapeutic effective amount” refer to an amount sufficient to treat or prevent a disease with a reasonable benefit / risk ratio applicable to any medical treatment or prevention. The effective dosage level may be determined based on the severity of the disease, the activity of the drug, the patient’s age, weight, health and gender, sensitivity to the drug, the timing of administration, the route of administration and the elimination rate of the composition of the present disclosure, the duration of treatment, drugs used simultaneously or in combination with the composition of the present disclosure, and other factors known in the medical field.

[0043] The composition of one embodiment may be administered locally to an injection site as a single or split injection. The composition of one embodiment may be administered by injection into a localized fat deposit site by split injection. The injection may include, for example, a needle or a cannula.

[0044] The composition of one embodiment may be administered in a single or multiple treatment session. In a multiple treatment session, the composition of one embodiment may be administered at intervals of 12 months, 6 months, 4 months, or 3 months or less. In a multiple treatment session, the administration interval of the composition includes a first treatment and a second treatment, and the dosage of the second treatment may be less, more, or equal to the dosage of the first treatment.

[0045] A pharmaceutical package according to one embodiment of the present invention may comprise 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 through the stopper of one embodiment.

[0046] The composition of one embodiment may comprise at least one selected from cholic acid, deoxycholic acid, chenoteoxycholic acid, taurorosodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, taurine or glycine conjugates thereof, and pharmaceutically acceptable salts thereof as bile acids. The pharmaceutically acceptable salt of the bile acid may be a sodium salt or a potassium salt. For example, the composition of one embodiment may comprise cholic acid, deoxycholic acid, and / or salts thereof as bile acids.

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

[0048] For example, the composition of one embodiment may contain bile acid (e.g., cholic acid, deoxycholic acid, or salts thereof) at a concentration of 0.4% or more and 5.0% or less, 0.5% or more and 5.0% or less, 1.0% or more and 5.0% or less, 1.0% or more and 4.0% or less, or 1.5% or more and 3.0% or less. Here, the concentration of the bile acid may be w / v%.

[0049] For example, the composition of one embodiment may contain cholic acid or a salt thereof at a concentration of 0.4% or more and 4.0% or less, 0.5% or more and 4.0% or less, 1.0% or more and 4.0% or less, 1.0% or more and 3.0% or less, 1.0% or more and 2.0% or less, or about 1.5%.

[0050] For example, the composition of one embodiment may contain deoxycholic acid or a salt thereof at a concentration of 0.4% or more and 4.0% or less, 0.5% or more and 4.0% or less, 0.5% or more and 3.0% or less, 0.7% or more and 2.0% or less, 0.7% or more and 1.5% or less, or about 1.0%.

[0051] The composition of one embodiment may further comprise a buffer solution. The term "buffer solution" 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 predetermined amount of acid or base is added to a solution containing a buffer solution, the change in the pH of the solution is very minimal. Buffer solutions are widely used in various chemical applications as a means of maintaining pH at a nearly constant value. Examples of suitable buffer solutions include phosphate buffers such as PBS and those known in the literature. For example, the buffer solution 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 hydrogen phosphate, 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, about 6 or more, and / or about 6.5 or more. For example, the pH of the composition of one embodiment may be about 6 or more and 8 or less, about 6.5 or more and 7.5 or less, about 7 or more and 7.5 or less, for example, about 7.4.

[0053] The composition of one embodiment may further include an ionic compound. For example, the ionic compound may include halides such as NaCl, NaBr, and / or KCl (e.g., fluorides, chlorides, bromides, iodides, etc.). In one embodiment, the ionic compound may improve patient compliance by being used as an isotonic solution to make the osmotic pressure of the formulation similar to the osmotic pressure in the body of the subject requiring administration.

[0054] Since the composition of one embodiment contains a halide, when BHT is eluted from the formulation, intermediate radicals generated during the synthesis of BHT into a dimer can be stabilized through chloride ions. Therefore, when BHT is eluted from the formulation, the reaction for generating BHT dimers can be accelerated. That is, the ionic compound of one embodiment may be a compound that accelerates radical coupling reactions.

[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 carbonate or potassium 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 having localized fat accumulation. Localized fat accumulation may include at least one disease or symptom selected from the group consisting of lower eyelid fat herniation, lipomas, lipodystrophy, and fat deposits associated with cellulite.

[0058] In one embodiment, fat deposition may be localized to the under-eyes, under-chin, under-arms, buttocks, calves, back, thighs, or ankles of the subject requiring this.

[0059] The composition of one embodiment can be formulated to be suitable for direct injection into the treatment site of a patient requiring fat reduction without the need for surgical intervention.

[0060] In one embodiment, the stopper may comprise an elastomeric material and be manufactured from the elastomeric material and may include a radical scavenger as a stabilizer or antioxidant. The elastomeric material may be 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 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 system. In one embodiment, the radical scavenger reacts first with free radicals generated when the elastomeric material is oxidized to prevent the oxidation chain reaction from proceeding, thereby inhibiting the decomposition of a stopper containing the elastomeric material. In one embodiment, the radical scavenger may be a phenolic additive.

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

[0063]

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

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

[0066] A stopper comprising an elastomeric material of one embodiment may have the characteristic of leaching out a phenolic additive upon contact with a bile acid composition described above or below.

[0067] When the aforementioned phenolic additives are released into the formulation, safety issues such as toxicity or stability issues such as changes in appearance may occur. For example, the above phenolic additives having a broad conjugated pi-electron system may be released into the formulation to form dimers, etc., either by themselves or through coupling reactions, thereby changing the appearance of the formulation (e.g., color) and causing problems with formulation stability and safety. However, the pharmaceutical package of one embodiment can prevent the release of phenolic additives, so stability and safety can be improved.

[0068] In this specification, even when trace amounts of antioxidants (e.g., radical scavengers) are eluted to an extent that is difficult to detect by an analytical instrument or does not pose a problem for drug approval, it is expressed as “antioxidants (including radical scavengers) are not eluted.”

[0069] In one embodiment, the stopper may be coated in at least a portion. For example, the portion of the stopper that contacts the composition may be coated, or the entire stopper may be coated.

[0070] In this specification, the term “contact” includes both configurations in which Configuration A and Configuration B are in direct contact and configurations in which they are in indirect contact. For example, if Configuration B in liquid form is vaporized and comes into contact with A, Configuration A and Configuration B are defined as being in indirect contact.

[0071] The stopper of one embodiment may be coated with a portion that can come into direct or indirect contact with the vaporized formulation of one embodiment (e.g., a portion exposed to the inside of the container when combined with the container to seal the container).

[0072] Any pharmaceutically acceptable material may be used, but the stopper of one embodiment may be coated with at least one coating agent selected from polypropylene, polyethylene, parylene, silicone (e.g., a cured siloxane polymer such as cross-linked silicone or polydimethylsiloxane), cyclic olefin copolymer, cyclic olefin polymer, silicon dioxide (e.g., applied by plasma deposition or liquid coating), and fluoropolymer (e.g., polytetrafluoroethylene, ethylene tetrafluoroethylene, fluorinated ethylene propylene, or perfluoroalkoxyalkane). For example, the stopper of one embodiment may be coated with a fluoropolymer.

[0073] In one embodiment, the amount of the aforementioned phenolic additive released into the formulation may be reduced. Therefore, safety issues or formulation stability issues, such as changes in appearance caused by the release of the phenolic additive, may not occur.

[0074] The composition of one embodiment may maintain 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 months, or about 24 months, or when stored 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 maintain stability for 5, 7, 10, 13, 15, 18, or 20 days at about 60°C when stored in the pharmaceutical package of one embodiment.

[0076] The composition of one embodiment may maintain stability for 1, 2, 3, 4, 5, 6, 7, 8, 9, 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 maintain stability 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 maintain stability 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, 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 25°C; about 3 months, about 4 months, about 5 months, or about 6 months at about 40°C; 5 days, 7 days, 10 days, 13 days, 15 days, 18 days, or 20 days at about 60°C; or 8 days, 10 days, 15 days, 20 days, 30 days, 1 month, 2 months, 3 months, or 4 months at about 80°C, the elution amount of dibutylhydroxytoluene may be less than 0.3 ppm or 0.5 ppm.

[0080] When the composition of one embodiment is stored in the pharmaceutical package of one embodiment 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 25°C; about 3 months, about 4 months, about 5 months, or about 6 months at about 40°C; 5 days, 7 days, 10 days, 13 days, 15 days, 18 days, or 20 days at about 60°C; or 8 days, 10 days, 15 days, 20 days, 30 days, 1 month, 2 months, 3 months, or 4 months at about 80°C; the content of the dibutylhydroxytoluene dimer may be less than 0.15 ppm, 0.2 ppm, or 0.25 ppm.

[0081] In one embodiment, the dimer may include a compound of Formula 1 as a main component and a compound of Formula 2 and / or Formula 3 as a minor component. In addition to the compounds of Formula 2 and Formula 3, the compound of one embodiment may further include an additional dibutylhydroxytoluene dimer as a minor component.

[0082]

[0083] When the composition of one embodiment is stored at 80°C for 14 days, the UV absorbance at a wavelength of 400 nm to 500 nm, for example, 425 nm, may be 0.05 or less, 0.04 or less, or 0.03 or less.

[0084] The composition of one embodiment may be stored in an inverted state in direct contact with a stopper or in an upright state not in direct contact with a stopper. For example, the composition of one embodiment may be stored in an upright state.

[0085] Experimental Example

[0086] 1. Evaluation of the stability of the bile acid composition

[0087] To evaluate the long-term stability of the bile acid composition, a bile acid formulation was prepared containing 1.5% (w / v) cholic acid, appropriate amounts of PBS (sodium hydrogen phosphate hydrate and sodium chloride) and sodium hydroxide to create a pH 7.4 composition. Five vials of the formulation from the above example 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 is mixed, the cholic acid dissolves in the formulation in the form of a sodium salt. Subsequently, 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 product (glass) and Company A’s catalog number 7001-8452 product (silicone-coated chlorobutyl elastomer container and 13 mm diameter rubber stopper).

[0090] No discoloration was detected at 18 months of storage at 25°C, but yellow discoloration was confirmed in one of 5 vials at 24 months, and yellow discoloration was confirmed in all 10 vials at 6 months of storage at 40°C.

[0091] 2. Analysis of substances causing discoloration

[0092] To identify substances affecting discoloration of the formulation, appropriate amounts of cholic acid, sodium hydroxide, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride were combined to prepare a total of 22 samples as shown in Table 1. These samples were placed in vials and maintained at 60°C in a constant temperature and humidity chamber to induce discoloration. Each sample was marked as 0 if it did not contain the substance and + if it did.

[0093] The vials were stored upright using B Company’s catalog number 1666091 product (glass) and WEST Company’s catalog number 7001-8452 product (silicone-coated chlorobutyl elastomer container and 13 mm diameter rubber stopper).

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

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

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

[0097] Sample No. 14 (cholic acid, sodium chloride, sodium hydroxide) and Sample No. 21 (cholic acid, sodium chloride, sodium hydroxide, sodium dihydrogen phosphate) changed from colorless to yellow on the 18th day, and Sample No. 20 (cholic acid, sodium chloride, sodium hydroxide, sodium monohydrogen phosphate) changed to yellow on the 35th day.

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

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

[0100] 3. Evaluation of the Impact 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 'Evaluation of Stability of Bile Acid Compositions' section. Vials were then stored in constant temperature and humidity chambers at 60°C and 80°C, respectively, and the appearance was observed once a day to check for discoloration. To confirm the reproducibility of discoloration, storage at 60°C was tested a total of two times, and storage at 80°C was tested a total of three times to check the appearance.

[0102] The vial stored at 60°C changed 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 changes in appearance on the 11th, 15th, and 17th days in a total of three tests.

[0103] 4. Stability evaluation based on packaging materials and storage conditions

[0104] To determine the effect of primary packaging materials on vial discoloration, the rubber stoppers and vials shown in Table 2 were combined and packaged under four different conditions. The appearance was observed visually for 21 days under storage conditions of 80°C and upright and inverted positions, and the absorbance was measured once a week at 425 nm.

[0105] Cap 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 a pharmaceutical package of one embodiment.

[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] It was observed that the specimens of the rubber stopper (Normal) + Type 1 glass vial group and the rubber stopper (Normal) + Type 1 plus glass vial group changed from colorless to yellow on the 11th day.

[0109] The specimens of 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 without any change in appearance for 21 days.

[0110] The absorbances 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 visually, were measured at 0.0634 and 0.0566 on day 14, respectively, confirming that they had high absorbances, while the absorbances of the remaining sample groups were found to be less than 0.03 until day 21.

[0111] In other words, in the case of coated rubber stopper (Mormal) packaging, no change in the properties of the formulation occurred, whereas in the case of uncoated rubber stopper packaging, a change in the properties of the formulation occurred.

[0112] 5. Identification of the discoloration substance

[0113] Extraction and separation of discolored substances

[0114] About 200 mL of the example formulation that had changed from colorless to yellow (the same formulation as the example formulation prepared in Experimental Example 1 above) was taken, 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, the yellow diethyl ether (organic layer) was separated to remove the main components and excipients of the aqueous layer. The diethyl ether was removed using a rotary concentrator.

[0116] After adding 20 mL of acetonitrile (ACN) and mixing thoroughly with a vortex mixer, any excess active ingredients and excipients of the example formulation that were insoluble in ACN were removed by filtration using a 0.22 μm pore size filter, and then the ACN was removed using a rotary concentrator. This step was repeated 2 to 3 times, after which the substance causing the discoloration was identified using HPLC. The HPLC results are shown in Figures 2A and 2B.

[0117] Figure 2 is a graph showing the HPLC results for the discoloration-causing substances. Figure 2A is the result analyzed under the conditions of Table 4 below, and Figure 2B is the result analyzed under the HPLC conditions of Table 5.

[0118] HPLC Parameters Column: YMC Triart ExRS (150 x 4.6 mm l. D. s - 3 μm, 8 nm) Auto Sampler Temperature: 20 ℃ Column Temperature: 40 ℃ 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% 60 40 15 60 40 45 35 65 46 10 90 53 10 90 53 16 0 40 65 60 40 Operation Time: 65 min PDA Detector UV Wavelength: 289 nm

[0119] HPLC Parameters Column: YMC Triart ExRS (150 x 4.6 mm l. D. s - 3 μm, 8 nm) Auto Sampler: Temperature 20 ℃ Column Temperature 40 ℃ Flow Rate 0.9 mL / min Injection Volume 100 μL Mobile Phase: 0.1% FA in 90% ACN, v / v Pump Mode: Isocratic Mode Operation Time 90 min PDA Detector: UV Wavelength 420 nm

[0120] Peaks 1 and 2, which are the substances causing discoloration, were detected through the HPLC analysis results in Fig. 2. After confirming that the yellow-colored substance is Peak 2, it was separated using HPLC, and as will be described later, LC-MS and 1 The structure was predicted by measuring H-NMR.

[0121] Determination of the structure of the substance causing discoloration

[0122] Figures 3 and 4 are graphs showing the LC-MS measurement results for the discoloration-causing substance. As shown in Figure 3, the molecular weight of Peak 1 was confirmed using LC-MS. The result of the molecular weight determination showed an m / z value of 235.1688, which corresponds to a form with one hydrogen ion attached in positive mode. To be described later 1 The structure was determined by comprehensive analysis with 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 determined using LC-MS equipment, resulting in an m / z value of 409.3088, which corresponds to a form with one hydrogen ion attached in positive mode. To be described later 1 The structure was determined by comprehensive analysis with H-NMR results, and the measured molecular weight is BHT dimer (C 28 H 40 It matched the molecular weight of O2.

[0124] For the Peak 2 material, using the VANCE NEO 500 MHz instrument 1 H-NMR analysis was performed. Through the analysis results, the structure of the substance causing discoloration was confirmed as shown in Table 6, and the substance at peak 2 was identified as the BHT dimer below.

[0125] Chemical shift (ppm) Structure confirmation Number of hydrogens 1.37 CH3(1)36 7.71 CH (2)4

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

[0127] Verification of the cause of discoloration

[0128] To verify whether the BHT dimer identified above is indeed the substance causing discoloration, 0.1, 1, 10, and 100 ppm BHT were added to the example formulations, respectively (Fig. 5), and after storing at 80°C for 2 weeks, the appearance was checked and HPLC analysis was performed. Fig. 5 shows the appearance of the solution after storing the formulation of one example at 80°C for 2 weeks.

[0129] After 2 weeks, observation of the appearance showed that 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 with 0.1, 1, 10, and 100 ppm of BHT added. As confirmed in Figures 6a to 6c, as time progresses, BHT is depleted and the amounts of BHT aldehyde and BHT dimer increase, and a tendency was observed that the amount of BHT dimer generated increases as the amount of BHT added increases. Through this, it was confirmed that BHT is eluted from the rubber stopper, and the properties of the finished pharmaceutical product change as the eluted BHT passes through aldehyde to form a dimer.

[0131] Additional structure of the discoloration-causing substance

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

[0133]

[0134] Confirmation of BHT dimer dissolution conditions

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

[0136] Since BHT dimers are insoluble in water, the peak of BHT dimers could not be observed when dissolved in excess in PBS (pH 7.4). When the cholic acid concentration was 0.4% or higher, the solubility of BHT dimers increased rapidly. Since surfactants form a micelle structure above the critical micelle concentration (CMC), it is believed that the solubility of BHT dimers increased rapidly in cholic acid formulations (pH 7.4) at approximately 0.4% or higher, which is the critical micelle concentration of cholic acid.

[0137] 5. Confirmation of discoloration for the deoxycholic acid formulation

[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 (an appropriate amount of sodium hydrogen phosphate hydrate and sodium chloride) and an appropriate amount of sodium hydroxide. Additionally, a vial of a deoxycholic acid (1.0%) formulation was prepared, additionally containing an appropriate amount of benzyl alcohol.

[0139] Two manufactured DCA formulations were each placed in rubber stoppers (Normal) + Type 1 glass vials and maintained at 60°C in a constant temperature and humidity chamber to induce discoloration. It was confirmed that the appearance of both DCA formulations changed to yellow on the 22nd day of storage. Through this, it was confirmed that the discoloration phenomenon applies equally to other bile acid formulations as well as to cholic acid.

[0140] 6. Summary

[0141] After synthesizing all the above data, it was confirmed that the BHT contained in the rubber stopper forms a dimer after elution, causing a change in the properties of the example formulation.

[0142] It is believed that if the formulation contains ionic compounds such as halides, the intermediate radicals generated during the process of BHT forming dimers can be stabilized, thereby accelerating changes in properties.

[0143] Since the formulation of one embodiment contains bile acid at a concentration above the micelle threshold, the hydrophobic BHT dimer dissolves in the formulation and exhibits a change in appearance.

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

Claims

1. A container for holding a pharmaceutical composition comprising a bile acid or a pharmaceutically acceptable salt thereof; and a stopper for sealing the container, comprising The above stopper is manufactured of an elastomeric material and includes a radical scavenger as an antioxidant, and the portion of the stopper in contact with the composition is coated. A pharmaceutical package having maintained stability when stored for 18 months at 25°C, 3 months at 40°C, 20 days at 60°C, or 10 days at 80°C.

2. In Paragraph 1, A pharmaceutical package in which the above radical scavenger is a phenolic additive.

3. In Paragraph 2, The above phenolic additive includes dibutylhydroxytoluene, and A pharmaceutical package having a dissolution amount of dibutylhydroxytoluene of less than 0.5 ppm when the above pharmaceutical 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.

4. In Paragraph 2, The above phenolic additive includes dibutylhydroxytoluene, and A pharmaceutical package having a dibutylhydroxytoluene dimer content of less than 0.25 ppm when the above pharmaceutical 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.

5. In Paragraph 1, A pharmaceutical package having a UV absorbance of 0.03 or less at a wavelength of 425 nm when stored at 80°C for 14 days.

6. In Paragraph 1, A pharmaceutical package in which the above composition further comprises an ionic compound.

7. In Paragraph 6, A pharmaceutical package in which the above ionic compound comprises a halide.

8. In Paragraph 1, A pharmaceutical package comprising the above composition containing the bile acid or a pharmaceutically acceptable salt thereof at a concentration greater than or equal to the micelle critical concentration.

9. In Paragraph 1, A pharmaceutical package comprising at least one selected from 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 in which the above composition further comprises a buffer solution.

11. In Paragraph 1, A pharmaceutical package comprising at least one selected from isoprene rubber, butadiene rubber, butyl rubber, butyl halogenated rubber, ethylene propylene diene rubber, silicone rubber, natural rubber, and styrene-butadiene rubber, wherein the above elastomeric material comprises at least one of isoprene rubber, butadiene rubber, butyl rubber, butyl halogenated rubber, ethylene propylene diene rubber, silicone rubber, natural rubber, and styrene-butadiene rubber.

12. In Paragraph 1, A pharmaceutical package in which the above stopper is in indirect contact with the above composition.

13. In Paragraph 1, A pharmaceutical package in which the portion of the above stopper in 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 in which the above composition is a topical administration formulation for the non-surgical removal of localized fat deposits on a subject.

15. A container for holding a pharmaceutical composition comprising a bile acid or a pharmaceutically acceptable salt thereof; and a stopper that seals the container and comprises an elastomeric material and a radical scavenger as an antioxidant, and The above stopper comes into contact with the bile acid or a pharmaceutically acceptable salt thereof in an uncoated state to elute the radical scavenger, and The portion of the above stopper that comes into contact with the above composition is coated, and A pharmaceutical package in which the radical scavenger does not elute when the above 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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