KR20210095115A - Subcutaneous injection composition containing deoxycholic acid for hypotonic lipolysis and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a composition for subcutaneous injection, containing deoxycholic acid, and a manufacturing method thereof. The present invention relates to the composition for non-surgical removal of localized fat deposits, wherein the composition is microparticles which comprise deoxycholic acid and a biodegradable polymer, and are formed such that deoxycholic acid is evenly distributed in a spherical biodegradable polymer. According to the present invention, a lipolysis effect lasts for 1 to 3 months from a single injection, a phenomenon in which surrounding tissues are destroyed during administration is prevented, and a drug release effect can be maintained at an effective amount of adipolysis concentration.

Description

Composition for subcutaneous injection containing deoxycholic acid and method for preparing the same

The present invention relates to a composition for subcutaneous injection containing deoxycholic acid and a method for preparing the same. More specifically, it relates to a composition for subcutaneous injection containing deoxycholic acid, which is microparticles containing deoxycholic acid, which exhibits a long-lasting lipolytic effect with a single administration, and a method for preparing the same.

Liposuction, also known as lipoplasty, liposculpture suction lipectomy, or simply lipo, is a cosmetic surgical operation that removes fat from many different parts of the body. Surgical sites range from the abdomen, thighs and buttocks to the neck and back of the arm.

The amount of fat that can be safely removed in one operation is limited by several factors. There are downsides to getting rid of too much fat. Abnormal lumpiness and/or dents in the skin may be observed in "over-suctioned" patients. The greater the amount of fat removed, the higher the risk of surgery.

Injection lipolysis is a cosmetic procedure in which a mixture of drugs is injected into a patient for the purpose of destroying fat cells. This procedure, which generally uses phosphatidylcholine (PPC) and deoxycholate (DCA)-based drugs, originated from the initial intravenous use of the drug formulation to treat blood diseases.

PPCs are phospholipids into which choline is introduced as a head group. It is a major component of biological membranes and can be readily obtained from a variety of readily available sources such as egg yolk or soybeans, from which PPC is mechanically or chemically extracted using hexane. PPC prevents fat accumulation and is used to treat liver failure induced by fatty liver, myocardial ischemia, cerebrovascular disease, and dementia. In addition, PPC has recently been introduced for lipolysis for the treatment of obesity in the United States, Europe, and other countries around the world.

DCA is one of the secondary bile salts that are metabolic byproducts of intestinal bacteria. DCA has been used in various fields of human medicine since its discovery, and is publicly used in combination with PPC in lipolytic injection. DCA has been used to improve the solubility of drugs such as PPC and, more recently, amphotericin B, taxol, and diazepam. The highly purified PPC can be rapidly sterilized in combination with DCA, an antimicrobial agent, benzyl alcohol, and water to form a stable, mixed micelle formulation that can be used for intravenous administration.

Recently, US-based Kythera Biopharmaceuticals is developing a lipolytic injection using DCA that does not contain PPC. Based on the fact that PPC functions as an emulsifier in DCA and is used in the treatment of hyperlipidemia, PPC has been regarded as an active ingredient in lipolytic injections. In these prior art compositions, a surfactant such as DCA was simply added to disperse or dissolve the PPC considered active ingredient. In practice, however, it has been found that DCA is an active ingredient in localized fat emulsification.

Since DCA is one of the strong surfactants in the bile salt series, administration of DCA causes destruction of surrounding tissues from the injection site. This is a problem caused by injecting high-concentration injections to break down fat.

Accordingly, it is necessary to develop a composition capable of maintaining the lipolytic effect for a long period of time and preventing side effects upon exposure to a high concentration drug by the initial injection administration.

(Patent Document 1) KR 10-2007-0110351 A1

It is an object of the present invention to provide a composition for subcutaneous injection containing deoxycholic acid and a method for preparing the same.

Another object of the present invention is to provide a composition for subcutaneous injection containing deoxycholic acid, which maintains a lipolytic effect for 1 to 3 months through a single injection, and a method for preparing the same.

Another object of the present invention is to provide a composition for subcutaneous injection containing deoxycholic acid, which prevents the destruction of surrounding tissues upon administration, and maintains the drug release effect at an effective amount of a fat-dissolving concentration, and a method for preparing the same.

In order to achieve the above object, the composition for subcutaneous injection containing deoxycholic acid according to an embodiment of the present invention is a composition for non-surgically removing localized fat deposits, and the composition is It includes micro-particles containing oxycholic acid and a biodegradable polymer, wherein the micro-particles are spherical particles and have a plurality of pores formed therein, and the internal pores may include deoxycholic acid. .

The micro particles are a W ₁ (Water)/O(Oil)/W ₂ (Water) double emulsion.

The deoxycholic acid may be included in the form of deoxycholic acid or a pharmaceutically acceptable salt thereof.

The average diameter of the microparticles is 30 to 70 μm.

The micro-particles continuously release deoxycholic acid for 1 to 3 months, thereby maintaining the lipolytic effect.

The biodegradable polymer is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoesters, polycaprolactones, polyhydroxyvalates, polyhydroxybutyrates, polyamino acids, and combinations thereof.

The localized fat accumulation may be selected from the group consisting of lower eyelid fat herniation, lipomas, lipodystrophy, fat deposits associated with cellulite, and combinations thereof. .

The fat deposition is localized to a site of the subject selected from the group consisting of under the eyes, under the chin, under the arms, buttocks, calves, back, thighs, ankles, stomach, and combinations thereof.

A lipolysis injection formulation according to another embodiment of the present invention includes the composition.

A method for preparing a composition for subcutaneous injection containing deoxycholic acid according to another embodiment of the present invention comprises the steps of: 1) dissolving deoxycholic acid in water to prepare a first mixture; 2) preparing a second mixture by dissolving the biodegradable polymer in an organic solvent; 3) injecting the first mixture of step 1) into the microchannel in a straight direction to flow; 4) The second mixture of step 2) is injected into the microchannels formed on both sides or one side so that the first mixture of step 3) can form an intersection with the straight-flowing microchannels to flow, 1 The linear flow of the mixture and the flow of the second mixture intersect to prepare a _{W 1} /O emulsion in which an aqueous solution of deoxycholic acid is distributed in a spherical biodegradable polymer organic solvent; 5) dissolving the surfactant in water to prepare a third mixture; 6) The third mixture of step 5) _{is injected into microchannels formed on both sides or one side so that the W 1} /O emulsion of step 4) can form an intersection point with the microchannel flowing in a straight direction, The linear flow of the W ₁ /O emulsion and the flow of the third mixture intersect to prepare a _{spherical W 1} /O/W _{2 double emulsion;} 7) collecting the _{W 1} /O/W ₂ double emulsion produced at the intersection of step 6); _{8) stirring the W 1} /O/W ₂ double emulsion collected in step 7), and removing the organic solvent present in the double emulsion by evaporating; and 9) _{washing and drying the micro particles prepared by the W 1} /O/W ₂ double emulsion in step 8), wherein the average particle diameter of the micro particles is 30 to 70 μm.

The second mixture may further include a surfactant.

Hereinafter, the present invention will be described in more detail.

The composition for subcutaneous injection according to an embodiment of the present invention is a composition for non-surgical removal of localized fat deposits, wherein the composition comprises deoxycholic acid and a biodegradable polymer. It includes micro-particles, wherein the micro-particles are spherical particles with a plurality of pores formed therein, and the internal pores include deoxycholic acid.

In order to solve the problem of localized fat accumulation in animals by providing a non-surgical method for reducing fat deposition, the present invention prepares micro-particles using a biodegradable polymer, wherein a plurality of pores in the micro-particles are is formed, and deoxycholic acid is located in the pores.

That is, the micro-particles are not observed in a smooth form on the outside, but a number of pores are formed inside, and the pores are filled with deoxycholic acid, partially filled, or included to the extent that they are slightly buried. can

The present invention relates to the use of bile acids or salts thereof for reducing fat in an animal, preferably a mammal, more preferably a human. In one embodiment, the bile acid or a salt thereof is included in the form of deoxycholic acid or a pharmaceutically acceptable salt thereof.

The deoxycholic acid or its salt is (4R)-4-((3R,5R,10S,12S,13R,17R)-3,12-dihydroxy-10 having an alkali metal or ammonium ion as a cation; Refers to pharmaceutically acceptable salts of 13-dimethylhexadecahydro-1H-cyclic penta[a]phenanthren-17-yl)pentanoate.

The present invention is provided as a composition for subcutaneous injection in order to reduce subcutaneous fat accumulation in mammals by topically administering a pharmaceutically acceptable agent to a target site, wherein micro particles are included in the composition for subcutaneous injection, The microparticles themselves are administered topically at the target site. The microparticles are composed of a biodegradable polymer, a plurality of pores are formed therein, deoxycholic acid is distributed in the pores, and as the biodegradable polymer of the microparticles is decomposed in subcutaneous fat, deoxycholine It has the effect of releasing the acid to the target site.

The present invention relates to a composition that uses deoxycholic acid, which is known to dissolve fat cells related to cellulite and extra fat deposition, and can sustain a lipolytic effect for 1 to 3 months with a single injection.

More specifically, the composition for decomposition of fat of the present invention includes deoxycholic acid or a pharmaceutically acceptable salt thereof, and the deoxycholic acid is not used alone, and microparticles are use in the form

That is, when the microparticles are prepared using the biodegradable polymer, deoxycholic acid or a pharmaceutically acceptable salt thereof is included in the internal pores of the prepared microparticles to be deoxycholic acid or a pharmaceutically acceptable salt thereof. It is characterized in that possible salts are distributed.

The biodegradable polymer is a polymer that can be decomposed in the body, and the decomposed polymer is not harmful to the human body. Therefore, the micro-particles are slowly decomposed in the body, and at this time, deoxycholic acid or a pharmaceutically acceptable salt thereof contained in the exposed pores may be released.

In order to continuously release such deoxycholic acid or a pharmaceutically acceptable salt thereof for 1 month to 3 months, the average diameter of the microparticles is 30 to 70 μm. If the average diameter of the microparticles is less than 30㎛, the size of the particles is too small, the possibility of being engulfed by macrophages after injection into the body increases, which may affect the release and absorption of effective drugs in vivo.

In addition, if the thickness exceeds 70 μm, foreign body sensation and pain may increase when the injection is administered, and the particle size distribution of the prepared particles increases, making it difficult to prepare micro particles having a uniform particle size.

Preferably, the microparticles of the present invention are prepared according to the manufacturing method described later, and in this case, microchannels are used. As one condition for controlling the size of the particles, the width length (w) and height length (d) of the microchannel cross section must be adjusted within the range of the average diameter and a certain length ratio of the microparticles to be manufactured.

More specifically, the width (w) of the channel cross-section is in the range of 0.7 to 1.3 with respect to the average diameter (d') of the micro-particles. The width should be set between 70 and 130 μm.

In addition, the height (d) of the channel cross-section is in the range of 0.7 to 1.3 with respect to the average diameter (d') of the micro-particles. should be set to 70 to 130 μm.

In order to prepare the microparticles of the present invention, a liquid mixture must be injected into the microchannel, and at this time, by adjusting the width (w) and height (d) of the cross section of the microchannel as described above, microparticles of a desired size can be obtained. It is characterized in that it can be manufactured.

The biodegradable polymer is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, It is selected from the group consisting of polyorthoesters, polycaprolactones, polyhydroxyvalates, polyhydroxybutyrates, polyamino acids, and combinations thereof, but is not limited to the above examples.

The localized fat accumulation may be selected from the group consisting of lower eyelid fat herniation, lipomas, lipodystrophy, fat deposits associated with cellulite, and combinations thereof. .

The fat deposits may be localized to a site of the subject selected from the group consisting of under the eyes, under the chin, under the arms, buttocks, calves, back, thighs, ankles, stomach, and combinations thereof. Preferably under the chin, more specifically to address the localized fat deposits that cause a double chin.

The lipolytic injection preparation according to another embodiment of the present invention may include the composition for subcutaneous injection.

The lipolytic composition is directly injected into the subcutaneous fat layer of the user's body to selectively destroy fat cells, thereby causing a reduction in fat volume and reducing and correcting the face and body shape. In this case, the lipolytic composition may be injected into the subcutaneous fat layer, such as the user's double chin.

That is, when the lipolytic composition is injected into human tissue, the microparticles are slowly decomposed, and deoxycholic acid or a salt thereof is released, and at this time, the cells of the tissue into which the deoxycholic acid or its salt is injected ( For example, fat cells, etc.) are swollen due to the difference in osmotic pressure, and the cells swollen by the difference in osmotic pressure make the destruction of fat cells by deoxycholic acid more effective.

As such, by directly injecting the lipolytic composition into the double chin of a user with relatively few motor nerves, the lipolytic effect can be maximized and side effects caused by permanent damage to the motor nerves can be reduced.

By the action of the lipolytic composition of the present invention injected into the subcutaneous fat layer, the fat cell membrane is destroyed, and the fat is changed into water-soluble. Thereafter, the water-soluble lipid may be excreted out of the body through urine or sweat.

A method for preparing a composition for decomposing fat according to another embodiment of the present invention comprises the steps of 1) dissolving deoxycholic acid in water to prepare a first mixture; 2) preparing a second mixture by dissolving the biodegradable polymer in an organic solvent; 3) injecting the first mixture of step 1) into the microchannel in a straight direction to flow; 4) The second mixture of step 2) is injected into the microchannels formed on both sides or one side so that the first mixture of step 3) can form an intersection with the straight-flowing microchannels to flow, 1 The linear flow of the mixture and the flow of the second mixture intersect to prepare a _{W 1} /O emulsion in which an aqueous solution of deoxycholic acid is distributed in a spherical biodegradable polymer organic solvent; 5) dissolving the surfactant in water to prepare a third mixture; 6) The third mixture of step 5) _{is injected into microchannels formed on both sides or one side so that the W 1} /O emulsion of step 4) can form an intersection point with the microchannel flowing in a straight direction, The linear flow of the W ₁ /O emulsion and the flow of the third mixture intersect to prepare a _{spherical W 1} /O/W _{2 double emulsion;} 7) collecting the _{W 1} /O/W ₂ double emulsion produced at the intersection of step 6); _{8) stirring the W 1} /O/W ₂ double emulsion collected in step 7), and removing the organic solvent present in the double emulsion by evaporating; and 9) washing and drying the microparticles prepared by _{the W 1} /O/W _{2 double emulsion of step 8).}

Dissolving deoxycholic acid in water to prepare a mixture containing deoxycholic acid, preparing a mixture containing a biodegradable polymer in which a biodegradable polymer is dissolved in an organic solvent, and then injecting each into a microchannel to flow _{, W 1} /O emulsion can be prepared at the intersection of the flow of the mixture containing deoxycholic acid and the flow of the mixture containing the biodegradable polymer. Thereafter, the mixture in which the surfactant is dissolved in water is injected to cross the flow in the straight direction of _{the W 1 /O emulsion, and the flow of the W 1} /O emulsion and the mixture containing the surfactant intersects to form a spherical W ₁ /O/W ₂ double emulsions can be prepared.

More specifically, at this time, when the first mixture is injected into the microchannel in a straight direction, it is injected under a constant pressure condition and flows at a constant flow rate, and the pressure condition at this time is 100 to 500 mbar, preferably 300 mbar, but limited to examples doesn't happen In addition, when the second mixture is injected into the microchannels of both sides or one side, it is injected under a constant pressure condition and flows at a constant flow rate, and the pressure condition at this time is 500 to 1000 mbar, preferably 700 mbar, but is not limited to examples. does not

In addition, when the third mixture is injected into the microchannels on both sides or one side, it is injected under a constant pressure condition to flow at a constant flow rate, and the pressure condition at this time is 1000 to 2000 mbar, preferably 1500 mbar, but is not limited to examples. does not

That is, in order to make the flow of the second mixture forming an intersection with the flow of the first mixture flow at a faster flow rate than the first mixture injected into the linear microchannel, the second mixture is flowed under a higher pressure condition.

Similarly, _{in order to make the flow of the third mixture forming an intersection with the microchannels in which the W 1} /O emulsion flows in a straight direction flow at a faster flow rate, the third mixture is flowed under a higher pressure condition.

As described above, by differentiating the flow rates of the first mixture and the second mixture, and making the flow rate of the third mixture _{faster than the flow rate of the mixture containing the W 1} /O emulsion, the flow of the first mixture and the flow of the second mixture are The second mixture having a relatively higher flow rate at the meeting point compresses the first mixture, and at this time, a W ₁ /O emulsion is formed due to the repulsive force of the first mixture and the second mixture.

The W ₁ /O emulsion is a state in which deoxycholic acid contained in the first mixture is dissolved in the solvent by the flow of the second mixture faster than the flow of the first mixture, that is, the first mixture itself is the flow of the second mixture. is compressed into a spherical shape by

When the W ₁ /O emulsion is formed in this _{way, the formed W 1} /O emulsion flows along the microchannel in a straight direction while being included in the second mixture.

Then, when the W ₁ /O emulsion flows in a straight direction, it crosses the flow of the third mixture faster than the flow rate of the flow, thereby _{forming a W 1} /O/W ₂ double emulsion.

The W ₁ /O/W ₂ double emulsion is an oil phase, that is, a biodegradable polymer uniformly dissolved in an organic solvent, in the form of collecting a large number of deoxycholic acid dissolved in an aqueous phase in a spherical shape, again with the third By the flow of the mixture, as it transforms into a spherical shape, a W ₁ /O/W ₂ double emulsion is formed. More specifically, a plurality of deoxycholic acid solutions are formed in a spherically entrapped form in a spherical biodegradable polymer capsule.

Thereafter, in the step of collecting the micro particles, the micro particles are collected in the water tank containing the third mixture to prevent aggregation between the initially generated micro particles.

The step of collecting the micro particles is to use a third mixture, that is, a mixed solution of a surfactant and water. After preparing the third mixture, a part is injected into the microchannel, and the other part is moved to a water tank collecting micro particles. This is used to prevent aggregation between the collected micro-particles.

After the step of collecting the microparticles, a step of stirring the collected microparticles in a water bath. The microparticles are stirred under a constant temperature condition and a stirring speed, and the organic solvent present on the surface of the microparticles is evaporated and removed.

At this time, the stirring conditions include the steps of primary stirring at a speed of 300 to 500 rpm for 1 to 2 hours at 16 to 18 ℃; After the first stirring step, the second stirring step at a speed of 500 to 700 rpm for 2 to 4 hours at 30 to 50 ℃; And after the second stirring step, proceed in the order of the third stirring step at a speed of 500 to 700 rpm for 1 to 2 hours at 0 to 15 ℃.

In the case of the first and second step stirring processes, after stirring while raising the temperature, the evaporation rate of the solvent present in the surface and internal pores of the microparticles can be adjusted. That is, by slowly evaporating the solvent present in the microparticles, it is possible to prepare microparticles having a smooth surface and having only deoxycholic acid present in the internal pores.

In addition, as the stirring process is performed at a low temperature in the final third step, the surface of the microparticles can be maintained evenly after stirring, and the properties can be maintained even after drying.

That is, the inside of the microparticles before the stirring process contains a number of deoxycholic acid solutions in a spherical form, and removing the solution inside and leaving only deoxycholic acid is an important problem.

At this time, when the stirring conditions are changed from 1 to 3 temperature conditions as described above, as the external solvent is removed, a smooth surface is obtained and only the internal solvent is removed at the same time, so that a large number of pores in the microparticles are formed. formed, and only deoxycholic acid remains in the pores.

More specifically, the stirring process is preferably stirred at 17°C for 1 hour, and secondly, stirring at 40°C for 3 hours. After that, stirring is performed at 10° C. for 1 hour a third time.

The temperature when the first mixture to the third mixture flows through the microchannel is also 16 to 18°C, preferably 17°C. That is, after flowing through the microchannel and forming an intersection to generate microparticles, the low temperature is constantly maintained at 16 to 18°C until the collected microparticles are first stirred. It is possible to manufacture and maintain spherical particles only by maintaining a low temperature in the manufacturing process of micro particles. That is, when it is not a low temperature condition, it is difficult to manufacture particles having a constant spherical shape.

Finally, in the step of washing and drying the microparticles, the microparticles from which all organic solvents on the surface are removed by stirring are washed several times with sterilized filtered purified water to remove the surfactant remaining in the microparticles, and then freeze-dried.

The micro-particles may be prepared by injecting the mixture into a micro-channel formed on a wafer and allowing the mixture to flow.

More specifically, aluminum is deposited on a silicon wafer using an e-beam evaporator, and photoresist is patterned on the aluminum using a photolithography technique. Thereafter, aluminum is etched using photoresist as a mask, silicon is etched by DRIE (deep ion reactive etching) using aluminum as a mask after photoresist is removed, and after aluminum is removed, glass is anodized on the wafer and sealed. Thus, the microchannel is prepared.

The organic solvent of the present invention is immiscible with water, for example, any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof, preferably dichloromethane, but It is not limited to, an organic solvent capable of dissolving the biodegradable polymer, not limited to the above examples, and any organic solvent that can be easily selected by those skilled in the art will be used.

The surfactant of the present invention can be used without limitation as long as the biodegradable polymer solution can help form a stable emulsion. Specifically, it is at least one selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof, and more specifically, methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol , polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, ester amine, linear diamine, pattiamine, and any one or more selected from the group consisting of mixtures thereof, preferably It is polyvinyl alcohol, but is not limited to an example.

The second mixture may further include a surfactant. In general, the surfactant was dissolved in water, but _{in order to prepare a W 1} /O/W ₂ double emulsion, a surfactant was additionally dissolved in the second mixture to form a uniform W ₁ /O/W _{2 only during production.} Allows the preparation of double emulsions.

Preferably, the second mixture is prepared by dissolving a biodegradable polymer and a second surfactant in an organic solvent, and may include 10 to 20 wt% of a biodegradable polymer, 1 to 3 wt% of a surfactant, and the remaining organic solvent.

When used within the above range _{, it is possible to prepare a W 1} /O/W ₂ double emulsion having a uniform shape, and to enable the preparation of a W ₁ /O/W ₂ double emulsion as a long-acting formulation.

As used herein, “patient,” “subject,” “individual,” and the like are used interchangeably herein and may be adapted to the methods described herein, either in vitro or in vitro. refers to any animal, or cell thereof. In certain non-limiting embodiments, the patient, subject or individual is a human.

A "composition" or "pharmaceutical composition" of the present invention comprises at least one compound of the present invention and a carrier, stabilizer, diluent, dispersant, suspending agent, thickening agent, and/or mixtures of other chemical components such as excipients. The pharmaceutical composition facilitates administration of the compound to an organism.

In the present invention, "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" are non-toxic but sufficient to provide the desired biological result. indicates. The result may be a reduction and/or alleviation of a sign, symptom, or cause of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

"Local administration" of the present invention means administering a pharmaceutical ingredient to or around a muscle or subdermal location of a patient by a non-systemic route. Therefore, topical administration excludes administration via systemic routes such as intravenous or oral administration.

"Pharmaceutically acceptable" of the present invention is acceptable to pharmaceutical chemists preparing from a pharmacological/toxicological and physical/chemical point of view with respect to composition, formulation, stability, patient acceptance and bioavailability. Indicates possible properties and/or substances. "Pharmaceutically acceptable carrier" refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.

The "composition for subcutaneous injection containing deoxycholic acid" of the present invention is a spherical particle, having a smooth appearance, a number of pores formed on the inside, and deoxycholic acid containing deoxycholic acid inside the pores. It relates to a composition for subcutaneous injection, including microparticles, wherein the microparticles are mixed with water for injection and the microparticles themselves can be administered subcutaneously.

According to the composition for subcutaneous injection containing deoxycholic acid of the present invention and its preparation method, the lipolytic effect is sustained for 1 to 3 months through a single injection, and also prevents the destruction of surrounding tissues during administration, - To provide a composition for subcutaneous injection containing deoxycholic acid, which has a sustained drug release effect at an effective amount of a dissolved concentration, and a method for preparing the same.

1 is a photomicrograph of _{W 1} /O/W ₂ double emulsion according to an embodiment of the present invention.
2 is a photomicrograph of _{W 1} /O/W ₂ double emulsion according to an embodiment of the present invention.
3 is an SEM photograph of microparticles according to pressure conditions upon injection into a microchannel according to an embodiment of the present invention.
4 is an SEM photograph of microparticles when a surfactant is included in a second mixture according to an embodiment of the present invention.
5 is an SEM photograph of microparticles in the case where a surfactant is not included in the second mixture according to an embodiment of the present invention.
6 is an SEM photograph of microparticles according to agitation conditions according to an embodiment of the present invention.
7 is an SEM photograph of micro particles according to agitation conditions according to an embodiment of the present invention.
8 is an SEM photograph of micro particles according to agitation conditions according to an embodiment of the present invention.
9 is a result of drug release time of microparticles according to an embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail so that those of ordinary skill in the art can easily carry out the present invention. However, the present invention may be embodied in many different forms and is not limited to the embodiments described herein.

Preparation Example 1

Preparation of micro-particles containing deoxycholic acid

A first mixture was prepared by dissolving 0.5 g of deoxycholic acid in 20 ml of water. A second mixture was prepared by dissolving polylactide-co-glycolide (PLGA) and Span 80 in dichloromethane. The second mixture consisted of 15% by weight of PLGA, 2% by weight of span 80 and the remainder of dichloromethane.

Polyvinyl alcohol as a surfactant was mixed with water to prepare a third mixture containing 0.25% by weight of polyvinyl alcohol.

The first mixture, the second mixture, and the third mixture were injected into the microchannel formed on the silicon wafer to flow. The first mixture was injected at a pressure of 300 mbar to flow in a straight direction, and the second mixture was injected and flowed at a pressure of 700 mbar from the side to form an intersection with the flow of the first mixture.

The flow of the first mixture and the flow of the second mixture were crossed _{to prepare a W 1} /O emulsion. The W ₁ /O emulsion was made to flow in a straight direction again, and the flow of the third mixture was injected at a pressure of 1500 mbar from the side so that the flow of _{the W 1 /O emulsion and the flow of the third mixture could cross.}

_{The W 1} /O emulsion formed by the intersection of the flows of the first mixture and the second mixture _{and the W 1} /O/W ₂ emulsion formed at the intersection of the flow of the third mixture and the flow of the third mixture are collected in a water tank containing the third mixture. did.

The W1/O/W2 emulsion collected in the water bath was first stirred at 17° C. at a speed of 400 rpm for 1 hour, the temperature was raised to 40° C., and the second stirred at a speed of 600 rpm for 3 hours, followed by 10° C. The temperature of the furnace was lowered, and the mixture was stirred a third time at a speed of 600 rpm for 1 hour.

After stirring, the micro-particles were washed several times with sterilized filtered purified water and freeze-dried to prepare micro-particles.

Preparation 2

When preparing the second mixture, it was prepared in the same manner as in Preparation Example 1, except that span 80 was not added.

Preparation Examples 3 to 7

When injecting the first mixture, the second mixture, and the third mixture, the pressure conditions were adjusted as shown in the table below.

Preparation 3 Preparation 4 Preparation 5 Preparation 6 Preparation 7 first mixture 100 500 50 300 300 second mixture 500 900 700 400 700 third mixture 1300 1700 1500 1500 1200

(Unit mbar) Preparation Example 8 During the stirring process, it was prepared in the same manner as in Preparation Example 1, except that the temperature of the first, second and third stirring processes was maintained at 17°C.

Preparation 9

During the stirring process, it was prepared in the same manner as in Preparation Example 1, except that the temperature of the first, second and third stirring processes was maintained at 40°C.

Preparation 10

During the stirring process, it was prepared in the same manner as in Preparation Example 1, except that the temperature of the first, second and third stirring processes was maintained at 10°C.

[Experimental Example 1: Whether or not uniform micro-particles are generated]

For the microparticles prepared as in Preparation Example 1 and Preparation Examples 3 to 7, the inner shape of the W1/O/W2 double emulsion was observed through a micrograph before performing a stirring process and freeze-drying.

The results observed with the naked eye through the micrograph were described in Table 2 below, and the results were classified according to the following criteria.

As shown in FIG. 1 , the case in which the first mixture (W1 Phase) is uniformly included in the oil phase is denoted by O, and the case in which it is non-uniformly included as shown in FIG. 2 is denoted by X.

Preparation Example 1 Preparation 3 Preparation 4 Preparation 5 Preparation 6 Preparation 7 Whether or not uniform micro-particles O O O X X X

As shown in Table 2 above, when the first mixture, the second mixture, and the third mixture are injected into the microchannel, it will be said that the first mixture is uniformly collected in the oil phase depending on the pressure conditions. That is, when injected within the pressure conditions of the present invention, deoxycholic acid may be uniformly included in the microparticles, but if it does not fall within that range, the deoxycholic acid in the microparticles is not uniformly included, resulting in drug release The duration cannot be controlled.

As shown in FIG. 2 , a result of taking an SEM photograph of the internal shape of the microparticles formed non-uniformly is shown in FIG. 3 . Referring to FIG. 3 , it can be seen that the internal pores are formed very non-uniformly.

If the internal pores are non-uniformly formed, the amount of deoxycholic acid present in the pores is very small or very large, so it will be impossible to control the drug release effect within a desired period.

[Experimental Example 2: Generation of micro-particles]

After preparing the micro-particles as in Preparation Example 1 and Preparation Example 2, the properties of the prepared micro-particles were measured by SEM photography to confirm the results.

The results are shown in FIGS. 4 and 5 .

When the second mixture was prepared as shown in FIG. 4, when a surfactant was included, microparticles with even particles were generated, but in the case of Preparation Example 2 as shown in FIG. 5, the microparticles were broken and converted into uniform spherical microparticles. It was confirmed that manufacturing was impossible.

When a surfactant is included in the second mixture, when the W ₁ /0 emulsion is formed, the first mixture of the aqueous phase is included in the oil phase in a spherical form, where the surfactant is the sphere of the first mixture at the interface. It will help you keep it in shape.

Therefore, as in Preparation Example 2, when a surfactant is not included in the second mixture, when the W ₁ /O emulsion is formed, the first mixture cannot be smoothly maintained in a spherical shape, and then W ₁ /O/ W ₂ Forms a double emulsion, and cracks occur during stirring and freeze-drying, making it impossible to produce spherical micro-particles.

On the other hand, _{during the formation of the W 1} /O emulsion of Preparation Example 1 above, the surfactant present at the interface is separated from the inside during the stirring process and the freeze-drying process, and thus does not exist in the finally prepared microparticles.

[Experimental Example 3: Differences in Micro Particles According to Stirring Conditions]

In order to confirm the change in the properties of the microparticles according to the stirring conditions, SEM photographs of the microparticles prepared in the same manner as in Example 1 and Examples 8 to 10 were checked.

The experimental results are shown in Table 3 and FIGS. 6 to 8 .

Preparation Example 1 Preparation 8 Preparation 9 Preparation 10 Whether or not uniform micro-particles O X X X

In the case of Preparation Example 1, as shown in FIG. 6, it is possible not only to prepare micro-particles having an even particle diameter, but also to produce micro-particles with an even surface and no agglomeration between particles. Preparation Examples 8 to In the case of 10, unlike Preparation Example 1, it was confirmed that there was a problem in that aggregation between particles occurred or pores were generated on the surface of the ruler, so that the surface was not formed evenly. That is, depending on the stirring conditions, the surface is even and the particles are Agglomeration may occur, and stirring must be carried out within the range of the stirring conditions of the present invention, thereby making it possible to produce micro-particles that have an even surface and do not cause agglomeration between particles.

[Experimental Example 4: Blood concentration test of microparticles]

The microparticles of Example 1 were mixed with water for injection to prepare a long-acting injection formulation, administered to beagle dogs, and blood samples were collected to measure the concentration of deoxycholic acid in the blood over time.

The drug release test results are shown in FIG. 9 below.

As a result of the experiment, the microparticles of Example 1 not only exhibit an effective blood concentration in the initial stage, but also confirm the effective blood concentration level even after 600 hours have elapsed, confirming that there is an effect of releasing deoxycholic acid for a long time.

Based on the experimental results, it will be said that the microparticles according to an embodiment of the present invention can confirm the effect of continuous release of deoxycholic acid for 1 to 3 months.

Although the preferred embodiment of the present invention has been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims are also provided. is within the scope of the

Claims (11)

A composition for non-surgical removal of localized fat deposits, comprising:
The composition includes micro-particles containing deoxycholic acid and a biodegradable polymer,
The micro-particles are spherical particles, have a smooth appearance, and have a number of pores formed inside,
In the form containing deoxycholic acid inside the pores
A composition for subcutaneous injection comprising deoxycholic acid. According to claim 1,
The micro particles are W ₁ /O/W ₂ double emulsion
A composition for subcutaneous injection comprising deoxycholic acid. According to claim 1,
The deoxycholic acid is included in the form of deoxycholic acid or a pharmaceutically acceptable salt thereof.
A composition for subcutaneous injection comprising deoxycholic acid. The method of claim 1,
The average diameter of the micro particles is 30 to 70㎛
A composition for subcutaneous injection comprising deoxycholic acid. The method of claim 1,
The micro-particles continuously release deoxycholic acid for 1 to 3 months to maintain the lipolytic effect.
A composition for subcutaneous injection comprising deoxycholic acid. The method of claim 1,
The biodegradable polymer is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, and combinations thereof
A composition for subcutaneous injection comprising deoxycholic acid. The method of claim 1,
The localized fat accumulation is selected from the group consisting of lower eyelid fat herniation, lipomas, lipodystrophy, fat deposits associated with cellulite, and combinations thereof.
A composition for subcutaneous injection comprising deoxycholic acid. The method of claim 1,
The fat deposition is localized to a site of a subject selected from the group consisting of under the eyes, under the chin, under the arms, buttocks, calves, back, thighs, ankles, stomach, and combinations thereof.
A composition for subcutaneous injection comprising deoxycholic acid. 9. A composition comprising the composition according to any one of claims 1 to 8
lipolytic injection formulation. 1) dissolving deoxycholic acid in water to prepare a first mixture;
2) preparing a second mixture by dissolving the biodegradable polymer in an organic solvent;
3) injecting the first mixture of step 1) into the microchannel in a straight direction to flow;
4) The second mixture of step 2) is injected into the microchannels formed on both sides or one side so that the first mixture of step 3) can form an intersection with the straight-flowing microchannels to flow, 1 The linear flow of the mixture and the flow of the second mixture intersect to prepare a _{W 1} /O emulsion in which an aqueous solution of deoxycholic acid is distributed in a spherical biodegradable polymer organic solvent;
5) dissolving the surfactant in water to prepare a third mixture;
6) The third mixture of step 5) _{is injected into microchannels formed on both sides or one side so that the W 1} /O emulsion of step 4) can form an intersection point with the microchannel flowing in a straight direction, The linear flow of the W ₁ /O emulsion and the flow of the third mixture intersect to prepare a _{spherical W 1} /O/W _{2 double emulsion;}
7) collecting the _{W 1} /O/W ₂ double emulsion produced at the intersection of step 6); _{8) stirring the W 1} /O/W ₂ double emulsion collected in step 7), and removing the organic solvent present in the double emulsion by evaporating; and
9) Washing and drying the microparticles prepared by _{the W 1} /O/W ₂ double emulsion of step 8),
The average particle diameter of the micro particles is 30 to 70㎛
Method for producing a composition for subcutaneous injection comprising deoxycholic acid. 11. The method of claim 10,
The second mixture further comprises a surfactant
Method for producing a composition for subcutaneous injection comprising deoxycholic acid.

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