Composition for localized fat reduction without pain, edema and side effects and method of administration thereof

Abstract

To provide a composition useful for reducing localized fat in a subject having localized fat deposits, without pain, edema, or side effects.SOLUTION: A composition for localized fat reduction with reduced pain and side effects, comprising: (i) phosphatidylcholine; and (ii) at least one selected from a group consisting of glycocholic acid (GCA), taurocholic acid (TCA), and salts thereof, wherein (i) and (ii) have a molar ratio of (ii) / (i) of 0.7 to 3.0, and wherein the composition is administered to an affected area of a subject at intervals of less than 4 weeks at a concentration of 25 to 50 mg / ml. The composition according to the present invention provides a safe and stable formulation, is highly effective in reducing fat cells without various side effects, and can maximize its effects by being administered to the affected area at shorter intervals.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to a composition useful for reducing local fat in a subject having localized fat deposits using phosphatidylcholine without pain, edema and side effects, and a method of administering the same. More specifically, it comprises (i) phosphatidylcholine; and (ii) at least one selected from the group consisting of glycolic acid (GCA), taurocholic acid (TCA) and salts thereof, wherein (i) and (ii) have a molar ratio of (ii) / (i) of 0.7 to 3.0. A composition for reducing local fat with reduced pain and side effects, wherein the composition is administered to the affected area of the subject at a concentration of 25 to 50 mg / mL and administered at intervals of less than 4 weeks.

Background Art

[0002] Localized fat deposits are of particular concern to many people. People with unnecessary convex or bulging fat on the face or part of the body may not be aesthetically attractive and may look older. Such causes may be due to aging, lifestyle or genetic factors, and although exercise therapy and dietary therapy are attempted to improve this, the fat-reducing effect is limited.

[0003] As methods for reducing locally deposited fat, there are cosmetic surgical procedures and cosmetic minimally-invasive procedures. However, surgical methods take a long time to heal, and specific individuals such as smokers and diabetics may experience a significant delay in healing. They also involve potential complications and risks such as fatal side effects, the danger of general anesthesia, excessive bleeding, internal organ damage, bacterial infection, scars, birthmarks, swelling, and pain. Cosmetic minimally-invasive procedures have potential hazards in that their stability and effectiveness have not been ensured due to the absence of large-scale clinical trials. Therefore, there is a need to develop new pharmaceuticals that are clinically beneficial for local fat reduction.

[0004] Injectable drugs for localized fat reduction, as preparations that induce adipocyte reduction by injecting drugs into the subcutaneous fat layer, typically include PPC (Polyene Phosphatidylcholine) injection. The conventionally known PPC injection is an injection that uses DCA (deoxycholic acid) as a solubilizing agent, and its fat-reducing pharmacological active ingredient is known as DCA. These injections of DCA alone or PPC solubilized with DCA dissolve not only adipocytes (3T3L1 adipocytes) non-selectively but also normal fibroblasts, endothelial cells, and skeletal muscle cells. Therefore, they are cell-lysing injections rather than lipolytic injections (Non-Patent Document 1).

[0005] Therefore, the present inventors confirmed that a PPC-alone composition without added DCA induces apoptosis rather than necrosis in adipocytes, only reduces adipocytes, and does not affect fibroblast reduction (Non-Patent Document 2). Based on this, through additional research, they found that a composition produced by adding taurocholic acid (TCA), particularly glycochenodeoxycholic acid (GCA), to phosphatidylcholine (PPC) at a specific mixing ratio is safe, not only has excellent formulation stability, but also causes fat reduction without pain, swelling, and side effects, and thus completed the invention (Patent Document 1).

[0006] On the other hand, in the treatment using a DCA-alone or PPC injection solubilized with DCA, multiple administrations are performed. However, local adverse events such as inflammation, accompanied by swelling, pain, erythema, and hematoma occur at the affected area during administration, and it takes 4 weeks for the symptoms to disappear. Therefore, it has been reported that as a general treatment method, injections should be given at intervals of at least 4 weeks or more between each administration (Non-Patent Documents 3, 4, 5, and 6).

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0009] The inventor has conducted further research on a composition prepared by adding the above-mentioned taurocholic acid (TCA), particularly glycochenodeoxycholic acid (GCA), to phosphatidylcholine (PPC) at a specific mixing ratio. As a result, it has been confirmed that the injection composition can maximize its effect and improve patient convenience by administering it at a shorter interval rather than at an interval of four weeks or more as known, and thus the present invention has been completed.

[0010] Accordingly, the present invention provides a composition for reducing local fat, which contains i) phosphatidylcholine; and ii) at least one selected from the group consisting of glycochenodeoxycholic acid (GCA), taurocholic acid (TCA), and salts thereof, wherein the molar ratio of ii) / i) is 0.7 to 3.0, and the composition is administered to the affected part of the subject at a concentration of 25 to 50 mg / mL and at an interval of less than four weeks.

Means for Solving the Problems

[0011] To achieve the above object, the present invention provides a composition for local fat reduction with reduced pain and side effects, comprising: i) phosphatidylcholine; and ii) at least one selected from the group consisting of glycolic acid (GCA), taurocholic acid (TCA), and salts thereof, wherein the molar ratio of ii) / i) is 0.7 to 3.0, and the composition is administered at a concentration of 25 to 50 mg / mL to the affected area of a subject at intervals of less than 4 weeks.

[0012] The present invention will be described in detail below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0013] The inventors divided and administered a test drug (AYP-101) according to the present invention, which is phosphatidylcholine (PPC) solubilized with glycolic acid (GCA), into test group 1 (AYP-101 25 mg / mL, 0.2 mL / Point), test group 2 (AYP-101 50 mg / mL, 0.2 mL / Point), test group 3 (AYP-101 50 mg / mL, 0.4 mL / Point), and a control group (AYP-101 0 mg / mL, 0.2 mL / Point), which were administered at 4-week intervals; and test group 1 (AYP-101 25 mg / mL), test group 2 (AYP-101 50 mg / mL), and a control group (placebo of AYP-101), which were administered at 2-week intervals, and confirmed the effects.

[0014] As a result, in the case of the test groups administered at 4-week intervals, for the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and the Patient-Reported Submental Fat Rating Scale (PR-SMFRS), which are the primary evaluation variables, the subjects whose evaluations improved by one grade or more at the 12th week after the final administration compared to the baseline value were 42.31% (11 / 26) in Test Group 1, 46.15% (12 / 26) in Test Group 2, and 40.00% (12 / 30) in Test Group 3. Compared with 10.71% (3 / 28) in the control group, it was confirmed that all test groups were superior to the control group. In the case of the test groups administered at 2-week intervals, for the Estimator-Reported Submental Fat Rating Scale (ER-SMFRS) and the Subject-Reported Submental Fat Rating Scale (SR-SMFRS), which are the weekly evaluation variables, the subjects whose evaluations improved by one grade or more at the 4th week after the final administration compared to the baseline value were 69.70% (23 / 33) in Test Group 1, 48.39% (15 / 31) in Test Group 2, and 22.58% (7 / 31) in the control group. It was confirmed that both Test Group 1 and Test Group 2 had the effect of reducing submental fat compared to the control group. That is, when administered at 2-week intervals compared to when administered at 4-week intervals at a dose of 25 mg / mL, the effect was significant.

[0015] Therefore, the present invention provides a composition for local fat reduction with reduced pain and side effects, comprising (i) phosphatidylcholine; and (ii) at least one selected from the group consisting of glycolic acid (GCA), taurocholic acid (TCA), and their salts, wherein the molar ratio of (ii) / (i) is 0.7 to 3.0, and the composition is administered to the affected part of the subject at a concentration of 25 to 50 mg / mL at intervals of less than 4 weeks.

[0016] For a more detailed description of the composition according to the present invention, that is, the composition according to the present invention which is PPC solubilized with GCA, reference can be made to the prior art Korean Registered Patent No. 10-1887586, and the entire document is incorporated herein by reference as a reference of the present invention.

[0017] As long as the composition according to the invention is used for the purpose of reducing fat (especially local fat reduction), its formulation is not particularly limited, but includes, for example, injectables such as patches, subcutaneous depots, etc., and preferably can be a composition of an injectable formulation (injectable). That is, the present invention relates to a composition that can be directly injected into the treatment site of a patient who requires fat removal without surgery.

[0018] The composition of the present invention can be administered by a method suitable for the patient or subject, from the viewpoints of, but not limited to, the severity of the disease, the age, sex and other conditions of the patient, etc. Such a route is not particularly limited in the method, but can be directly administered to the subcutaneous fat layer (tissue), and can be administered by subcutaneous injection or intradermal injection.

[0019] The subcutaneous injection or intradermal injection is preferably administered multiple times to the same affected area. Between each administration, an interval of at least one week and less than four weeks, preferably at least one week and at most three weeks, more preferably at least one week and at most two weeks, and most preferably an interval of two weeks can be set for administration, but it is not limited thereto. When the subcutaneous injection or intradermal injection is administered multiple times, the total number of administrations can be 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, and preferably can be 4 to 8 times, but it is not limited thereto. That is, according to known compositions and their administration methods, the total treatment / duration required for treatment can be extended from at least four weeks (when administered twice) to a maximum of 40 weeks (when administered 10 times), and usually 16 to 32 weeks (when administered 4 to 8 times) are required. However, according to the composition and its administration method of the present invention, it is sufficient from a minimum of two weeks (when administered twice) to a maximum of 20 weeks (when administered 10 times), and the treatment / duration can usually be completed in 8 to 16 weeks (when administered 4 to 8 times). On the other hand, when administered once, the injection composition according to the present invention is preferably administered at a concentration of 25 to 50 mg / mL.

[0020] The composition according to the present invention can be administered by setting a plurality of target sites (i.e., injection points or points) at regular intervals for the affected area when administered once. The terms "target site", "injection point" or "point" mean exactly the point where one injection is performed for the affected area, and in this specification, the terms are used interchangeably in combination.

[0021] At this time, the interval may be a grid interval of 0.5 to 2.0 cm, preferably 0.7 to 1.3 cm, and most preferably 1.0 cm. The number of target sites (injection points or points) can be appropriately determined by an ordinary technician considering various conditions described above.

[0022] The amount administered to each of the target sites (injection points) can be 0.1 to 0.5 mL, preferably 0.2 to 0.4 mL, and most preferably 0.2 mL per each target site (injection point or point). Therefore, considering all these conditions, the composition according to the present invention is such that phosphatidylcholine can be administered at 2.5 mg to 25 mg, preferably 5 mg to 20 mg, and most preferably 5 mg to 10 mg per 1.0 cm of the target site (injection point or point) for the affected area. 2 Although not limited thereto.

[0023] In addition, although not limited thereto, the composition of the present invention can be administered at various levels (depths) under the skin, for example, including 0.1 to 4 inches, 0.5 to 3 inches, and 1 to 2 inches under the skin.

[0024] The composition for reducing fat according to the present invention can be applied to local sites, and although the sites are not limited thereto, preferably, they can be applied and / or administered to the fat deposited in the eyelid, under the eyes, submandibular, back, arms, legs, brassiere line, flanks, abdomen, buttocks, thighs, and calves, and to lipoma sites.

[0025] The composition for local fat reduction according to the present invention is a pharmaceutical composition for treating adipose tissue hyperplasia or overaccumulation disorder (disease). As long as the disorder is known in the art to be one in which adipose tissue hyperplasia or overaccumulation pathologically occurs, the type thereof is not particularly limited. For example, it includes obesity (such as abdominal obesity), lower eyelid ptosis, lipoma, Dercum’s disease, Madelung’s neck, adipose edema, piezogenic nodules, xanthelasma, lipodystrophy, or fat accumulation related to cellulite.

[0026] The injection is prepared by dissolving the active ingredient (PPC solubilized with GCA in the present invention) and, if necessary, other additives in water for injection, filtering this solution through a bacterial filter for sterilization, and then filling it into vials, ampoules, or prefilled syringes in a sterile state and sealing it. When manufacturing the injection, in order to fill the remaining volume, water for injection other than water can be used. The water for injection is not particularly limited as long as it is distilled water for injection or a buffer solution for injection prepared for dissolving solid injections or diluting water-soluble injections. For example, a phosphate buffer solution or a sodium dihydrogen phosphate (NaH2PO4)-citric acid buffer solution in the pH range of 3.5 to 7.5 can be used. The phosphate used at this time may be in the form of a sodium salt or a potassium salt, or in the form of an anhydride or a hydrate, and citric acid may also be in the form of an anhydride or a hydrate. Examples of the water for injection include, but are not limited to, glucose injection, xylitol injection, D-mannitol injection, fructose injection, physiological saline, dextran 40 injection, dextran 70 injection, amino acid injection, Ringer's solution, and lactated Ringer's solution.

[0027] The following description relates to the composition according to the present invention (i.e., PPC solubilized with GCA) itself. More detailed content is described in the prior art Korean Registered Patent No. 10-1887586.

[0028] The term "phosphatidylcholine" in the present invention refers to a phospholipid and means a compound represented by the IUPAC name 1,2-diacyl-sn-glycero-3-phosphocholine, which is described as PPC in this specification.

[0029] As used herein, the term "bile acid" includes steroid acids (and / or their carboxylic acid anions) and their salts, and as found in the bile of animals (e.g., humans), "deoxycholic acid" is a type of bile inflammation, and the IUPAC name (4R)-4-[(3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid means the compound represented by. In the specification of the present invention, it is described as DCA.

[0030] "Glycocholic acid" is a type of bile inflammation, and the IUPAC name 2-[[((4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]acetic acid means the compound represented by. In this specification, it is described as GCA.

[0031] "Taurocholic acid" is a type of bile inflammation, and the IUPAC name 2-[[(4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonic acid means the compound represented by. In this specification, it is described as TCA.

[0032] In the present invention, the phosphatidylcholine is a phospholipid widely present in animals, plants, yeasts, and fungi, also known as lecithin, polyene phosphatidylcholine, 3-sn-phosphatidylcholine, and has a basic structure as shown in the following Chemical Formula 1. It is mainly contained in mammalian membrane spherical phospholipids such as brain marrow, nerves, blood cells, and egg yolk. In plants, it is contained in soybeans, sunflower seeds, wheat germ, etc., and is rarely found in bacteria. Generally, a saturated fatty acid is often bonded to the 1st position of glycerol, and an unsaturated fatty acid is often bonded to the 2nd position, and most of the acyl groups are C12 - C22 (12 to 22 carbon atoms). [Chem.]

[0033] The phosphatidylcholine of the present invention has a structure as shown in Chemical Formula 1, where R1 is a saturated or unsaturated fatty acid having 12 to 22 carbon atoms, and R2 can be a saturated or unsaturated fatty acid having 12 to 22 carbon atoms. The saturated or unsaturated fatty acids can take a straight-chain or branched-chain form, and the unsaturated fatty acid can contain single unsaturation or multiple (e.g., double, triple, or quadruple, etc.) unsaturations. The phosphatidylcholine of the present invention may be a single compound, or may be a mixture of a plurality of compounds with various carbon numbers of R1 and R2 acyl groups. Preferably, the phosphatidylcholine of the present invention can have a molecular weight of 700 g / mol to 1000 g / mol, and more preferably a molecular weight of 750 g / mol to 800 g / mol.

[0034] The phosphatidylcholine of the present invention can be extracted and used from any one selected from the group consisting of various animals or plants, such as soybeans, sunflower seeds, wheat germ, and egg yolk. Alternatively, the phosphatidylcholine of the present invention can be purchased and used commercially available ones, or those produced by chemical synthesis methods known in the art can be used.

[0035] The phosphatidylcholine of the present invention can preferably be isolated from soybean or egg yolk. The typical structure of phosphatidylcholine generally isolated from soybean is as shown in Chemical Formula 2 below. Also, the typical structure of phosphatidylcholine generally derived from egg yolk is as shown in Chemical Formula 3 below. The phosphatidylcholine used in the present invention may be a single compound consisting only of the compound of Formula 2 or Formula 3 below, or may be a mixture further incorporated with a plurality of compounds having various carbon numbers of the R1 and R2 acyl groups based on the following Chemical Formula 1 as the basic structure. In the mixture, the compound of Formula 2 or Formula 3 below may be substantially contained in the mixture at 50% by weight or more, more preferably 70% by weight or more, and most preferably 90% by weight or more. [Chemical formula] [Chemical formula]

[0036] Most preferably, the phosphatidylcholine of the present invention may be extracted from soybean, or may be a mixture containing a compound having a structure like Chemical Formula 2 above at a ratio of 93.0% by weight or more.

[0037] In the injectable composition for local fat reduction of the present invention, the phosphatidylcholine is characterized by containing 0.625 to 15.0% (w / v) based on the whole composition, and may preferably contain 1.25 to 12.5% (w / v), and more preferably may be contained at 2.5 to 10.0 (w / v)% in the whole composition. Most preferably, the phosphatidylcholine may be contained at 2.5 to 7.5% (w / v) based on the whole composition. When the concentration of phosphatidylcholine is less than 0.625% (w / v), there is no fat decomposition effect, and when it exceeds 15% (w / v), due to the high viscosity, multiple administrations to the subcutaneous fat layer are inconvenient and an excessive amount of solubilizer is required, resulting in the manifestation of moderately adverse events of inflammatory reactions and severe occurrence of side effects such as pain, swelling, and inflammation.

[0038] The composition for local fat reduction of the present invention is characterized by containing any one or more selected from the group consisting of glycolic acid, taurocholic acid, and their salts (hereinafter abbreviated as (ii)) / phosphatidylcholine (PPC, hereinafter abbreviated as (i)) in a molar ratio of 0.7 to 3.0. In other words, the molar ratio of (ii) / (i) can be 0.7 to 3.0, more preferably the molar ratio of (ii) / (i) can be 0.7 to 2.60, and most preferably it can be composed of a molar ratio of 0.7 to 1.73. When contained in a molar ratio (mol / mol) of less than 0.7, it is difficult to form stable micelles and the formulation safety decreases. Therefore, the lower limit value of the molar ratio is preferably 0.70 or more, and a more preferable lower limit value can be 0.76. When contained in a molar ratio of 3.04 or more as the upper limit value, the inflammation is at least mild, the edema is at least moderate, and the skin lesions are at least severe, and pain, edema, and side effects appear significantly. It will be accompanied by cell necrosis rather than giving a positive effect on the apoptosis and lipolysis effects inherent to PPC, and will limit the inherent functions of PPC. At a molar ratio of 3.0 or less, these side effects and pain are significantly reduced. Especially when contained in a molar ratio of 2.60 or less, swelling, lesions, and inflammation are identified as absent or mild, although clinically weak edema may be seen, but this corresponds to a level with substantially no pain and side effects, so it is adopted in a more preferable range in the present invention. Most preferably, when contained in a molar ratio of 1.73 or less, clinical pain and edema due to swelling, lesions, and inflammation do not occur.

[0039] Specifically, the composition for local fat reduction of the present invention is characterized by containing "glycocholic acid or its salt" in a specific mixing ratio in the composition. The glycocholic acid, as a bile salt, has a molecular weight of about 465.63 g / mol and can be described as GCA or GC in this specification. Glycocholic acid can be used in the form of a pharmaceutically acceptable salt. From the above, "pharmaceutically acceptable" means physiologically acceptable and does not usually cause an allergic reaction or a similar reaction when administered to humans, and is not limited thereto, and can be, for example, a sodium salt, a potassium salt, or an ammonium salt. Preferably, the glycocholate of the present invention can be sodium glycocholate (Sodium Glycocholate, GCNa).

[0040] The above glycocholic acid or its salt can be extracted from the intestine of an animal and used according to a method known in the art, can be commercially purchased and used, or can be used a product manufactured by a chemical synthesis method known in the art.

[0041] More specifically, as the minimum formulation composition for producing a transparent solution capable of microfiltration with a micelle (mixed micelle) formulation of 10 nm or less that can be stably and safely subcutaneously injected, the minimum molar ratio of GCA / PPC is 0.76 (PPC 5.0% + GCA 2.2%). At a molar ratio less than the above minimum molar ratio, the stability of the formulation is low due to precipitation. Therefore, the glycocholic acid or its salt may preferably be contained such that the GCA / PPC molar ratio is 0.76 to 3.0 (GCA 2.2 to 8.65% (w / v) based on PPC 5%), and for the specific range, refer to the above molar ratio content. When glycocholic acid is used in its salt form, it is preferable to calculate the molar ratio based only on the glycocholic acid portion of the glycocholate.

[0042] The composition for local fat reduction of the present invention is characterized by containing "taurocholic acid or its salt" in a specific blending ratio in the composition. Taurocholic acid, as a bile salt, has a molecular weight of about 515.71 g / mol and can be referred to as TCA in this specification. Taurocholic acid can be used in the form of a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable" means physiologically acceptable and does not normally cause an allergic reaction or a similar reaction when administered to humans, and includes, but is not limited to, for example, sodium salts, potassium salts, or ammonium salts. Preferably, the taurocholate of the present invention can be sodium taurocholate (TCNa).

[0043] The above-mentioned taurocholic acid or its salt can be extracted from the intestines of animals according to methods known in the art for use, purchased commercially for use, or those produced by chemical synthesis methods known in the art can be used.

[0044] More specifically, for producing a transparent solution that can be microfiltered in a 10 nm or less micelle (mixed micelle) formulation that can be stably and safely subcutaneously injected, the minimum blending composition, the minimum molar ratio of TCA / PPC is 0.78 (PPC 5% + TCA 2.5%). At a molar ratio less than the above minimum molar ratio, the stability of the formulation is low due to precipitation. Therefore, the glycolic acid or its salt may preferably be contained such that the TCA / PPC molar ratio is 0.78 to 3.0 (TCA 2.5 to 9.57% (w / v) based on PPC 5%). For specific ranges and preferred examples, etc., refer to the content of the above-mentioned molar ratio. When using taurocholic acid in the form of its salt, the molar ratio can preferably be calculated based only on the taurocholic acid portion of the taurocholate.

[0045] The above-mentioned GCA, TCA or their salts, when included in the fat-reducing injection composition of the present invention at a specific dosage (or compounding ratio, molar ratio) as described above, not only have excellent formulation stability, but also the solubilizers (especially deoxycholate and its salt types) contained in existing PPC injection compositions cause cell necrosis, accompanied by pain and edema in the body, and are different from causing side effects such as hematoma, anesthesia, erythema, swelling, sclerosis, itching, nodules, etc. Instead, together with PPC, it induces highly efficient lipolysis and adipocyte death (apoptosis) effects, and the pain and the above-mentioned side effects are substantially reduced to such an extent that it can be said that there are almost no side effects. It is characterized by showing excellent effects in fat reduction (pain and edema are reduced by more than 80%, and erythema, hematoma, sclerosis, itching, nodules other than bruises caused by injection needles are also reduced by more than 80%). Accordingly, it is also a feature that an anti-inflammatory agent or / and an analgesic component for separate pain management do not necessarily need to be contained in the composition or used in combination.

[0046] On the other hand, the composition of the present invention can further contain one or more selected from the group consisting of preservatives; isotonic agents; pH adjusters.

[0047] Specifically, the composition for local fat reduction of the present invention preferably further contains one or more substances selected from the group consisting of a preservative of 0.1 to 5% (w / v), an isotonic agent of 0.1 to 10% (w / v), and a pH adjuster of 0.01 to 2% (w / v) based on the total composition.

[0048] The preservative is not limited thereto, and can be selected from the group consisting of benzyl alcohol, lidocaine, procaine, and chlorobutanol. More preferably, it can be benzyl alcohol. The benzyl alcohol is one of the aromatic alcohols and is a colorless transparent liquid. The concentration of benzyl alcohol contained in the injection composition of the present invention is preferably 0.1% (w / v) to 2% (w / v).

[0049] When the isotonic agent is administered into the body with the composition of the present invention containing phosphatidylcholine, it plays a role in appropriately maintaining (regulating) the osmotic pressure, and also shows an additional effect of further stabilizing phosphatidylcholine on the solution. The isotonic agent can be a pharmaceutically acceptable sugar, salt, or any combination or mixture thereof. Examples thereof include glucose as a sugar, or water-soluble inorganic salts such as sodium chloride, calcium chloride, sodium sulfate, glycerin, propylene glycol, polyethylene glycol having a molecular weight of 1000 or less, etc., and more preferably sodium chloride. These can be used in one or a combination of two or more forms. The concentration of the isotonic agent is preferably 0.1% (w / v) to 5% (w / v), and the solution preparation containing all the respective mixtures can be adjusted to an appropriate content so as to become an isotonic solution according to the types, amounts, etc. of the components contained in the composition of the present invention.

[0050] The pH adjuster of the present invention plays a role in adjusting the pH of an injection and contains both acidic substances and basic substances. The acidic substances include, but are not limited to, hydrochloric acid, acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ethyloxyacetate, malic acid, succinic acid, stannic acid, fumaric acid, citric acid, etc. The basic substances include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite), organic bases (e.g., basic amino acids such as lysine, arginine, etc., meglumine, etc.), etc., but are not limited to these. In the present invention, the pH adjuster may contain the acidic substance and the basic substance separately in the composition, or two or more kinds of each substance may be used in combination. More preferably, the pH adjuster of the present invention can be sodium hydroxide or / and hydrochloric acid. The amount of the pH adjuster added can be changed according to the types and amounts of the components constituting the composition of the present invention, and preferably can be 0.01% (w / v) to 1.32% (w / v), more preferably 0.01% (w / v) to 1% (w / v). The composition of the present invention can preferably be provided in the range of pH 6.5 to pH 8.5. Therefore, those skilled in the art can change the conditions according to the specific composition of the solution for the type and addition amount of the pH adjuster.

[0051] In the present invention, the term "side effect" means the side effects of a PPC preparation containing a specific cholangitis that is already known or commercially available, particularly a PPC injection solubilized with DCA (for example, Lipostabil, Essential, Lipovin) that is already known as an existing injection for local fat reduction or a DCA single agent (for example, Kybera), which means an adverse effect on the body in addition to the main effect (the intended fat reduction effect in the present invention) that the drug is expected to have a therapeutic effect. Specifically, but not limited thereto, it means any one or more selected from the group consisting of edema, anesthesia (particularly anesthesia at the administration site), extensive swelling, erythema, hematoma, blister, sclerosis, paresthesia, nodule, itching, burning sensation, dysphagia, necrosis of cells other than adipocytes (such as muscle cells, fibroblasts, vascular endothelial cells), etc., except for hematoma and blister caused by the injection needle. The injection composition for local fat reduction of the present invention is characterized in that local adverse events are reduced and the side effects are reduced to such an extent that it can be said that there are substantially no side effects.

[0052] In this specification, the term "pain and side effects are reduced" includes all meanings such as pain and side effects being decreased, removed, weakened (partially removed), substantially eliminated (substantially removed), completely eliminated (completely removed), etc.

[0053] Terms such as "patient", "subject", "individual", etc. are used interchangeably in this specification and refer to any animal, or its cells, that can conform to the methods described in this specification (such as in vitro or in situ). In certain non-limiting embodiments, the patient, subject or individual is a human.

[0054] As used herein, the terms "composition" or "pharmaceutical composition" can mean a mixture of at least one compound or composition used in the present invention and any additional carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients and other chemical components. The pharmaceutical composition facilitates the administration of the compound to a living being.

[0055] As used herein, the terms "effective amount", "pharmaceutically effective amount", and "therapeutically effective amount" refer to an amount that is non-toxic yet sufficient to produce the desired biological result. The result can be a decrease and / or alleviation of a sign, symptom, or cause of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be determined by a person of ordinary skill using routine experimentation.

[0056] As used herein, the term "efficacy" can mean the maximum effect (Emax) achieved within an assay method.

[0057] "Local administration" means administering a pharmaceutical component to or in the vicinity of a patient's muscle or subdermal location by a non-systemic route. Thus, local administration excludes administration via systemic routes such as intravenous or oral administration.

[0058] "Therapeutic" treatment is treatment administered to a subject exhibiting a pathological sign or symptom for the purpose of reducing or eliminating the sign or symptom.

[0059] As used herein, the terms "treatment" or "treating" are defined as applying or administering to a patient a therapeutic agent, i.e., the composition of the present invention (alone or in combination with other pharmaceutical agents), to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, a symptom of a condition contemplated herein, or the likelihood of progression to a condition contemplated herein, where the conditions contemplated herein may include symptoms of a condition contemplated herein or the likelihood of progression to a condition contemplated herein. The treatment can be specifically adjusted or modified based on knowledge obtained from the field of pharmacology.

[0060] Ranges: Throughout this disclosure, various aspects of the invention can be presented in range format. The description of range values herein is to be considered as including the recited boundary values, i.e., all values from the lower limit value or more to the upper limit value or less, unless otherwise specifically stated. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, a range description should be considered to specifically disclose not only the individual numerical values within that range, but also all possible subranges. For example, a range description such as 1 - 6 should be considered to specifically disclose the individual numerical values within the above range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6, as well as subranges such as 1 - 3, 1 - 4, 1 - 5, 2 - 4, 2 - 6, 3 - 6, etc. This applies regardless of the width of the range.

[0061] The "%" used for indicating the composition content in the present invention means the w / v% content unless otherwise specified, and means the w / v% value based on the total composition unless otherwise specified.

[0062] In the present invention, the " / " mark in the description of "selected from the group consisting of glycolic acid or taurocholic acid and their salts, or one or more thereof / phosphatidylcholine" is the display of a fraction in the commonly used format.

Advantages of the Invention

[0063] The injectable composition for local fat reduction of the present invention containing taurocholic acid or glycolic acid (or its salt) and phosphatidylcholine (PPC) in a specific mixing ratio has a safe and stable formulation, has no various side effects, is excellent in the effect of reducing adipocytes, and can maximize the effect by administering at shorter intervals to the affected area.

Brief Description of the Drawings

[0064]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0065] Hereinafter, the present invention will be described in detail. However, the following examples illustrate the present invention, and the content of the present invention is not limited to the following examples.

Examples

[0066] Example 1. Preparation of the Test Drug AYP-101 was manufactured by dissolving 25.0 mg or 50.0 mg of PPC (phosphatidylcholine) in 1 mL with GCA (glycolic acid), and adding 9 mg (0.9%) of benzyl alcohol. The specific manufacturing process is as follows. Injectable water was put into a washed and sterilized preparation tank (at room temperature), and sodium hydroxide (0.04 - 0.72%) was put into the injectable water. Then, glycolic acid (GCA), benzyl alcohol, and sodium chloride were added, stirred, and dissolved. Then phosphatidylcholine was added, and it was stirred at 200 RPM under light-shielded, sealed, room temperature (25°C), and nitrogen pressure conditions. After the stirring was completed, the pH was adjusted (if necessary, with additional 0.001 - 0.04% sodium hydroxide or 0.001 - 0.6% hydrochloric acid), filtered through a 0.2 μm filter, and then filled and sealed in vials.

[0067] Example 2. Clinical Trial - Determination of Optimal Dosage (Dosing Interval: 4 Weeks) 2-1. Objectives of Clinical Trials Using the test drug (AYP-101) manufactured in Example 1 above, after administering the test drug and the control drug (placebo of AYP-101) for the non-surgical appearance improvement of patients with moderate and severe prominent or excessive submental fat in adults, the optimal dosage of the test drug was determined, and its safety and efficacy were evaluated.

[0068] For this purpose, the clinician (independent evaluator) and the subject evaluated the improvement degree of submental fat, and for the dose groups at 12 weeks after the final administration of the investigational drug compared to the baseline, both the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and the Patient-Reported Submental Fat Rating Scale (PR-SMFRS) reported by the clinician were confirmed to determine whether the proportion of those with an improvement of one grade or more was superior to the improvement rate of the control group. In this study, it was designed with Test Group 1 (AYP-101, 25 mg / mL, 0.2 mL / Point), Test Group 2 (AYP-101, 50 mg / mL, 0.2 mL / Point), Test Group 3 (AYP-101, 50 mg / mL, 0.4 mL / Point), and Control (AYP-101, 0 mg / mL, 0.2 mL / Point).

[0069] 2-2. Clinical Trial Plan This clinical trial was conducted as a multi-center, randomized, double-blind, placebo-controlled clinical trial. When subjects who met the selection and exclusion criteria agreed in writing to participate in the clinical trial, after performing the necessary medical examinations and tests according to the clinical trial protocol, randomization was performed only on those subjects whose subject eligibility assessment results met the selection criteria. The randomized subjects were assigned (1:1:1:1) to any of Test Group 1, Test Group 2, Test Group 3, and the control group, and the investigational drug for the clinical trial was administered at 4-week intervals at 50 points (injection points) at 1-cm grid stripe intervals, up to 6 times. The overall schedule of this clinical trial was as shown in Figure 1.

[0070] 2-3. Demographic Information and Other Baseline Characteristics This clinical trial was conducted at a total of 4 institutions in South Korea. A total of 219 subjects underwent screening tests after providing written consent, and 65.30% (143 / 219 subjects) of them were randomized. 37 subjects were assigned to Test Group 1 (AYP-101, 25 mg / mL, 0.2 mL / Point), 34 subjects to Test Group 2 (AYP-101, 50 mg / mL, 0.2 mL / Point), 35 subjects to Test Group 3 (AYP-101, 50 mg / mL, 0.4 mL / Point), and 37 subjects to the control group (AYP-101, 0 mg / mL, 0.2 mL / Point). Among the subjects assigned to each group, 75.68% (28 / 37 subjects), 85.29% (29 / 34 subjects), 85.71% (30 / 35 subjects), and 75.68% (28 / 37 subjects) completed the trial.

[0071]

Table 1

[0072] 2-4. Efficacy Evaluation Results The primary evaluation variable was analyzed for 110 subjects in the FAS (Full Analysis Set). For both the CR-SMFRS and PR-SMFRS at 12 weeks after the final dose compared to the baseline value, which was the primary evaluation variable, the proportions of subjects with an improvement of at least one grade were 42.31% (11 / 26 subjects) in Test Group 1, 46.15% (12 / 26 subjects) in Test Group 2, 40.00% (12 / 30 subjects) in Test Group 3, and compared to 10.71% (3 / 28 subjects) in the control group. Statistical significance was confirmed in all test groups (P = 0.0081, P = 0.0037, P = 0.0109). This means that the test drug AYP-101 is effective in reducing submandibular fat.

[0073]

Table 2

[0074] In the secondary evaluation variable analysis conducted to obtain further clinical research information, it was confirmed that the proportion of subjects with an improvement of at least one grade in the CR-SMFRS at 12 weeks after the final dose was statistically significant in all test groups compared to the control group.

[0075] [Table 3]

[0076] In this clinical trial, it was confirmed that the submental fat reduction effect of all doses of AYP-101 groups was superior to that of the control group. 2 than 5 or 10 mg / cm 2 It was confirmed that a higher concentration may be more effective, but a higher concentration does not guarantee a better effect on improving submandibular fat, and the maximum severity of pain and some adverse events or adverse drug events tended to be slightly higher at 20 mg / cm 2 was not considered to be the optimal dose.

[0077] 2-5. Medication Compliance Evaluation Results In the 4-week dosing interval study of AYP-101, medication compliance averaged 99.0% or higher in all AYP-101 and control groups, with no significant differences observed for both study subjects and those who terminated the study early. There were no statistically significant differences in the number of clinical trial drug administrations and total number of administrations between groups. The total dose (mL) and total dose (mg) of clinical trial drug varied between groups depending on the dose and AYP-101 SPC concentration.

[0078] [Table 4]

[0079] 2-6. Safety Evaluation Results The incidence rates of adverse cases and local drug adverse events were 100.00% in all test groups and the control group. The incidence rate of systemic adverse cases was 5.41% (2 / 37 cases, 2 cases) in Test Group 1, 6.06% (2 / 33 cases, 2 cases) in Test Group 2, 17.14% (6 / 35 cases, 8 cases) in Test Group 3, and 5.41% (2 / 37 cases, 2 cases) in the control group. The incidence rates of systemic adverse cases in each group showed no statistically significant difference (P = 0.2754). The incidence rate of systemic drug adverse cases was 2.86% (1 / 35 cases, 1 case) in Test Group 3, and no systemic drug adverse cases occurred in Test Group 1, Test Group 2, and the control group. The incidence rates of systemic adverse cases in each group showed no statistically significant difference (P = 0.4789). The incidence rates of other adverse cases were 29.73% (11 / 37 cases, 23 cases) in Test Group 1, 36.36% (12 / 33 cases, 21 cases) in Test Group 2, and 45.71% (16 / 35 cases, 34 cases) in Test Group 3. The incidence rate of other adverse cases in the control group was 32.43% (12 / 37 cases, 22 cases). The incidence rates of other adverse cases in each group showed no statistically significant difference (P = 0.5177). The incidence rate of other drug adverse cases was 6.06% (2 / 33 cases, 2 cases) in Test Group 2, 8.57% (3 / 35 cases, 4 cases) in Test Group 3, and no other drug adverse reactions occurred in Test Group 1. The incidence rate of other drug adverse reactions in the control group was 2.70% (1 / 37 cases, 1 case). The incidence rates of other drug adverse reactions in each group showed no statistically significant difference (P = 0.2396). The incidence rate of other serious adverse cases was 2.70% (1 / 37 cases, 1 case) in Test Group 1, and no other serious adverse cases occurred in Test Group 2 and Test Group 3. The incidence rate of other serious adverse cases in the control group was 2.70% (1 / 37 cases, 1 case). The incidence rates of other significant adverse cases in each group showed no statistically significant difference (P = 1.0000). In this clinical trial, no local serious adverse cases, local serious drug adverse reactions, trial termination due to local adverse cases, systemic serious drug adverse reactions, trial termination due to systemic adverse cases, other serious drug adverse reactions, and trial termination due to other adverse events occurred.

[0080] The occurrence status of adverse cases is shown in Table 5, and the number of occurrences by adverse case investigation item is shown in Table 6. All local adverse cases: In the 37 subjects in Test Group 1, the incidence rate of local adverse cases was 100.00% (37 / 37 subjects, 1,190 cases). Looking in detail, in order were "pain" 100.00% (37 / 37 subjects, 183 cases), "local edema" 91.89% (34 / 37 subjects, 147 cases), "skin retraction" 81.08% (30 / 37 subjects, 129 cases), etc. In the 33 subjects in Test Group 2, the incidence rate of local adverse cases was 100.00% (33 / 33 subjects, 1,035 cases). Looking in detail, in order were "pain" and "local edema" each 100.00% (33 / 33 subjects, 172 cases, 130 cases), "hematoma" 87.88% (29 / 33 subjects, 86 cases), "heat sensation" 81.82% (27 / 33 subjects, 106 cases), etc. In the 35 subjects in Test Group 3, the incidence rate of local adverse cases was 100.00% (35 / 35 subjects, 1,204 cases). Looking in detail, in order were "pain" 100.00% (35 / 35 subjects, 185 cases), "skin retraction" 97.14% (34 / 35 subjects, 134 cases), "local edema" 94.29% (33 / 35 subjects, 147 cases), etc. In the 37 subjects in the control group, the incidence rate of local adverse cases was 100.00% (37 / 37 subjects, 820 cases). Looking at the details, in order were "pain" 94.59% (35 / 37 subjects, 144 cases), "local edema" 72.97% (27 / 37 subjects, 107 cases), "hematoma" 67.57% (25 / 37 subjects, 80 cases), etc. The phenomenon of the occurrence of local adverse cases was classified into five categories of "+1 day", "+3 days", "+5 days", "+7 days", and "+10 days" according to the duration. As a result, there was no significant difference in the incidence rate of adverse cases, but as the duration increased, the number of adverse cases showed a tendency to decrease.

[0081] As a result of analyzing the severity of all local drug adverse reactions except pain, it was 1.02 ± 0.14 points in Test Group 1, 1.07 ± 0.27 points in Test Group 2, and 1.09 ± 0.31 points in Test Group 3. As a result of analyzing the severity of all local drug adverse reactions except pain in the control group, it was 1.10 ± 0.31 points. There was a statistically significant difference between the control group and Test Group 1 (P < 0.0001), but no statistically significant difference was found between the control group and Test Group 2 or Test Group 3 (P = 0.0088, 0.1777). As a result of analyzing the maximum severity among all local drug adverse reactions except pain, in Test Group 1, it was "mild" at 67.57% (25 / 37 cases), "moderate" at 29.73% (11 / 37 cases) in that order, and no local drug adverse reaction corresponding to "severe" occurred. In Test Group 2, it was "mild" at 51.52% (17 / 33 cases), "moderate" at 45.45% (15 / 33 cases), "severe" at 3.03% (1 / 33 cases) in that order. In Test Group 3, it was "mild" at 48.57% (17 / 35 cases), "moderate" at 37.14% (13 / 35 cases), "severe" at 14.29% (5 / 35 cases) in that order. As a result of analyzing the incidence rate of local drug adverse reactions by severity in the control group, it was "mild" at 59.46% (22 / 37 cases), "severe" at 24.32% (9 / 37 cases), "moderate" at 5.41% (2 / 37 cases) in that order.

[0082] There were 37 cases of systemic adverse reactions in Test Group 1, and the incidence rate of systemic adverse reactions was 5.41% (2 / 37 cases, 2 cases). Looking in detail, it was "upper respiratory tract infection" and "influenza" each at 2.70% (1 / 37 cases, 1 case each). There were 33 cases in Test Group 2, and the incidence rate of systemic adverse reactions was 6.06% (2 / 33 cases, 2 cases). Looking in detail, it was "non-pharyngitis" and "influenza" each at 3.03% (1 / 33 cases, 1 case each). There were 35 cases in Test Group 3, and the incidence rate of systemic adverse reactions was 17.17% (6 / 35 cases, 8 cases). Looking in detail, it was "influenza" at 5.71% (2 / 35 cases, 2 cases), and "headache", "non-pharyngitis", "upper respiratory tract infection", etc. were each at 2.86% (1 / 35 cases, 3 cases, 1 case, 1 case) in that order. There were 37 cases in the control group, and the incidence rate of systemic adverse reactions was 5.41% (2 / 37 cases, 2 cases). Looking in detail, it was "upper respiratory tract infection" at 5.41% (2 / 37 cases, 2 cases).

[0083] In the case of drug adverse reactions, no drug adverse reactions occurred in 37 subjects in Test Group 1. The incidence of drug adverse reactions in 33 subjects in Test Group 2 was 6.06% (2 / 33 subjects, 2 cases). After classifying drug adverse reactions into "SOC" and "PT", the incidence of "Dermal cyst" in "Disorders of the skin and subcutaneous tissue" and "Blood creatine phosphokinase increased" in "Investigations" was 3.03% (1 / 33 subjects, 1 case each). The incidence of drug adverse reactions in 35 subjects in Test Group 3 was 8.57% (3 / 35 subjects, 4 cases). After classifying drug adverse reactions into SOC, the order was 5.71% (2 / 35 subjects, 2 cases) in "Disorders of the skin and subcutaneous tissue", 2.86% (1 / 35 subjects, 1 case each) in "Gastrointestinal disorders" and "Nervous system disorders". After classifying by PT, the order was 2.86% (1 / 35 subjects, 1 case each) for "Erythema", "Pigmentation disorders", "Vomiting", etc. The incidence of drug adverse reactions in 37 subjects in the control group was 2.70% (1 / 37 subjects, 1 case). After classifying drug adverse reactions into "SOC" and "PT", the incidence of "Rash" in "Disorders of the skin and subcutaneous tissue" was 2.70% (1 / 37 subjects, 1 case).

[0084] In the case of serious adverse cases, the incidence of serious adverse cases in 37 subjects in Test Group 1 was 2.70% (1 / 37 subjects, 1 case). After classifying serious adverse cases into "SOC" and "PT", the incidence of "Fracture of hand" in "Injuries, poisoning, complications of medical care" was 2.70% (1 / 37 subjects, 1 case). Serious adverse cases did not occur in 33 subjects in Test Group 2 and 35 subjects in Test Group 3. The incidence of serious adverse cases in 37 subjects in the control group was 2.70% (1 / 37 subjects, 1 case). After classifying serious adverse cases into "SOC" and "PT", the incidence of "Meningitis" in "Infectious and parasitic diseases" was 2.70% (1 / 37 subjects, 1 case).

[0085] In the clinical laboratory tests, the number of clinically significant individual abnormal values was 71 cases among 27 subjects. There were 17 cases among 7 subjects in Test Group 1, 12 cases among 6 subjects in Test Group 2, 15 cases among 7 subjects in Test Group 3, and 27 cases among 7 subjects in the control group. When examining the clinically significant (CS) abnormal values in detail, in Test Group 1, the order was 6 cases of "ALT", 4 cases each of "AST" and "creatine kinase", and 1 case each of "CRP", "r-GT", and "TG"; in Test Group 2, the order was 5 cases of "creatine kinase", 3 cases of "TG", and 2 cases each of "ALT" and "r-GT"; in Test Group 3, the order was 3 cases of "ALT", 2 cases each of "CRP", "ESR", "glucose", etc., and 1 case each of "AST", "HbA1c", "r-GT", etc. When examining the clinically significant abnormal values (CSR) in the control group in detail, the order was 8 cases of "TG", 6 cases each of "ALT" and "r-GT", 2 cases each of "AST" and "uric acid", etc.

[0086]

Table 5

[0087]

Table 6

[0088] * Abandonment of institutional visits due to deterioration of meningitis %: n / (number of subjects in the safety test for each group) × 100 n (%): The number of subjects is tabulated separately for each item with duplication. Incidence rate %: (number of occurrences of each item / number of occurrences in each group) × 100 Degree: Mild (1), Moderate (2), Severe (3), excluding pain in local adverse cases

[0089] Example 3. Clinical Trial - Determination of Administration Interval 3-1. Objectives of Clinical Trials Using the test drug (AYP-101) manufactured in Example 1 above, the administration interval and optimal dose were determined after administering the test drug and the control drug (placebo of AYP-101) at 2-week intervals to patients with moderate and severe prominent or excessive submandibular fat in adults for non-surgical appearance improvement, and the safety and efficacy were to be evaluated.

[0090] For this purpose, by having the researchers and subjects participating in the clinical trial evaluate, it was confirmed that for the test groups by dose at the 4th week after the final administration of the investigational drug relative to the baseline value, the Estimator-Reported Submental Fat Rating Scale (ER-SMFRS) and the Subject-Reported Submental Fat Rating Scale (SR-SMFRS) reported by the evaluators, the ratio of improvement in all grades of 1 or above was superior to the ratio of improvement in the control group.

[0091] 3-2. Clinical Trial Plan When subjects who met the selection and exclusion criteria agreed in writing to participate in the clinical trial, after performing the necessary physical examinations and tests according to the clinical trial protocol, randomization was performed only on subjects whose subject eligibility evaluation results met the selection criteria. The randomized subjects were assigned to either test group 1 (AYP-101 25 mg / mL), test group 2 (AYP-101 50 mg / mL), or the control group (placebo of AYP-101) (1:1:1), and the investigational drug for the clinical trial was administered at intervals of 2 weeks at intervals of 1 cm grid stripes up to a maximum of 50 points and up to 6 times. The overall schedule of this clinical trial was as shown in Figure 2.

[0092] 3-3. Demographic and Other Baseline Characteristics The average age (full age) of the subjects included in SS was 38.82 ± 10.96 years in the test group 1, 41.03 ± 8.97 years in the test group 2, and 42.63 ± 11.16 years in the control group. There was no statistically significant difference between each test group and the control group (test group 1 vs. control group p = 0.1700, test group 2 vs. control group p = 0.5354). In terms of gender, in the test group 1, 21.21% (7 / 33) were male and 78.79% (26 / 33) were female; in the test group 2, 19.35% (6 / 31) were male and 80.65% (25 / 31) were female; in the control group, 21.88% (7 / 32) were male and 78.13% (25 / 32) were female. There was no statistically significant difference between each test group and the control group (test group 1 vs. control group p = 0.9482, test group 2 vs. control group p = 0.8048). The average weight was 65.93 ± 13.18 kg in the test group 1, 66.31 ± 12.06 kg in the test group 2, and 66.26 ± 14.42 kg in the control group. There was no statistically significant difference between each test group and the control group (test group 1 vs. control group p = 0.7133, test group 2 vs. control group p = 0.8961). The average BMI was 24.22 ± 3.59 kg / m 2 in the test group 2, 24.74 ± 3.63 kg / m 2 and 24.50 ± 4.05 kg / m in the control group 2 . There was no statistically significant difference between each test group and the control group (test group 1 vs. control group p = 0.7748, test group 2 vs. control group p = 0.8040).

[0093]

Table 7

[0094] 3-4. Efficacy Evaluation Results In the evaluation of the ratio of subjects in the FAS (Full Analysis Set), which is the main analysis group, whose ER-SMFRS and SR-SMFRS both improved by one grade or more four weeks after the final dose compared to the baseline value, which is the main evaluation variable, the results were 69.70% (23 / 33 subjects) in Test Group 1, 48.39% (15 / 31 subjects) in Test Group 2, and 22.58% (7 / 31 subjects) in the control group. Both Test Group 1 and Test Group 2 showed an effect of reducing submental fat compared to the control group. The statistical significance by multiple testing set in this study was shown to be significant with p = 0.0002 in Test Group 1, and it was confirmed that the optimal dose was Test Group 1 (AYP-101 25 mg / mL) when AYP-101 was administered at two-week intervals.

[0095]

Table 8

[0096] Regarding the ratio of subjects in whom the submental fat reported by clinicians and patients improved by one grade or more, the results of Example 2 above (see Table 2) with an administration interval of 4 weeks and the results of Example 3 (see Table 8) are compared and shown in Figure 3.

[0097] In the analysis of the ratio of subjects in whom both ER-SMFRS and SR-SMFRS at 12 weeks after the final dose improved by one grade or more compared to the baseline value, which is a secondary evaluation variable implemented to obtain additional clinical research information, a statistically significant submental fat reduction effect was confirmed in the control group compared to Test Group 1 at 12 weeks, and it was confirmed that the submental fat improvement effect was maintained at 4 weeks and 12 weeks after the final dose.

[0098] Also, the ratio of subjects in whom the ER-SMFRS compared to the baseline value improved by one grade or more was 69.70% (23 / 33 subjects) in Test Group 1, 54.84% (17 / 31 subjects) in Test Group 2, 25.81% (8 / 31 subjects) in the control group at 4 weeks after the final dose, and 72.73% (24 / 33 subjects) in Test Group 1, 58.06% (18 / 31 subjects) in Test Group 2, 25.81% (8 / 31 subjects) in the control group at 12 weeks. A statistically significant submental fat reduction effect was confirmed in all dose test groups compared to the control group.

[0099]

Table 9

[0100] In addition, the ratio of subjects with an improvement of the basal value ratio SR-SMFRS by one grade or more was 75.76% (25 / 33) in Test Group 1, 54.84% (17 / 31) in Test Group 2, and 29.03% (9 / 31) in the control group at the 4th week after the final dose, and 66.67% (22 / 33) in Test Group 1, 48.39% (15 / 31) in Test Group 2, and 25.81% (8 / 31) in the control group at the 12th week. A statistically significant effect of submental fat reduction was confirmed in the comparison between the control group and Test Group 1.

[0101]

Table 10

[0102] 3-5. Medication Compliance Evaluation Results In the 2-week dosing interval study of AYP-101, the compliance was only 1 subject (1.04%) in the control group for "when the drug compliance is less than 67% (when the total number of doses is less than 4 times)". There was no statistically significant difference in the average number of doses, average number of dosing points, and average dose of the total clinical trial drug between each test group and the control group (see Table 11).

[0103]

Table 11

[0104] T: Two test drugs, t-test / W: Wilcoxon rank sum test / NA: No information p-value [b]: Test between treatment groups

[0105] 3-6. Safety Evaluation Results In the 2-week dosing interval test of AYP-101, the incidence of adverse cases was 100.00% (33 / 33 subjects, 532 cases) in test group 1, 96.77% (30 / 31 subjects, 538 cases) in test group 2, and 62.50% (20 / 32 subjects, 180 cases) in the control group, showing a statistically significant difference between each test group and the control group (test group 1 vs. control group, p<0.0001; test group 2 vs. control group, p=0.0008). The incidence of local adverse cases was 100.00% (33 / 33 subjects, 525 cases) in test group 1, 96.77% (30 / 31 subjects, 529 cases) in test group 2, and 50.00% (16 / 32 subjects, 172 cases) in the control group, showing a statistically significant difference between each test group and the control group (each p<0.0001). The incidence of systemic adverse cases was 3.03% (1 / 33 subject, 1 case) in test group 1, 9.68% (3 / 31 subjects, 3 cases) in test group 2, and 6.25% (2 / 32 subjects, 2 cases) in the control group, and there was no statistically significant difference between each test group and the control group (test group 1 vs. control group, p=0.6132; test group 2 vs. control group, p=0.6719). The incidence of other adverse cases was 18.18% (6 / 33 subjects, 6 cases) in test group 1, 16.13% (5 / 31 subjects, 6 cases) in test group 2, and 18.75% (6 / 32 subjects, 6 cases) in the control group, and there was no statistically significant difference between each test group and the control group (test group 1 vs. control group, p=0.9529; test group 2 vs. control group, p=0.7841).

[0106] The incidence of drug adverse reactions was 100.00% (33 / 33 subjects, 525 cases) in test group 1, 96.77% (30 / 31 subjects, 532 cases) in test group 2, and 50.00% (16 / 32 subjects, 172 cases) in the control group, showing a statistically significant difference between each test group and the control group (each p<0.0001). The incidence of local drug adverse reactions was 100.00% (33 / 33 subjects, 525 cases) in test group 1, 96.77% (30 / 31 subjects, 529 cases) in test group 2, and 50.00% (16 / 32 subjects, 172 cases) in the control group, showing a statistically significant difference between each test group and the control group (each p<0.0001). Systemic drug adverse reactions and other drug adverse reactions were not reported in test group 1 and the control group, and occurred in 6.45% (2 / 31 subjects, 2 cases) and 3.23% (1 / 31 subject, 1 case) respectively in test group 2, and there was no statistically significant difference between test group 2 and the control group (systemic drug adverse reaction, p=0.2381; other drug adverse reaction, p=0.4921).

[0107] Serious adverse cases, serious local adverse cases, serious systemic adverse cases, serious other adverse cases, serious drug adverse reactions, serious local drug adverse reactions, serious systemic drug adverse reactions, and serious other drug adverse reactions have not been reported in all groups. The occurrence status of adverse cases is shown in Table 12, and the occurrence status of local drug adverse reactions by investigation item is shown in Table 13.

[0108]

Table 12

[0109] Values are "number of subjects (%), [number of cases]" 95% CI: 95% normal approximation confidence interval C: Chi-square test / F: Fisher's exact probability test / NA: No information p-value [b]: Test between treatment groups

[0110]

Table 13

[0111] Values are "number of subjects (%), [number of cases (%)]" [Number of cases (%)] = (Number of local drug adverse reaction occurrences for the corresponding item / Number of overall adverse case occurrences for the corresponding item) * 100 95% CI: 95% normal approximation confidence interval C: Chi-square test / F: Fisher's exact probability test / T: Two-sample t-test for the two test drugs / W: Wilcoxon rank-sum test / NA: No information p-value [b]: Test between treatment groups (Note) Severity: Mild (1), Moderate (2), Severe (3) Duration (days) = Date of disappearance of adverse case - Date of onset + 1

Industrial Applicability

[0112] The injectable composition for local fat reduction of the present invention containing taurocholic acid or glycocholic acid (or a salt thereof) and phosphatidylcholine (PPC) in a specific mixing ratio has a safe and stable formulation, is excellent in the effect of reducing fat cells without various side effects, and can maximize its effect by administering it at shorter intervals to the affected area, and has high industrial applicability.

Claims

**Claim 1** (i) phosphatidylcholine; and (ii) at least one selected from the group consisting of glycolic acid (GCA), taurocholic acid (TCA), and salts thereof, and wherein (i) and (ii) are characterized in that the molar ratio of (ii) / (i) is 0.7 to 3.0, and it is a composition for local fat reduction with reduced pain and side effects, wherein the composition is administered to the affected part of the subject at a concentration of 25 to 50 mg / mL and at intervals of less than 4 weeks, a composition for local fat reduction. **Claim 2** The composition for local fat reduction according to claim 1, wherein the composition is administered at intervals of 3 weeks or less. **Claim 3** The composition for local fat reduction according to claim 1, wherein the composition is administered at intervals of 2 weeks or less. **Claim 4** The composition for local fat reduction according to claim 1, wherein the composition is administered a total of 2 to 10 times. **Claim 5** The composition for local fat reduction according to claim 1, wherein the composition is administered to 1 to 50 target sites at a grid interval of 0.5 to 2.0 cm at the time of one administration. **Claim 6** The composition for local fat reduction according to claim 5, wherein the composition is administered at 0.1 to 0.5 mL per target site. **Claim 7** The composition for local fat reduction according to claim 5, wherein 2.5 mg to 25 mg of phosphatidylcholine is administered per target site. **Claim 8** The composition for local fat reduction according to claim 5, wherein 5 mg to 10 mg of phosphatidylcholine is administered per target site. **Claim 9** The composition for local fat reduction according to claim 1, wherein the composition is administered to any one or more sites selected from the group consisting of the eyelid, under the eyes, under the chin, back, arms, legs, brassiere line, flanks, abdomen, buttocks, thighs, and calves.

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