Molecular aggregates of bile acids or bile salts and pharmaceutical compositions for topical fat removal containing the same

Abstract

The present invention relates to a molecular association of a bile acid or a bile salt and a composition containing the same, and more specifically, to a skin-permeable formulation of deoxycholic acid, a lipolytic pharmacological agent, which has been developed as an external preparation rather than a conventional injection, and which dramatically improves patient compliance.

Description

Technical Field

[0001] The present invention relates to a molecular aggregate of a bile acid or bile salt and a pharmaceutical composition for topical fat removal containing the same. Specifically, the present invention relates to a molecular aggregate of a bile acid or bile salt, which is a lipolytic pharmacological substance, developed as a topical skin preparation instead of a conventional injection, and a pharmaceutical composition for topical fat removal containing the same, which epochally improves patient compliance.

Background Art

[0002] Bile acids and bile salts can emulsify fats, promote the action of lipase, which is a digestive enzyme, and dissolve fatty acids. Since they are also components present in the digestive organs of the human body, they can play a role in decomposing and digesting and absorbing the eaten fats. Using such a pharmacological mechanism, Allergan, a global company, developed a fat removal injection using deoxycholic acid, a type of bile acid, and developed Belkyra (registered trademark, in Canada). The Belkyra (registered trademark, in Canada) is a mechanism that is transmitted subcutaneously by injection, causes irreversible destruction of fat cells, and then promotes the generation of new collagen in the treatment site to improve double chins. It is an injection with less risk than fat removal surgery, but due to side effects such as pain, inflammation, rash, swelling, bruising, and in severe cases, facial muscle weakness and chin nerve damage, it requires the operation of a medical professional and has the inconvenience of requiring several hospital visits even after the operation.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present invention aims to provide a molecular aggregate of bile acids or bile salts that can penetrate the skin, which is applied to the skin rather than being delivered by a surgical method of directly injecting drugs using needles and syringes. This molecular aggregate has fat-removing properties similar to subcutaneous injections, and does not have the side effects of injections, thus ensuring patient convenience.

[0005] Furthermore, the present invention aims to provide a skin-penetrating molecular aggregate of bile acids or bile salts that can penetrate the skin, after confirming its storage stability by mass production and application to animals, and confirming its effectiveness.

[0006] Furthermore, the present invention aims to provide a pharmaceutical composition for local fat removal that includes the aforementioned molecular aggregate and is permeable to the skin. [Means for solving the problem]

[0007] The present invention provides a molecular aggregate in which molecules of bile acids or bile salts are physically bound together, and when the molecular aggregate is formed with a composition containing water, the molecular aggregate in the composition has an aggregated structure.

[0008] Furthermore, according to one embodiment of the present invention, a molecular aggregate can be provided in which the pH of the molecular aggregate is greater than 8.5 and less than 10.

[0009] Furthermore, according to one embodiment of the present invention, a molecular aggregate can be provided in which the average particle size of the molecular aggregate is 1.0 to 10 nm or less.

[0010] Furthermore, according to one embodiment of the present invention, it is possible to provide a molecular aggregate that is amorphous.

[0011] Furthermore, according to one embodiment of the present invention, it is possible to provide a molecular aggregate in which, under accelerated conditions of 40±2℃ / 75±5%, the rate of change in concentration over 12 months is greater than 1 and less than 10%.

[0012] Furthermore, according to one embodiment of the present invention, it is possible to provide a molecular aggregate in which, under accelerated conditions of 40±2℃ / 75±5%, the rate of change in particle size over 12 months is greater than 1 and less than 10%.

[0013] Furthermore, according to one embodiment of the present invention, it is possible to provide a molecular aggregate in which the rate of change of pH over 12 months is greater than 0 and less than 5% under accelerated conditions of 40±2℃ / 75±5%.

[0014] Furthermore, according to one embodiment of the present invention, a molecular aggregate can be provided in which the bile acid is any of the group consisting of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid, and the bile salt is a salt of any one of the group consisting of succinic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid.

[0015] Furthermore, according to one embodiment of the present invention, a pharmaceutical composition for local fat removal containing the molecular aggregate can be provided.

[0016] Furthermore, according to one embodiment of the present invention, the composition can be used as a topical skin preparation, applied by a non-surgical, non-invasive method, to provide a pharmaceutical composition for local fat removal.

[0017] Furthermore, according to one embodiment of the present invention, the composition further comprises one or more selected from the group consisting of glycerin, chia seed oil, glucan, hyaluronic acid, honeysuckle extract, collagen, ceramide, lecithin, betaine, trehalose, panthenol, squalane, caprylic / capric triglyceride, butylene glycol, propanediol, pentylene glycol, sodium levulinate, hydrogenated lecithin, and sodium hyaluronate, providing a pharmaceutical composition for topical fat removal.

[0018] Furthermore, according to one embodiment of the present invention, the composition provides a pharmaceutical composition for local fat removal containing 0.05 to 10% by weight of the molecular aggregate.

[0019] Furthermore, according to one embodiment of the present invention, a pharmaceutical composition for local fat removal can be provided for treating diseases selected from the group consisting of obesity, fat redistribution syndrome, submental fat (a double chin caused by localized fat accumulation), lower eyelid fat herniation, lipoma, Dercum's disease, lipodystrophy, buffalo hump dystrophy, and combinations thereof.

[0020] Furthermore, according to one embodiment of the present invention, a pharmaceutical composition for localized fat removal can be provided, which is localized to a site selected from the group consisting of abdominal and cervical fat, inner thigh fat, upper arm fat, visceral fat accumulation, fat generated after breast augmentation surgery, chest fat, fat spread around the arms, fat under the eyes, fat under the chin, buttock fat, calf fat, back fat, thigh fat, ankle fat, cellulite, and combinations thereof.

[0021] Also, according to an embodiment of the present invention, a pharmaceutical composition for local fat removal can be provided, which is used as any one dosage form selected from the group consisting of gels, creams, ointments, unguents, sprays, thickened dosage forms, and dressings.

[0022] Also, according to an embodiment of the present invention, a pharmaceutical composition for local fat removal can be provided, in which the concentration of bile acids measured in plasma 3 hours after application to the skin is 0.001 to 0.2 μg / ml.

Advantages of the Invention

[0023] The present invention is not a surgical method of directly injecting and delivering drugs using needles and syringes, but can be directly applied to the skin, which has the advantage of reducing the labor of the administration method. Also, different from the conventional product form, although it is not an injection dosage form, it has the advantage of excellent effects on skin permeability, lipolysis, and reduction of accumulation.

[0024] Also, the gap between the skin is 80 nm, and it was difficult for conventional pharmaceutical products to penetrate into the skin. However, in the case of the present invention, since it has a small size of 0.5 to 5 nm, it has the effect of increasing skin permeability.

[0025] Also, nano-sized dispersed particles are easily exposed to aggregation or Ostwald ripening phenomena, so their storage stability is low. On the other hand, the molecular aggregates and compositions of the present invention have the effect of excellent stability with little change in properties, pH, and particle size under accelerated conditions of 40 ± 2°C / 75 ± 5%.

[0026] Also, the present invention has the advantage that it does not necessarily require the use of a third substance such as surfactants, micelles, cyclodextrins, lipids, albumin, water-soluble polymers, stabilizers / dispersants, nanoparticles, porous particles, etc. which are additionally used in addition to APIs and water to improve solubility in the prior art.

Brief Description of the Drawings

[0027] [Figure 1] This is the result of an analysis of the Zetasizer particle size of deoxycholic acid molecular aggregates. [Figure 2] This is a TEM image of a molecular aggregate of deoxycholic acid. [Figure 3] This is a graph showing the calibration curve of deoxycholic acid molecular aggregates. [Figure 4] This figure illustrates the destructive ability of deoxycholic acid molecular aggregates to adipocyte precursor cells. [Figure 5] This is the process of differentiation of adipose-derived progenitor cells into adipocytes. [Figure 6] This figure illustrates the ability of deoxycholic acid molecular aggregates to destroy adipocytes. [Figure 7] This figure shows the amount of deoxycholic acid permeation measured after a single injection of a deoxycholic acid precursor into the subcutaneous tissue of a live mouse, followed by continuous application of the same amount of deoxycholic acid precursor and the deoxycholic acid molecular aggregate of the present invention onto the skin, and then collection of subcutaneous tissue. [Figure 8] This figure shows the amount of deoxycholic acid precursor absorbed into the subcutaneous tissue of a live mouse, followed by the application of the same amount of deoxycholic acid precursor and the molecular aggregate of deoxycholic acid according to the present invention to the skin. Subcutaneous tissue samples were then taken and the distribution of the substances within the skin tissue was compared. [Figure 9] This figure compares the distribution of deoxycholic acid precursor and molecular aggregate in the plasma over time between a single subcutaneous injection of the precursor into the skin of a live mouse and continuous topical application of the same amount to the skin. [Figure 10] This shows the H&E staining results for evaluating the histological effects of deoxycholic acid precursor and molecular aggregates on subcutaneous tissue depending on the application time, when the same amount as when the precursor was injected subcutaneously once into the skin of a live mouse is applied repeatedly to the skin. [Figure 11]This figure shows the results of Masson's Trichrome staining, which increased the area of ​​the blue-stained region due to the destruction of adipocytes or the increase in collagen, in order to evaluate the histological effects of the deoxycholic acid precursor and molecular aggregate on the subcutaneous tissue depending on the application time, when the same amount of the deoxycholic acid precursor was applied to the skin of a live mouse once subcutaneously. [Figure 12] This figure shows the change in body weight of obese mice after applying 1.0% and 2.5% deoxycholic acid molecular aggregates to the skin twice a day for 4 weeks, compared to a negative control group (N=5). [Figure 13] This figure shows the changes in waist circumference when obese mice were treated with 1.0% and 2.5% deoxycholic acid molecular aggregates twice daily for 4 weeks, compared to a negative control group (N=5). [Figure 14] This figure shows the changes in waist circumference of obese mice after applying 1.0% and 2.5% deoxycholic acid molecular aggregates to the skin twice a day for 4 weeks, compared to a negative control group. [Modes for carrying out the invention]

[0028] Poorly soluble drugs have extremely low saturation solubility in aqueous solutions, extremely high interfacial energy with water, and are thermodynamically unstable, leading to precipitation (sedimentation) or phase separation. Therefore, to increase the drug content (i.e., solubility) to a pharmacologically meaningful degree, a third substance is needed, such as a surface active agent to lower the interfacial energy or a carrier capable of containing a high concentration of the drug.

[0029] Conventional solubility enhancement techniques commonly require the use of a third substance other than APIs and water, or these substances act as core factors in improving solubility. Examples of such third substances include surfactants, micelles, cyclodextrins, lipids, albumin, water-soluble polymers, stabilizers / dispersants, nanoparticles, and porous particles.

[0030] However, the inventors of the present invention have completed the present invention by confirming that, without using the aforementioned third substance, they can produce molecular aggregates utilizing polar interactions or hydrogen bonds, increase the permeability to phospholipid membranes by making the surface of the structure hydrophobic, adjust the particle size of the aggregates to the 1.0-10 nm level, increase the permeability to skin gaps with a size of about 80 nm, and thereby deliver pharmacological substances to adipocytes in the skin, exhibiting excellent effects in lipolysis and reduction of fat accumulation.

[0031] The following provides a more detailed explanation.

[0032] term In the present invention, "bile acid" and "bile salt" mean steroid acids (and / or their carboxylic acid anions) and their salts, which are found in the bile of animals (e.g., humans). Non-limiting examples include bile acids selected from the group consisting of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid, and bile salts which are salts thereof.

[0033] In the present invention, the term "molecular aggregate of bile acid or bile salt" refers to a molecular aggregate produced by applying shear stress to a solution containing bile acid, such that the bile acid molecules or bile salt molecules are physically bonded together, and means a structure in which the bile acid molecules are clustered together.

[0034] In the present invention, "bile acid molecule or bile salt molecule" means the bile acid or bile salt molecule itself that is a precursor or precursor used to produce the bile acid or bile salt molecule aggregate according to the present invention, and can also be called a "precursor." That is, the bile acid or bile salt molecule according to the present invention means a bile acid or bile salt that is not subjected to shear stress.

[0035] In this invention, the terms “patient,” “subject,” and “individual” are used interchangeably herein and refer to any animal or its cells, in vitro or in situ, that can be adapted to the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human.

[0036] In the present invention, the term "composition" or "pharmaceutical composition" means a mixture of at least one compound of the present invention and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates the administration of the compound as an organism.

[0037] In this invention, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutic effective amount” refer to an amount that is non-toxic but sufficient to provide the desired biological effect. The effect may be a reduction and / or mitigation of signs, symptoms, or the cause of disease, or any other desired alteration of the biological system. In any individual case, the appropriate therapeutic amount can be determined by a skilled technician using conventional experiments.

[0038] In this invention, the term "efficacy" refers to the maximum effect (Emax) achieved within the analytical method.

[0039] In the present invention, “treatment” or “treating” is defined as applying or administering a therapeutic agent, i.e., a compound of the present invention (alone or in combination with other pharmaceutical agents) to a patient in order to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or influence the condition, symptoms of the condition, or potential to progress to the condition, as considered herein, as defined as applying or administering a therapeutic agent to tissue or cell lines isolated from a patient (e.g., for diagnostic or ex vivo application) having the condition, symptoms of the condition, or potential to progress to the condition, as considered herein. The treatment can be specifically adapted or modified based on knowledge derived from the field of pharmacology.

[0040] In the present invention, the "therapeutically effective amount" is the amount of the compound of the present invention that, when administered to a patient, improves the symptoms of the disease. The amount of the compound of the present invention constituting the "therapeutically effective amount" can vary depending on the compound, the state and severity of the disease, the age of the patient being treated, and so on. The therapeutically effective amount can usually be determined by a person of ordinary art in consideration of their knowledge and this disclosure.

[0041] In the present invention, the term "application as a topical agent" means, for example, applying a pharmaceutical composition to the outside of the skin in a non-surgical, non-injection manner to deliver a drug into the skin, and can also be otherwise determined by a person with ordinary art in the art, taking into consideration their knowledge and this disclosure.

[0042] In the present invention, the term "local fat removal" means an act for treating a disease selected from the group consisting of, for example, obesity, fat redistribution syndrome, submental fat (a double chin caused by localized fat accumulation), lower eyelid fat herniation, lipoma, Dercum's disease, lipodystrophy, buffalo hump dystrophy, and combinations thereof, and other such acts may be normally determined by a person of ordinary art in consideration of their knowledge and this disclosure.

[0043] In the present invention, the term "localized fat" means fat that is localized to a site selected from the group consisting of, for example, fat of the abdomen and neck, fat of the inner thighs, fat of the upper arms, accumulation of visceral fat, fat that develops after breast augmentation surgery, fat of the chest, fat that has spread around the arms, fat under the eyes, fat under the chin, fat of the buttocks, fat of the calves, fat of the back, fat of the thighs, fat of the ankles, cellulite, and combinations thereof, and can also be normally determined by a person with ordinary art in the art, taking into consideration their own knowledge and this disclosure.

[0044] In the present invention, the term "topical skin preparation" means, for example, a dosage form that can be applied to the skin, and is used as one of the group consisting of gels, creams, ointments, unguents, sprays, thickened dosage forms, and poultices, and may otherwise be determined by a person of ordinary art in consideration of their knowledge and this disclosure.

[0045] molecular aggregates of bile acids or bile salts The present invention provides a molecular aggregate in which bile acid molecules or bile salt molecules are physically bound together, and when the molecular aggregate is formed with a composition containing water, the molecular aggregate has an aggregated structure in the composition.

[0046] In the present invention, the average particle size of the molecular aggregate may be 1.0 to 10 nm or less, preferably 1.5 nm or more, 2.0 nm or more, and also 7.0 nm or less, 5.0 nm or less, or 3.0 nm or less. The average particle size of the molecular aggregate can be measured by diffraction experiments, preferably using a Zetasizer or Small Angle Neutron Scattering (SANS). Alternatively, an image can be measured using Transmission Electron Microscopy. If the average particle size of the molecular aggregate exceeds 10 nm, there is a problem of decreased dispersibility, transparency, and transmittance. Furthermore, there is no special lower limit to the average particle size of the molecular aggregate, but one with a particle size of approximately 1.0 nm or more can be used.

[0047] The molecular aggregates according to the present invention are manufactured by applying shear stress to bile acid molecules or bile salt molecules. As a result, despite being manufactured at the nanoscale, they can have an amorphous form, which not only makes size adjustment easy but also improves skin permeability.

[0048] Furthermore, the molecular aggregate according to the present invention may have a pH greater than 8.5 and less than 10. When the pH value is within the above range, not only is the skin permeability of the molecular aggregate increased, but after reaching adipocytes, it can effectively decompose fat. Also, unlike substances used in conventional injectable preparations, the molecular aggregate according to the present invention is used as a topical preparation, so its pH may be relatively high, and a higher pH can further improve storage stability. Specifically, the pH of the molecular aggregate may be greater than 8.6, greater than 8.7, greater than 8.8, greater than 8.9, greater than 9.0, greater than 9.1, and may be less than 9.9, less than 9.8, less than 9.7, less than 9.6, less than 9.5, less than 9.4, or less than 9.3.

[0049] Furthermore, the molecular aggregates according to the present invention exhibit excellent storage stability. While typical nano-sized dispersed particles are easily exposed to aggregation or Ostwald ripening and therefore have poor storage stability, the molecular aggregates and compositions of the present invention exhibit excellent stability, with minimal changes in properties, pH, and particle size under accelerated conditions of 40±2℃ / 75±5%.

[0050] Specifically, the molecular aggregate according to the present invention may have a concentration change rate of more than 1 and less than 10% over 12 months under accelerated conditions of 40±2℃ / 75±5%, preferably more than 1 and less than 5%, and more preferably more than 1 and less than 4%. Furthermore, the molecular aggregate according to the present invention may have a concentration change rate of more than 1 and less than 10% over 3 months under accelerated conditions of 40±2℃ / 75±5%, preferably more than 1 and less than 5%, and more preferably more than 1 and less than 3%.

[0051] Specifically, the molecular aggregate according to the present invention may have a particle size change rate of more than 1 and less than 10% over 12 months under accelerated conditions of 40±2℃ / 75±5%, preferably more than 1 and less than 7%, and more preferably more than 1 and less than 5%. Furthermore, the molecular aggregate according to the present invention may have a particle size change rate of more than 1 and less than 10% over 3 months under accelerated conditions of 40±2℃ / 75±5%, preferably more than 1 and less than 5%, and more preferably more than 1 and less than 3%.

[0052] Specifically, the molecular aggregate according to the present invention may have a pH change rate of less than 5% above zero over 12 months under accelerated conditions of 40±2℃ / 75±5%, preferably less than 3% above zero, and more preferably less than 1.5% above zero. Furthermore, the molecular aggregate according to the present invention may have a pH change rate of less than 5% above zero over 3 months under accelerated conditions of 40±2℃ / 75±5%, preferably less than 3% above zero, and more preferably less than 1.5% above zero.

[0053] The aforementioned rate of change refers to the average rate of change obtained by calculating the average of the rate of change for each month up to the aforementioned period.

[0054] As described above, it can be seen that the molecular aggregates according to the present invention have excellent stability.

[0055] Method for producing molecular aggregates A molecular aggregate of bile acid or bile salt according to one embodiment of the present invention can be produced by applying shear stress to a solution containing bile acid or bile salt, which is a precursor of the molecular aggregate.

[0056] The shear stress applied to the solution containing the bile acid or bile salt, which is a precursor of the molecular aggregate, may be either mechanical shear stress or ultrasonic application.

[0057] The mechanical shear stress may be applied by passing the solution through a silica-filled column or filter paper. The mechanical shear stress will be described in detail below.

[0058] According to one embodiment of the present invention, the mechanical shear stress may be applied by passing a solution containing bile acid or bile salt, which is a precursor of the molecular aggregate, through a silica-packed column. When the solution containing bile acid or bile salt passes through a silica-packed column, the bile acid or bile salt, which is a precursor of the molecular aggregate, is subjected to very high shear stress by passing through a physically narrow region.

[0059] The silica may be spherical or angular, but its shape is not limited.

[0060] The average particle size of the silica may be 1.0 to 50 μm, specifically 1.5 μm or more, 2 μm or more, 40 μm or less, 30 μm or less, 20 μm or less, 10 μm or less, or 5 μm or less. If the size of the silica is less than 1.0 μm or greater than 50 μm, even if the solution containing the bile acid or bile salt passes through the silica-packed column, no shear stress is applied, and therefore there may be no change in the molecular aggregate.

[0061] A negative pressure of 0.1 bar to 1.0 bar or 0.2 bar to 0.9 bar can be applied to the bottom of the silica-packed column. If the negative pressure applied to the bottom of the silica-packed column is less than 0.1 bar, the time required for the solution containing the bile acid or bile salt to pass through the column will increase, which may delay the production time of the bile acid or bile salt molecular aggregate according to the present invention. If the negative pressure applied to the bottom of the silica-packed column exceeds 1.0 bar, the time required for the solution containing the bile acid or bile salt to pass through the column will decrease, which may shorten the production time of the bile acid or bile salt molecular aggregate according to the present invention, but this may increase production costs because additional pump equipment is required.

[0062] According to another embodiment of the present invention, the mechanical shear stress may be applied by passing the solution containing the bile acid or bile salt through one or more filter papers. By passing through the one or more filter papers, the bile acid or bile salt, which is a precursor of the molecular aggregate, is subjected to very high shear stress by passing through a physically narrow region.

[0063] The filter paper may be a single filter paper or two or more filter papers. If the filter paper is two or more filter papers, the filter papers can be stacked and arranged. If the filter paper is two or more filter papers, it can provide a higher shear stress than a single filter paper.

[0064] The pore size of the filter paper may be 0.1 to 5.0 microns or 0.3 to 4.5 microns. If the pore size of the filter paper is less than 0.1 microns, the amount of the bile acid-containing solution that passes through or is filtered by the filter paper may be very small, which may reduce the production rate of the bile acid or bile salt molecular aggregate according to the present invention. If the pore size of the filter paper exceeds 5.0 microns, the bile acid-containing solution may simply pass through the filter paper, and shear stress may not be effectively applied.

[0065] The aforementioned shear stress may be applied using ultrasound. The application of ultrasound will be described in detail below.

[0066] According to one embodiment of the present invention, the shear stress may be applied by applying ultrasound to a solution containing the bile acid or bile salt.

[0067] When the aforementioned ultrasound is added to a solution containing the bile acid or bile salt, a pressure wave is generated, and this pressure wave may apply shear stress to the bile acid or bile salt, which is a precursor of the molecular aggregate.

[0068] The intensity of the applied ultrasonic wave may be 200 J / sec to 800 J / sec or 400 J / sec to 600 J / sec.

[0069] The energy added per unit volume by the applied ultrasound can be calculated as follows: ultrasound intensity (J / sec) × duration of application (sec) / volume measured (ml).

[0070] According to one embodiment of the present invention, the energy per unit volume of ultrasound applied to the solution containing the bile acid or bile salt may be 100 J / ml to 90 kJ / ml.

[0071] If the ultrasonic energy is less than 100 J / ml, sufficient shear stress may not be applied to the solution containing the bile acid or bile salt, making it difficult to form molecular aggregates. Conversely, if the ultrasonic energy exceeds 90 kJ / ml, excessive heat may be applied to the solution containing the bile acid or bile salt, making it difficult to form molecular aggregates.

[0072] The ultrasound can be applied at a temperature of 10°C to 80°C for 10 seconds to 60 minutes. If the ultrasound is applied at a temperature below 10°C, there is no change in the solution containing the bile acid or bile salt. If the ultrasound is applied at a temperature above 80°C, a phase change occurs in the solution containing the bile acid or bile salt, making it difficult to form the molecular aggregate of bile acid or bile salt according to the present invention. Also, if the ultrasound is applied for less than 10 seconds, there is no change in the solution containing the bile acid or bile salt. If the ultrasound is applied for a period exceeding 60 minutes, the molecular aggregate in the solution containing the bile acid or bile salt deforms, making it impossible to form the molecular aggregate of bile acid or bile salt according to the present invention.

[0073] According to another embodiment of the present invention, a silica-filled column can be coupled to an ultrasonic generator by the method of applying the shear stress described above. The silica-filled column can be placed inside the ultrasonic generator, or the silica-filled column and the ultrasonic generator can be separated and arranged in a continuous configuration.

[0074] For example, after pouring a solution containing the bile acid or bile salt into a silica-packed column, the column can be placed in an ultrasonic generator and ultrasonic waves can be applied. Alternatively, after applying ultrasonic waves to a solution containing the bile acid or bile salt, the solution can be passed through the silica-packed column.

[0075] Pharmaceutical composition for localized fat removal The present invention provides a pharmaceutical composition for local fat removal comprising the molecular aggregate.

[0076] In the present invention, the pharmaceutical composition for local fat removal may be used as any one dosage form from the group consisting of gel, cream, ointment, unguent, spray, thickened dosage form, and poultice.

[0077] In the present invention, the pharmaceutical composition for local fat removal may contain, in addition to the molecular aggregate, one or more selected from the group consisting of glycerin, chia seed oil, glucan, hyaluronic acid, honeysuckle extract, collagen, ceramide, lecithin, betaine, trehalose, panthenol, squalane, caprylic / capric triglyceride, butylene glycol, propanediol, pentylene glycol, sodium levulinate, hydrogenated lecithin, and sodium hyaluronate.

[0078] Furthermore, in the present invention, the pharmaceutical composition for local fat removal may further contain, without any special limitations, any ingredients used in the industry for use as a cream formulation, in addition to the aforementioned components.

[0079] In the present invention, the pharmaceutical composition for local fat removal may contain the molecular aggregate in an amount of 0.05% to 10.0% by weight, specifically 0.08% or more by weight, 0.1% or more by weight, 0.3% or more by weight, 0.5% or more by weight, 1.0% or more by weight, or 5% or less by weight, 3.0% or less by weight, 2.0% or less by weight, or 1.0% or less by weight.

[0080] In the present invention, the pharmaceutical composition for local fat removal may have a bile acid or bile salt concentration of 0.001 to 0.2 μg / ml measured in plasma 3 hours after application to the skin. Specifically, it may be 0.01 μg / ml or more, 0.05 μg / ml or more, 0.1 μg / ml or more, 0.18 μg / ml or less, 0.15 μg / ml or less, or 0.12 μg / ml or less. [Examples]

[0081] The present invention will be described in more detail below through examples of the present invention. It goes without saying that the present invention is not limited to these examples.

[0082] [Examples] Example 1-1. Preparation of molecular aggregates of deoxycholic acid (DCA) 3.6 g of deoxycholic acid (DCA) was placed in a 250 ml beaker and dissolved in 177 g of ethanol. 142 g of SYLOID 244 FP was placed in a 3 L beaker and stirred at 50 rpm using an overhead stirrer. 17 g of 1 M NaHCO3 and 5 g of 1 M Na2SO4 were gradually added to the stirring silica, and then the DCA solution was slowly added. The mixture was stirred for 30 minutes to allow the added aqueous solution to adhere well to the silica. 1780 g of ethanol was placed in a 3 L beaker, and the silica loaded with deoxycholic acid was slowly added while stirring at 70 rpm. After the addition was complete, the mixture was stirred for a further 45 minutes to allow sufficient time for efflux. After stirring was complete, the mixture was filtered sequentially using a 1 μm paper filter and a 0.45 μm membrane filter. The filtered efflux was 1450 g, and was concentrated to 704 g by removing some of the ethanol using a rotary evaporator. 1640g of water was placed in a beaker, 30.3g of NaHCO3 was added, and then the aforementioned primary concentrate was added. This diluted solution was concentrated in a rotary evaporator for about 3 hours to obtain 112g of a colorless, transparent liquid. The concentration of this solution was 2.34%, and the pH was 9.22. The recovery rate of DCA during this process was 69%.

[0083] Examples 1-2. Preparation of molecular aggregates of deoxycholic acid (DCA) Prepare the DCA solution by adding 2.0g of deoxycholic acid (DCA) and 98.75g of ethanol to a 500mL beaker and stirring with a magnetic stirrer. Add 80g of ethanol to 8.2g of SYLOID 244 FP and thoroughly moisten the silica. Prepare 1.3mL of co-salt solution by mixing 1M NaHCO3 and 1M Na2SO4 aqueous solutions in a fixed ratio. Place a 1.00 μm paper filter in a Buchner funnel, moisten the paper filter with ethanol, and then use a pump to adsorb it to the bottom of the funnel. Gradually pour in the prepared moistened silica. When about 1cm of ethanol remains on top of the packed silica, gradually pour in the co-salt solution and 100g of purified water. Then, add another 100g of ethanol. After some of the ethanol has been filtered, stop the pump and replace the 1000ml filter bottle in the lower section. After restarting the pump, the prepared deoxycholic acid solution was slowly poured in, and an additional 202 g of ethanol was added. The resulting effluent was filtered using a 0.45 μm membrane filter to obtain 394.2 g of filtered filtrate. In another 2.0 L beaker, 920 g of a 4 mM NaHCO3 aqueous solution was prepared, and the filtered filtrate was gradually added to dilute it. This diluted liquid was concentrated using a rotary evaporator at 30°C and 180 rpm for 2 hours and 25 minutes. The final concentrated volume was 98.19 g, yielding 1.92% deoxycholic acid molecular aggregates with a particle size of 1.36 nm, a pH of 9.15, and a final recovery rate of 94.2%.

[0084] Examples 1-3. Molecular aggregates of sodium deoxycholate (NaDC) 18.0 g of sodium deoxycholate (NaDC, Sigma Aldrich #30970) was placed in a 1 L beaker and dissolved in 604 g of water using a magnetic bar. 60.5 g of Silica gel 60 (Merck) was placed in a 400 mL beaker containing 242 g of 0.1 M NaHCO3 and mixed with a spatula. The moistened silica was slowly packed into a vacuum filtration apparatus (pressure 200 mbar) equipped with a vacuum pump. The NaDC solution was added to the packed silica. Before the silica pad dried, 160 g of water was added in two 80 g increments. The total elution time was 1 hour. After elution was complete, the solution was filtered using a 0.45 μm membrane filter. The filtered eluate weighed 808 g. The concentration of this solution was 2.07%, and the pH was 7.67. The recovery rate of sodium deoxycholate during this process was 93%.

[0085] Example 2. Composition containing a molecular aggregate of deoxycholic acid Since Example 1 is in an aqueous solution state, it tends to run off when applied to the skin and may not be sufficiently delivered into the skin. Therefore, in order to produce a dosage form that can be applied transdermally, a gel-type dosage form was prepared by further adding 0.7% by weight of hyaluronic acid (HA) and 2% by weight of 1,2-hexanediol to 0.04% by weight and 0.08% by weight of the molecular aggregate from Example 1, respectively. The test results were confirmed by the confirmation of the destructive ability of adipose progenitor cells and differentiated adipocytes in Experimental Example 3 described later.

[0086] Comparative Example 1: Precursor of deoxycholic acid In Example 1, deoxycholic acid itself was used, without undergoing the process of passing through silica.

[0087] [Example of experiment] Experimental Example 1. Measurement of particle size of deoxycholic acid molecular aggregates Deoxycholic acid has a very low solubility in water (0.024%). To improve solubility and stabilize it in aqueous solution, in Example 1, deoxycholic acid was dissolved in ethanol, then water was added, and the ethanol was removed. This process of the present invention was used to produce a colorless, odorless, transparent liquid molecular aggregate of deoxycholic acid, in which the deoxycholic acid molecules form clusters. The particle size of the deoxycholic acid molecular aggregate was confirmed to be 1.6 nm through Zetasizer and TEM analysis.

[0088] Zetasizer analysis Using a Zetasizer (Malvern, Nano ZSP), the deoxycholic acid molecular aggregate from Example 1 was filtered through a 0.2 μm filter, and then measured 10 times under the conditions shown in Table 1 below. The average particle size of 1.6 nm was confirmed from the size distribution by volume (Figure 1). [Table 1]

[0089] TEM analysis A grid from EMS Corporation, specifically FCF300-Cu 50 / pk (Formvar / Carbon 300 Mesh, Copper), was placed on filter paper, and approximately 20 μl of the sample was dropped onto it using a micropipette. Negative staining was not performed, and the grid was allowed to dry for at least 15 minutes. The particle size of the deoxycholic acid molecular aggregates from Example 1 was measured using TEM imaging, and it was confirmed that the particle size was similar to that measured with a Zetasizer (Figure 2). [Table 2]

[0090] Experimental Example 2. Stability Test (1) Material To confirm the storage stability of the deoxycholic acid molecular aggregate to which the present invention is applied, 292g of DCA200265~67, which showed no change in physical properties, was prepared by the same method as in Example 1 and used as a sample for a 12-month stability test. [Table 3]

[0091] (1) Sample storage method SciLab, SL / Vi1361 5 mL serum vials were used to collect 1.7 mL of each sample. After placing each vial in a single vial, the storage cap was closed, and the vial and storage cap were secured using a capper. Parafilm was wrapped between the vial and storage cap and labeled (including substance name, batch number, and test date).

[0092] (2)Analysis method Properties I observed it with the naked eye. concentration For concentration analysis, HPLC analysis was performed as shown in Table 4 below, and the resulting calibration curve for deoxycholic acid is shown in Figure 3. [Table 4]

[0093] Particle size analysis The analysis was performed according to the analytical conditions and method of the Zetasizer in Example 1.

[0094] pH The deoxycholic acid molecular aggregate was filtered through a 0.45 μm filter and then measured using a Mettler Toledo S220.

[0095] (3) Results of the accelerated stability test Properties The liquid was colorless and transparent, and maintained the same properties for 12 months under accelerated conditions of 40±2℃ / 75±5%. concentration Table 5 below shows the changes in concentration under accelerated conditions for 12 months, and no significant changes in concentration were observed. Specifically, the changes in concentration were measured on a monthly basis for 12 months under accelerated conditions with a temperature of 40±2℃ / 75±5% and humidity, and the results are shown in Table 5 below. After calculating the difference between the initial (0 month) concentration and the subsequent concentration, the value divided by the initial concentration was calculated as the rate of change in concentration, and the average values ​​of these rate of change calculated for 3 months and 12 months, respectively, are shown in Table 5 below. [Table 5]

[0096] Particle size Table 6 below shows the change in particle size under accelerated conditions for 12 months, and there was no significant change in particle size. Specifically, the change in particle size under accelerated conditions with a temperature and humidity of 40±2℃ / 75±5% for 12 months was measured on a monthly basis, and the results are shown in Table 6 below. After calculating the difference between the initial (0 month) particle size and the subsequent particle size, the value divided by the initial particle size was calculated as the rate of change in particle size, and the average values ​​of these rate of change were calculated for 3 months and 12 months, respectively, and are shown in Table 6 below. [Table 6]

[0097] pH Table 7 below shows the pH change under 12-month accelerated conditions, demonstrating a stable pH without significant changes over time. Specifically, the pH change under accelerated conditions with a temperature and humidity of 40±2℃ / 75±5% for 12 months was measured on a monthly basis, and the results are shown in Table 7 below. After calculating the difference between the initial (0-month) pH value and the subsequent pH value, the value divided by the initial pH value was calculated as the pH change rate, and the average values ​​of these change rates calculated for 3 months and 12 months are shown in Table 7 below. [Table 7]

[0098] (4) Final results of the accelerated stability test The final results of the accelerated stability tests are summarized and shown in Table 8 below. [Table 8] As shown in Table 8, accelerated stability testing was conducted in three batches over a 12-month period, and no changes over time were observed in any of the test items, indicating stability.

[0099] Experimental Example 3. Confirmation of the ability to destroy adipose progenitor cells and differentiated adipocytes. (1) Test substance To compare the destructive power of adipose progenitor cells and differentiated adipocytes, deoxycholic acid, molecular aggregates of deoxycholic acid to which the present invention is applied (DCA2001JJ43, DCA2001JJ83-1), and molecular aggregates of deoxycholic acid salt (DCA2001JJ85-1) were used.

[0100] (2) Destructive ability of adipose-derived progenitor cells 3T3-L1 adipocytes were placed in a 96-well plate at a rate of 5 x 10⁶ cells per well. 396 cells were inoculated and grown in medium (high glucose DMEM, 10% bovine calf serum, 1% penicillin / streptomycin) for 16 hours. Then, preparations were made to contain the aforementioned drugs at concentrations of 0.04% and 0.08%, respectively, and treated for 4 hours. Dojingo CK04-11 cell counting kit-8 was added to each well in 10 μl increments according to the manual, and after reaction for 2 hours, The absorbance at 450 nm was measured using a spectrophotometer to compare the destructive ability of adipocyte precursor cells, which is shown in Figure 4.

[0101] As a result, at 0.04%, the destructive ability of the deoxycholic acid precursor, the deoxycholic acid molecular aggregate, and the deoxycholic acid molecular aggregate to deoxidative progenitor cells were the same. However, compared to the 24.6% precursor treated with 0.08%, the survival rate of adipocytes treated with the deoxycholic acid molecular aggregate decreased by 11.9% to 12.7% (*p=0.008), and the survival rate in the group treated with the deoxycholic acid molecular aggregate decreased by 13.8% to 10.8% (#p=0.01). This confirmed the increased destructive ability of the deoxycholic acid molecular aggregate to deoxidative progenitor cells when the technology of the present invention is applied.

[0102] (3) Destructive ability of adipocytes Following the Biovision 3T3 L1 differentiation kit manual, 3T3 L1 adipocyte progenitor cells were cultured in a culture dish under 100% confluence. After 6 days, the culture medium was replaced with differentiation maintenance medium, and adipocytes with numerous lipid droplets were induced (Figure 5). The adipocytes were treated with a 0.07% deoxycholic acid molecular aggregate (DCA2001JJ43), and 3D images were obtained at 2.5 frames per second using a Tomocube HT-2H microscope. Then, using the imaging software TomoStudio, the multi-point acquisition function was applied to capture changes in differentiated adipocytes at 25-second intervals for 40 minutes. As a result, it was confirmed that the cell membrane and intracellular structures of the adipocytes observed up to 5 minutes after acquisition rapidly thinned after 5 minutes, and at 8 minutes, the RI value around the lipid droplets was almost similar to that of the outside medium, confirming the destructive ability of differentiated adipocytes (Figure 6).

[0103] Experimental Example 4. Preclinical Trials (1) SD rat skin penetration experiment material Experiments were conducted to confirm the skin penetration and subcutaneous adipose tissue removal capabilities of deoxycholic acid molecular aggregates (DCA2002JJ84, produced by the method of Example 1) in SD rat mice.

[0104] Experimental method Ten-week-old SD rats (280-350g) with sufficient subcutaneous adipose tissue had their interscapular area (posterior neck area on the ear side) depilated and were anesthetized. Donor cells were attached to the depilated area with tape. 500 μl of the molecular aggregate of 2.5% deoxycholic acid (a precursor) and the deoxycholic acid of the present invention was applied to the donor cells, with 2.5% first, and then continuously applied to the skin for 3, 6, and 9 hours while the rats were under anesthesia. The distribution of deoxycholic acid in the subcutaneous tissue, skin, and plasma was checked to confirm skin permeability, and the destructive ability of the subcutaneous adipose cell layer was confirmed through tissue staining, as shown in the lower panel of Figure 7. A group of rats received subcutaneous injection of deoxycholic acid (1% DCA, 500 μl subcutaneous injection) as a positive control group.

[0105] Measurement results of DCA distribution in subcutaneous tissue When deoxycholic acid precursors and deoxycholic acid molecular aggregates were continuously applied to the skin of SD rats, the amount of deoxycholic acid permeated the skin increased over time in both groups, as confirmed by quantitative analysis of deoxycholic acid in the subcutaneous tissue. In the subcutaneous injection group, the amount of DCA in the subcutaneous tissue gradually decreased after subcutaneous injection, whereas in the skin application group, it increased over time, and the increase in permeability of the deoxycholic acid molecular aggregates was slightly greater than that of the deoxycholic acid precursor (Figure 7).

[0106] Measurement results of DCA distribution in the skin When deoxycholic acid precursors and molecular aggregates of deoxycholic acid were continuously applied to the skin of SD rats, both groups showed an increase in the distribution of deoxycholic acid in the skin over time. On the other hand, in the subcutaneous injection group, the distribution of deoxycholic acid in the skin tissue was highest after 6 hours, but after 9 hours it was lower than that of the skin application group (Figure 8).

[0107] Measurement results of the DCA distribution of plasma Figure 9 shows the DCA concentration in mouse plasma. DCA was detected in the plasma only in the group that received subcutaneous injection of deoxycholic acid, while no DCA was detected in the group that applied it to the skin. This confirms that deoxycholic acid molecules, which have a subcutaneous fat-removing effect when applied to the skin, do not transfer to the plasma and pose no safety concerns.

[0108] Results of histological analysis After subcutaneous injection of 1% deoxycholic acid (500 μL), subcutaneous application of 2.5% deoxycholic acid (500 μL), and continuous application of 2.5% deoxycholic acid molecular aggregate (500 μL) to sites where Franz cells were attached for 3, 6, and 9 hours, tissue (skin and subcutaneous tissue) from the intercapular sites was collected, fixed, and then subjected to H&E staining and Masson's trichome staining. Tissue changes were investigated through microscopic observation.

[0109] H&E staining revealed that the group receiving subcutaneous injection of deoxycholic acid showed significant tissue damage after injection. In the skin application group, a decrease in dermis white adipose tissue was observed over time, which was more clearly observed in the group receiving application of the deoxycholic acid molecular aggregate (Figure 10).

[0110] Masson's trichome staining was performed to observe the increase or decrease in collagen in the skin and subcutaneous tissue. The skin application group showed an increase in the area stained blue due to the destruction of adipocytes or an increase in collagen (Figure 11). In the deoxycholic acid subcutaneous injection group, hematoma and edema occurred in the tissue, resulting in severe tissue damage and tissue hardening during sectioning. In the 9-hour treatment group, adipose tissue hardening caused sectioning, making it impossible to obtain suitable tissue sections.

[0111] conclusion In the skin application group, the amount of deoxycholic acid distributed in the skin and subcutaneous tissue tended to increase over time, and the amount of deoxycholic acid distributed in the skin and subcutaneous tissue was higher in the deoxycholic acid molecular aggregate group compared to the deoxycholic acid precursor treatment group. Deoxycholic acid concentrations in plasma were detected only in the subcutaneous injection group, and in histological analysis, a decrease in adipose tissue in the tissue was observed over time after administration in the skin application group, and this phenomenon was more clearly shown in the group treated with the deoxycholic acid molecular aggregate. Based on the pharmacokinetic results, the amount of deoxycholic acid distributed in the subcutaneous tissue accumulated over time, and the histological analysis showed a decrease in dermis white adipose tissue in the skin, leading to the conclusion that the deoxycholic acid molecular aggregate effectively penetrated the skin and contributed to the reduction of adipose tissue.

[0112] (2) The effect of skin permeable lipolysis using an ob / ob obese mouse model. material A molecular aggregate of 2.52% deoxycholic acid was prepared using the same method as in Example 1 (DCA2103JJ134-02, 115 g, 95% recovery rate), and after dilution to 1.0% and 2.5%, it was formulated into dosage forms (1.0% SCAI-101, 2.5% SCAI-101) to evaluate its fat-reducing efficacy in ob / ob obese mice.

[0113] Experimental method Using an ob / ob obese mouse model, we attempted to confirm the fat-reducing effect of the deoxycholic acid molecular aggregates (1.0% SCAI-101, 2.5% SCAI-101) prepared in Example 1 after skin penetration. The fur on the back and abdomen (stomach) of ob / ob obese mice was removed, and 1 cm 2100 μL each of a solution (SCAI-101) containing molecular aggregates of 1.0% and 2.5% deoxycholic acid was applied to two locations on each side (four locations in total), twice daily, ensuring sufficient absorption. Weight changes, waist circumference, and abdominal fat volume obtained from micro-CT scans of the mouse abdomen were compared with a negative control group over four weeks, and skin permeability and lipolytic efficacy were confirmed as shown in Table 9. [Table 9]

[0114] Body weight change The body weight of the ob / ob obese control group increased steadily while consuming a normal diet, rising from 46.2±1.13g (week 0) to 51.1±0.89g (week 4) over four weeks. Compared to the control group's body weight at week 0, the increase was statistically significant at weeks 3 and 4 (p<0.01 and p<0.001, respectively). The 2.5% concentration application group also increased from 43.4±1.62g (week 0) to 48.3±1.49g (week 4), showing a statistically significant increase at week 4 compared to week 0 (p<0.05). However, the 1.0% concentration application group decreased from 42.1±2.14g (week 0) to 41.7±4.07g (week 4).

[0115] As shown in Table 10 and Figure 12 below, body weight was confirmed to have increased steadily in both the control group and the 2.5% application group. When comparing the body weight changes between the 1.0% and 2.5% application groups, no dose-dependent trend was observed. [Table 10]

[0116] Waist circumference and change in waist circumference Ob / ob ob-ob-treated mice were given the treatment twice daily for four weeks, and their waist circumference was measured. The waist circumference of the control group increased statistically significantly from week 0 to week 1, 2, 3, and 4 (all p<0.001). (Figure 13 and Table 11) [Table 11]

[0117] When a molecular aggregate of deoxycholic acid was applied, at a concentration of 1.0%, waist circumference increased slightly compared to week 0, showing a statistically significant increase at week 2 (p<0.001), but decreased from week 3 and remained similar to week 0 without a statistically significant increase until week 4. On the other hand, when compared with the control group's waist circumference at the same week after application, the 1.0% concentration application group was statistically significantly shorter at weeks 1, 2, 3, and 4 (all p<0.05) (Table 15). Consistent with this, the change in waist circumference (waist girth gain) was statistically significantly lower in the 1.0% concentration application group at weeks 1, 3, and 4 compared with the control group at the same week (all p<0.05) (Table 11). In the 2.5% concentration application group, waist circumference increased statistically significantly at week 3 compared to week 0 (p<0.01) (Table 11). However, the change in waist circumference (waist girth gain) was not statistically significant when compared to the control group, and this was judged to be a temporary result (Table 12). [Table 12]

[0118] Results of abdominal fat volume measurement using micro-CT scan The results of measuring fat volume around the waist (between lumbar vertebrae 3-5) of the lumbar region and abdomen, including the application site of the test substance, showed that the subcutaneous fat volume of the 1.0% and 2.5% concentration application groups was 2233.2±351.4 mm3 and 2589.7±93.4 mm3, respectively. Compared to the control group (2505.4±279.4 mm3), the difference was not statistically significant, and the percentage of subcutaneous fat volume was 89.1±14.03% and 103.4±3.73% of the control group, respectively. The subcutaneous fat volume of the 1.0% concentration application group was 10.9% lower on average than the control group, but no dose-dependent decreasing trend was observed compared to the 2.5% concentration application group. (Table 13) [Table 13]

[0119] Evaluation of the thickness of adipose tissue in the treated skin tissue. The thickness of adipocyte tissue in skin directly treated with the deoxycholic acid molecular aggregate (SCAI-101, DCA WP) prepared in Example 1 was measured after 4 weeks of application twice daily. The control group and the 1.0% and 2.5% concentration groups had thicknesses of 594.6±30.46 μm, 394.3±17.96 μm, and 492.4±11.42 μm, respectively. Both the 1.0% and 2.5% concentration groups showed a statistically significant decrease compared to the control group (all p<0.05). The percentage of adipose tissue thickness relative to the control group and the percentage of adipose tissue thickness (average) in the group treated with deoxycholic acid molecular aggregates were 66.0±2.94% (1.0% concentration group) and 82.6±1.87% (2.5% concentration group), respectively. A statistically significant reduction was observed only in the lower concentration group (1.0%) (p<0.05). It was confirmed that lipolysis and accumulation reduction were superior in the 1.0% concentration group compared to the 2.5% concentration group. (Figure 14 and Table 14) [Table 14]

[0120] conclusion After applying a 1.0% concentration solution (1.0% SCAI-101, DCA WP) twice daily for four weeks, statistically significant reductions were observed in waist circumference and fat cell thickness, confirming a pharmacological effect of reducing or breaking down skin fat after skin penetration. Unlike the generally known properties of deoxycholic acid, which makes skin penetration difficult, these results can be attributed to the pharmacological action of deoxycholic acid molecular aggregates that penetrated the skin after being directly applied.

[0121] Compared to the control group, the reductions in body weight, waist circumference, and subcutaneous fat volume are predicted to be due to the indirect effects of deoxycholic acid molecular aggregates that penetrated the skin, rather than their direct adipocyte-degrading action.

[0122] Therefore, the 1.0% concentration application group, which meets the conditions of the present invention, is judged to have the most appropriate concentration for skin-penetrating lipolysis. However, no dose-dependent trend was observed compared to the 2.5% concentration application group. Nevertheless, through further improvements in concentration and composition, it is possible to maximize the lipolysis effect of solutions containing molecular aggregates of deoxycholic acid.

Claims

1. A molecular aggregate formed by the physical bonding of bile acid molecules or bile salt molecules, When the molecular aggregate is formed from a composition containing water, In the above composition, the molecular aggregate has an aggregated structure, The aforementioned molecular aggregate is produced by applying shear stress to a bile acid molecule or a bile salt molecule. The average particle size of the molecular aggregate is 1.0 to 10 nm. Molecular association.

2. The molecular aggregate according to claim 1, wherein the molecular aggregate has a rate of change in concentration over 12 months greater than 1 and less than 10% under accelerated conditions of 40±2℃ / 75±5%.

3. The molecular aggregate according to claim 1, wherein the molecular aggregate has a particle size change rate of more than 1 and less than 10% over 12 months under accelerated conditions of 40±2℃ / 75±5%.

4. The molecular aggregate according to claim 1, wherein the rate of change in pH over 12 months under accelerated conditions of 40±2℃ / 75±5% is greater than 0 and less than 5%.

5. The molecular aggregate according to claim 1, wherein the bile acid is one of the group consisting of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid, and the bile salt is a salt of one of the group consisting of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid.

6. A pharmaceutical composition for local fat removal comprising the molecular aggregate of claim 1.

7. The composition is a pharmaceutical composition for local fat removal according to claim 6, which is used by applying it to the skin as a non-surgical, non-injection topical agent.

8. The pharmaceutical composition for topical fat removal according to claim 6, further comprising one or more selected from the group consisting of glycerin, chia seed oil, glucan, hyaluronic acid, honeysuckle extract, collagen, ceramide, lecithin, betaine, trehalose, panthenol, squalane, caprylic / capric triglyceride, butylene glycol, propanediol, pentylene glycol, sodium levulinate, hydrogenated lecithin, and sodium hyaluronate.

9. The pharmaceutical composition for local fat removal according to claim 6, comprising 0.05 to 10% by weight of the molecular aggregate.

10. The composition is a pharmaceutical composition for local fat removal according to any one of claims 6 to 8, characterized in that it is for treating a disease selected from the group consisting of obesity, fat redistribution syndrome, submental fat (a double chin formed by localized fat accumulation), lower eyelid fat herniation, lipoma, Dercum's disease, lipodystrophy, buffalo hump dystrophy, and combinations thereof.

11. A pharmaceutical composition for localized fat removal according to any one of claims 6 to 8, characterized in that the composition is localized to a site selected from the group consisting of fat in the abdomen and neck, fat in the inner thighs, fat in the upper arms, visceral fat accumulation, fat that has occurred after breast augmentation surgery, fat in the chest, fat that has spread around the arms, fat under the eyes, fat under the chin, fat in the buttocks, fat in the calves, fat in the back, fat in the thighs, fat in the ankles, cellulite, and combinations thereof.

12. The pharmaceutical composition for topical fat removal according to any one of claims 6 to 8, wherein the composition is used as one dosage form from the group consisting of a gel, cream, ointment, unguent, spray, thickened dosage form, and poultice.

13. The pharmaceutical composition for local fat removal according to any one of claims 6 to 8, wherein the concentration of bile acid measured in plasma 3 hours after application to the skin is 0.001 to 0.2 μg / ml.

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