WO2013151341A1

WO2013151341A1 - Injectable composition comprising phosphatidylcholine and method for preparing thereof

Info

Publication number: WO2013151341A1
Application number: PCT/KR2013/002794
Authority: WO
Inventors: Ki Teak Lee; Jong Hyuk Lee; Ilkyeong SEONG
Original assignee: Ami Pharm Co., Ltd.
Priority date: 2012-04-04
Filing date: 2013-04-04
Publication date: 2013-10-10
Also published as: KR20130112615A; KR101365252B1

Abstract

The present invention relates to an novel injectable composition comprising phosphatidylcholine and more particularly it relates to an novel injectable composition comprising phosphatidylcholine and a method for preparing thereof, and to an injectable composition comprising phosphatidylcholine which comprises phosphatidylcholine, sodium deoxycholate, benzyl alcohol, ethanol, macrogol 15 hydroxystearate, and water or injectable water, and a preparation method thereof. The injectable composition of the present invention does not pose problems, such as precipitation occurring during dilution, unlike conventional formulations, and can be injected without any additional operation. Thus, the composition of the present invention is convenient to use and is easily maintained in a sterile state to ensure safety. And the composition is useful for treating or reducing localized accumulations of fat.

Description

[DESCRIPTION]

[Invention Title]

INJECTABLE COMPOSITION COMPRISING PHOSPHATIDYLCHOLINE AND METHOD FOR PREPARING THEREOF

[Technical Field]

<i> This application claims priority from and the benefit of Korean Patent

Application No. 10-2012-0035135, filed on April 04, 2012, which is hereby incorporated by reference for all purposes as if fully set forth herein.

<2>

<3> The present invention relates to an injectable composition comprising phosphatidylcholine and a method for preparing thereof, and more particularly to an injectable composition comprising phosphatidylcholine which comprises phosphatidylcholine, sodium deoxycholate, benzyl alcohol, ethanol, macrogol 15 hydroxystearate, and water or injectable water, and a preparation method thereof .

<4>

[Background Art]

<5> Phosphatidylcholines are a class of phospholipids that contain choline as a head group. They are widely present in animals, plants, yeasts and fungi, and are also known as lecithin. They are the membrane phospholipids of mammals and are found mainly in brains , nerves , blood cells, egg yolks and the like. In plants, phosphatidylcholines are found in soybeans, sunflower seeds, wheat germs and the like. Phosphatidylcholines generally contain saturated fatty acid at position 1 and unsaturated fatty acid at position 2 of glycerol .

<6>

<7> Normally, liver cells synthesize phospholipids as required, but if liver cells are damaged, they cannot synthesize an increased amount of phospholipids required to restore the membrane structures within a short time. Generally, when the synthesis of albumin and coagulation factors decreases, a damagedliver has a significantly reduced ability to synthesize phospholi ids, and a significant amount of energy is consumed to produce new phospholipids.

<8>

<9> The loss of phospholipids by liver disease causes damage to liver cell membranes and organelles, which is difficult to restore. In an attempt to prevent this loss, there was developed a method in which high purity phosphatidylcholine is supplied into the body so that it is bound to the membrane structure of damaged liver cells to restore the membrane. When phosphatidylcholine is supplied, the exchange of nutrients and electrolytes across membranes is increased, the activity of phospholipid-dependent enzymes is also increased, and high-energy phosphatidylcholine molecules are bound to liver cells to reduce the burden to supply a large amount of energy required for the production of structural and functional components of membrane systems to the liver.

<io>

<u> Based on the above facts, injectable formulations containing high- purity phosphatidylcholine have been developed and used for recovery from hepatic coma caused by liver cirrhosis.

<12>

<i3> However, since it was recently reported that phosphatidylcholine has the effect of dissolving local fat deposits, injectable formulations comprising phosphatidylcholine have been widely used for local lipolysis for beauty purposes.

<14>

<i5> The mechanism whereby formulations comprising phosphatidylcholi e cause reduction of subcutaneous fat deposits is unknown, but several mechanisms have been proposed (ASAPS. American Society for Aesthetic Plastic Surgery. Lipoplasty (liposuction) without surgery, October, 2002). The first is that phosphatidylcholine can reduce the size of lipocytes by stimulating lipase activity. Alternatively, the PBFs have been postulated to function as a detergent that emulsifies lipocyte cell membranes. Detergents have been used in medicine for decades, specifically, as sclerosing agents commonly used in sclerotherapy (American College of Phlebology, 2003). Detergents possess unique polar and non-polar chemical properties which facilitate emulsif ication of insoluble substances by reducing surface tension at their interface (Goldman L, Bennet JC, Cecil RL. Cecil Textbook of Medicine. St. Louis, MO: W.B. Saunders Co., 2001). In fact, laboratory detergents like TritonX-100 and Empigen BB are commonly used to disrupt the lipid bi layer of cell membranes (Lichtenberg D et al. Biochim Biophys Acta 737:285-304, 1983, Womack MD et al. Biochim Biophys Actal^'33: 210-5, 1983, Lichtenberg D. Biochim Biophys Acta 821:470-8, 1985. Banerjee P et al . Chem Phys Lipids 77:65-78, 1995. Almgren M. Biochim Biophys Actal508^'- 146-63. 2000). Two major components of the PBFs, phosphatidylcholine and sodium deoxycholate, have these unique chemical properties and therefore have been used independently as detergents or emulsifying agents (Lichtenberg D et al . Biochemistry 18:3517-25, 1979. Womack MD et al . Biochim Biophys Acta 733:210-5, 1983. Banerjee P et al . Chem Phys Lipids 77:65-78, 1995. Almgren M. Biochim Biophys Acta 1508:146-63, 2000. Schuck S. Proc Natl Acad Sci 100:5795-800, 2003. Heerklotz H et al . Biophys 778:2435-40, 2000. Learn about lecithins. Oxford, CT: American Lecithin Company, 2003. Canty D, Zeisel S, Jolitz A. Lecithin and choline: research update on health and nutrition. Fort Wayne, IN: Central Soya Company, Inc . , 1996) .

<i6> However, if conventional injectable formulations comprising phosphatidylcholine are used for local lipolysis, these formulations are required to be diluted with injectable water immediately before use in order to maximize the effects while reducing the side effects. In this case, the dilution operation is inconvenient because it has to be carried out in a sterile state, and a medication error may occur due to the additional di lut ion operat ion.

<17> To overcome this inconvenience and medication error, the present inventors prepared a composition by diluting a conventional formulation with an injectable solution. However, it was shown that the composition was initially maintained in a transparent state, but formed a precipitate after a certain amount of time. <18> To solubilize a water- insoluble active ingredient to prepare an injectable formulation, a technique of solubilizing the active ingredient using an inclusion compound, a pH adjusting agent, a co-solvent, nanoparticles or the like may be used. However, the above solubilization technique cannot be used for high-purity phosphatidylcholine, because an injectable formulation containing high-purity phosphatidylcholine is administered, for example, intravenously, and phosphatidylcholine is a kind of lipid.

<i9> Thus, there is an urgent need for the development of a composition for solubilization of phospholipids, which can be injected intravenously and can improve a conventional medication method.

<20>

[Disclosure]

[Technical Problem]

<2i> Accordingly, the present inventors have conducted studies on the development of a diluted formulation which can be immediately injected without needing an additional operation for diluting the formulation and does not form a precipitate or the like, unlike conventional injectable formulations comprising phosphatidylcholine, and as a result, have found that, when a formulation comprising phosphatidylcholine contains ethanol and macrogol 15 hydroxystearate at specific concentrations, it does not form a precipitate or the like and the phosphatidylcholine is maintained in a uniformly dissolved state, thereby completing the present invention.

<22> Therefore, it is an object of the present invention to provide an injectable composition comprising phosphatidylcholine which comprises:

<23> 2-3% (w/v) of phosphatidylcholine;

<24> 0.5-2% (w/v) of sodium deoxycholate;

<25> 0.1-1% (w/v) of benzyl alcohol;

<26> 1-10% (w/v) of ethanol

<27> 1.1-5% (w/v) of macrogol 15 hydroxystearate and

<28> a balance of water or injectable water.

<29> <30> Another object of the present invention is to provide a method for preparing an injectable composition comprising phosphatidylcholine, the method comprising the steps of:

<3i> a) mixing, based on the total volume of the composition, 0.5-2% (w/w) of sodium deoxycholate and 0.1-1% (w/v) of benzyl alcohol and stirring the mixture until a clear solution is formed;

<32> (b) adding 2-3% (w/v) of phosphatidylcholine, 1.1-5% (w/v) of macrogol

15 hydroxystearate and 1-10% (w/v) of ethanol to the mixture of step (a) and stirring the resulting solution until the phosphatidylcholine is solubilized and

<33> (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.

<34>

<35> Still another object of the present invention is to provide a method for reducing a localized fat deposit in a subject having such a deposit, the method comprising administering to subject in need thereof an effective amount of the composition of the present invention.

<36>

[Technical Solution]

<37> To achieve the above object, the present invention provides an injectable composition comprising phosphatidylcholine which comprises;

<38> 2-3% (w/v) of phosphatidylcholine;

<39> 0.5-2% (w/v) of sodium deoxycholate,'

<40> 0.1-1% (w/v) of benzyl alcohol;

<4i> 1-10% (w/v) of ethanol

<42> 1.1-5% (w/v) of macrogol 15 hydroxystearate and

<43> a balance of water or injectable water.

<44>

<45> To achieve another object, the present invention provides a method for preparing an injectable composition comprising phosphatidylcholine, the method comprising the steps of^'-

<46> a) adding, based on the total volume of the composition, 0.5-2% (w/w) of sodium deoxycholate to 0.1-1% (w/v) of benzyl alcohol and stirring the mixture until a clear solution is formed;

<47> (b) adding 2-3% (w/v) of phosphatidylcholine, 1.1-5% (w/v) of macrogol

<48> (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.

<49>

<50> To achieve still another object, the present invention provides method for reducing a localized fat deposit in a subject having such a deposit, the method comprising administering to subject in need thereof an effective amount of the composition of the present invention.

<51>

<52> Hereinafter, the present invention will be described in detail.

<53> The injectable composition of the present invention is characterized by consisting 2-3% (w/v) of phosphatidylcholine;

<54> 0.5-2% (w/v) of sodium deoxycholate;

<55> 0.1-1% (w/v) of benzyl alcohol;

<56> 1-10% (w/v) of ethanol

<57> 1.1-5% (w/v) of macrogol 15 hydroxystearate and

<58> a balance of water Or injectable water.

<59>

<6o> An injectable formulation is obtained by dissolving an active ingredient and other additives in distilled water for injection, filtering the solution through a bacterial filter to remove bacterial cells, and filling the filtered solution into a vial in an aseptic condition, and then sealing the vial. Phosphatidylcholine that is contained in the injectable composition according to the present invention is also known as lecithin and is the most typical phospholipid. It accounts for about 70% of total phospholipids in yolk eggs and about 60% of total phospholipids in human serum. Soybean lecithin contains a component consisting of two fatty acids and linoleic acid, unlike other lecithins, and thus has the effect of improving lipid metabolism. In the composition of the present invention, the concentration of phosphatidylcholine is preferably 2-3% (w/v).

<61>

<62> In addition, sodium deoxycholate that is contained in the injectable composition according to the present invention is mainly extracted from the intestine of livestocks and it disassembles the cell membrane and lyses the cell. In the composition of the present invention, the concentration of sodium deoxycholate is preferably 0.5-2% (w/v).

<63>

<64> Moreover, benzyl alcohol that is contained in the injectable composition according to the present invention is one of aromatic alcohols, which is a colorless transparent liquid. It has a peculiar fragrance and a sharp taste and is generally used as a dissolution agent, an extraction agent, a volatilization inhibitor, a food spice and the like. The concentration of benzyl alcohol in the composition according to the present invention is preferably 0.1-1% (w/v).

<65> In addition, ethanol that is contained in the injectable composition according to the present invention is an alcohol with a hydroxyl radical replaced a hydrogen molecule of ethane having two carbons. The concentration of ethanol in the composition according to the present invention is preferably 1-10% (w/v) and more preferably l-5%(w/v).

<66> In addition, macrogol 15 hydroxystearate that is contained in the injectable composition according to the present invention is generally used as a nonionic surfactant, has good chemical stability and low toxicity and easily dissolves in water, ethanol and 2-propanol. The concentration of macrogol 15 hydroxystearate in the composition according to the present invention is preferably 1.1-5% (w/v) and more preferably l.l-2%(w/v).

<67>

<68> In addition, the water for injection that is contained in the injectable composition according to the present invention is distilled water made to dissolve a solid formulation or dilute a water-soluble formulation. Specific examples thereof include glucose injection, xylitol injection, D- mannitol injection, fructose injection, physiological saline, dextran 40 injection, dextran 70 injection, amino acid injection, Ringer solution, lactic acid-Ringer solution or the like.

<69> The above-described phosphat idylchol ine-containing injectable composition, which comprises phosphatidylcholine, sodium deoxycholate, benzyl alcohol, macrogol 15 hydroxystearate, and a balance of water or water for injection, has not been reported before the present invention.

<70>

<7i> Meanwhile, the composition of the present invention may further comprise 0.05-0.2% (w/v) of an isotonic agent or 0.01-0.1% (w/v) of a pH adjust ing agent .

<72> The isotonic agent in the present invention functions to maintain suitable osmotic pressure when the composition comprising phosphatidylcholine of the present invention is administered into the body, and it shows an additional effect of stabilizing phosphatidylcholine in solution.

<73> The isotonic agent may be any pharmaceutically acceptable sugar, salt or any combination or mixture thereof, and examples thereof include sugars such as glucose, and water-soluble inorganic salts suchas sodium chloride, calcium chloride or sodium sulfate. Preferably, the isotonic agent may be sodium chloride. These isotonic agents may be used alone or in combination of two or more. The concentration of the isotonic agent is preferably 0.05-0.2% (w/v), and the isotonic agent may be added in a suitable amount depending on the kinds and amounts of components contained in an injectable formulation containing the inventive composition so that the solution formulation becomes isotonic.

<74> The pH adjusting agent in the present invention functions to adjust the pH of the injectable formulation, and examples thereof include acidic substances and basic substances. Preferably, the pH adjusting agent may be a basic substance.

<75> Examples of the basic substance include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite, etc.), and organic bases (e.g., basic amino acids such as lysine or arginine, meglumine, etc.). More preferably, the pH adjusting agent in the present invention may be sodium hydroxide. The amount of pH adjusting agent added may vary depending on the kinds and amounts of components of the inventive composition and is preferably 0.01-0.1% (w/v).

<76>

<77> Meanwhile, the injectable composition of the present invention may further comprise riboflavin. Riboflavin, also known as vitamin B2, a kind of water-soluble vitamin, acts as an antioxidant and is yellow in color. Riboflavin is preferably contained in an amount of 0.001-0.005 parts by weight based on 100 parts by weight of the composition.

<78>

<79> The present invention provides a method for preparing an injectable composition comprising phosphatidylcholine, the method comprising the steps of:

<80> a) mixing, based on the total volume of the composition, 0.5-2% (w/w) of sodium deoxycholate and 0.1-1% (w/v) of benzyl alcohol and stirring the mixture until a clear solution is formed;

<8i> (b) adding 2-3% (w/v) of phosphatidylcholine, 1.1-5% (w/v) of macrogol

15 hydroxys tear ate and 1-10% (w/v) of ethanol to the mixture of step (a) and stirring the resulting solution until the phosphatidylcholine is solubilized; and

<82> (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.

<83>

<84> Hereinafter, each step of the method for preparing the injectable composition will be described.

<85>

<86> Step (a) of the method is a step of mixing, based on the total volume of the composition, 0.5-2% (w/w) of sodium deoxycholate and 0.1-1% (w/v) of benzyl alcohol and stirring the mixture until a clear solution is formed. <87> In step (a), sodium deoxycholate is added to benzyl alcohol, and the mixture is stirred until a clear solution is formed. The kinds and concentrations of sodium deoxycholate and benzyl alcohol in step (a) are as described for the injectable composition.

<88> Meanwhile, an isotonic agent may further be added in step (a).

Specifically, step (a) may be performed by mixing, based on the total volume of the composition, 0.5-2% (w/v) of sodium deoxycholate, 0.1-1% (w/v) of benzyl alcohol and 0.05-0.2% (w/v) and stirring the mixture until a clear solution is formed.

<89> The kind and concentration of isotonic agent in step (a) are as described for the injectable composition.

<90>

<9 i > Step (b) of the method is a step of adding 2-3% (w/v) of phosphatidylcholine, 1.1-5% (w/v) of macrogol 15 hydroxystearate and 1-10% (w/v) of ethanol to the mixture of step (a) and stirring the resulting solution until the phosphatidylcholine is solubilized.

<92> In step (b), phosphatidylcholine, macrogol 15 hydroxystearate and ethanol are added to the mixture of step (a) and stirred until the phosphatidylcholine is solubilized. The kinds and concentrations of phosphatidylcholine, macrogol 15 hydroxystearate and ethanol in step (b) are as described for the injectable composition.

<93>

<94> As used herein, the term "solubi 1 izing" means that a sparingly soluble substance is dissolved by a solubi lizer to an extent higher than the solubility to form a clear solution, and the expression "until the phosphatidylcholine is solubilized" means that the phosphatidylcholine is dissolved in the injectable solution to form a clear solution.

<95>

<96> Step (c) of the method is a step of adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.

<97> <98> In step (c), water or injectable water is added to the solution of step

(b) to reach a predetermined total volume, and the resulting solution is homogenized.

<99> Meanwhile, in step (c), a pH adjusting agent may further be added in an amount of 0.01-0.1% (w/v) to adjust the pH of the solution to 8-10, simultaneously with, before or after water or injectable water is added to the solution of step (b) to reach a predetermined total volume, and the resulting solution is homogenized.

<ioo> The kind and concentration of pH adjusting agent in step (c) are as described for the injectable composition. The amount of pH adjusting agent added is not specifically limited, as long as it can adjust the pH of the inventive injectable composition to 8-10. For example, the pH adjusting agent may be added at a concentration of 0.01-0.1 wt%, and preferably, it may be added in an amount of 5-6 mg per 5 ml of the inventive injectable composition. Injectable water in step (c) is as described for the injectable composition. The pH adjustment and the step of adjusting the solution to the total volume and homogenizing the solution can be carried out simultaneously or sequentially in any order.

<101>

<102> According to the preparation method of the present invention, it is possible to prepare a phosphat idylchol ine-containing injectable composition which has a lower phosphatidylcholine content than a conventional formulation containing phosphatidylcholine and does not form a precipitate or the like does not occur and phosphatidylcholine is uniformly dissolved.

<103>

<104> The composition of the present invention has local lipolytic effects and a low phosphatidylcholine content and does not form a precipitate or the like, and thus can be used without the risk of contamination or infection resulting from additional dilution.

<105>

<i06> Accordingly, the present invention provides a composition for local lipolysis containing the inventive injectable composition as an active ingredient .

<i07> As used herein, the term "local fat deposits" or " localized fat deposit" refers to fats excessively deposited in the forearm, the abdomen, the thigh, the face, the hip or the like. The mechanism whereby phosphatidylcholine contained in the inventive injectable composition dissolves local fat deposits is as described in the "Description of the Prior Art". In addition, the inventive composition for local lipolysis may further comprise, in addition to the inventive injectable composition, other components known to have local lypolytic effects.

<108> A method for administering the inventive injectable composition is not limited, and the inventive injectable composition can be administered to a patient by a suitable method depending on the severity of the disease, the patient' s age, sex and other conditions. The inventive injectable composition is preferably injected subcutaneous ly, transdermal ly, intramuscularly, intraper i toneal ly or the like, but is not limited thereto.

<109>

<iio> In another aspect, the injectable composition of the present invention can be used for the treatment for obesity, especially local obesity, because it effectively dissolves local fat deposits. Thus, the present invention provides a pharmaceutical composition for preventing or treating obesity, which comprises, as an active ingredient, a mixture composed of 2-3% (w/v) of phosphatidylcholine, 0.5-2% (w/v) of sodium deoxycholate, 0.1-1% (w/v) of benzyl alcohol, 1-10% (w/v) of ethanol , 1.1-5% (w/v) of macrogol 15 hydroxystearate, and a balance of water or injectable water.

<iii> And the present invention provides a pharmaceutical composition for dissolving or reducing a localized fat deposit, which comprises, as an active ingredient, a mixture composed of 2-3% (w/v) of phosphatidylcholine, 0.5-2% (w/v) of sodium deoxycholate, 0.1-1% (w/v) of benzyl alcohol, 1-10% (w/v) of ethanol, 1.1-5% (w/v) of macrogol 15 hydroxystearate, and a balance of water or injectable water.

<112>

<ii3> The composition of the present invention may comprise a pharmaceutically acceptable composition alone or further comprise one or more pharmaceutically acceptable carriers.

<114>

<ii5> A pharmaceutically acceptable carrier, for example, carriers for the parenteral or oral preparations may be included and the parenteral ones are preferable. The carriers for the oral preparations maycomprise lactose, starch, cellulose derivatives, magnsium stearate, stearic acid. In addition, the carriers for the parenteral preparations may comprise water, oil, saline, aqueous glucose and glycol, and may further stabilizers and preservatives. The examples of the stabilizers may be antioxidant such as sodium hydrogen sulfite, sodium sulfite, and ascorbic acid. The examples of the preservatives may be benzalkonium chloride, methyl- or prophyl-par ben, and chlorobutanol . The list of pharmaceutically acceptable carriers are disclosed in Remington' s Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995.

<ii6> As used herein, the "pharmaceutically effective amount" refers to the amount showing more reaction compared to a negative group and preferably it refers to the effective amount for treating or preventing local obesity. Total effective amount of the composition of the present invention may be administered to a patient by a single dose or fractionated treatment protocol of multiple dose for long period. Pharmaceutically acceptable amount of the composition of the present invention according to the present invention is 0.0001 to lOOmg/kg body weight/day. However, the pharmaceutically acceptable amount may be determined by considering various factors, such as disease and its severity, age, body weight, sex, administration route and treatment period but it may be chosen properly by the skilled person in the art. As long as they show the effect of the present invention, the formulation, administration route and administration method are not limited thereto.

<117>

<ii8> In addition, the present invention provides method for reducing a localized fat deposit in a subject having such a deposit, wherein the deposit is contacted with 2-3% (w/v) of phosphatidylcholine, 0.5-2% (w/v) of sodium deoxycholate, 0.1-1% (vv/v) of benzyl alcohol, 1-10% (w/v) of ethanol, 1.1-5% (w/v) of macrogol 15 hydroxystearate, and a balance of water or injectable water of an effective amount.

<119>

<i20> As used herein, "treatment" refers improvement, relief or complete recoyery of a symptom. As used herein, "subject" As used herein, the "subject" refers to mammals, particularly, patients having localized fat deposit. As used herein, "effective amount" refers the effective amount for preventing or treating obesity by lipolysis in vitro or in vivo, or dissolving or reducing a localized fat deposit.

<121>

<i22> In one Example of the present invention, the stability of a dilution of a conventional phosphat idylchol ine-containing injectable formulation in injectable water and the stability of the inventive composition were comparatively compared. As a result, it was observed that the dilution of the conventional formulation was initially maintained in a clear state, but formed a visible precipitate with the passage of time, unlike the inventive composition.

<123> In another Example of the present invention, in order to find an injectable composition capable of dissolving phosphatidylcholine from dilutions of conventional phosphat idylchol ine-containing injectable formulations in injectable water, the phospholipid solubilizing capacity of a composition containing each of polysorbate 80 and macrogol 15 hydroxystearate, which are relatively safe surfactants, was evaluated.

<i24> As a result, it was observed that the composition containing polysorbate 80 formed a precipitate after a certain amount of time, but the composition containing more than 1% (w/v) of macrogol 15 hydroxystearate did not form a precipitate.

<125> In another Example of the present invention, solubilities at various ethanol concentrations were compared. As a result, it was observed that compositions containing 1% (w/v) or more of ethanol easily achieved solubilization, but compositions containing less than 1% (w/v) of ethanol showed unsuitable appearance. In addition, it was observed that, even if ethanol was contained at a concentration of 1% (w/v) or more, suitable properties were shown when macrogol 15 hydroxystearate was contained at a concentration of more than 1% (w/v).

<126>

[Advantageous Effects]

<i27> Accordingly, the present invention provides an injectable composition comprising phosphatidylcholine, sodium deoxycholate, benzyl alcohol, ethanol, macrogol 15 hydroxystearate and water or injectable water. The injectable composition of the present invention does not pose problems, such as precipitation occurring during dilution, unlike conventional formulations, and can be injected without any additional operation. Thus, the composition of the present invention is convenient to use and is easily maintained in a sterile state to ensure safety. And the composition is useful for treating or reducing localized accumulations of fat.

<128>

[Description of Drawings]

<i29> FIG. 1 shows a comparison of stability between a conventional formulation (Al) and a dilution (A2) of the conventional formulation.

<i30> FIG. 2 shows a comparison of appearance between compositions for solubilizing phosphatidylcholine, and the numbers shown in FIG. 2 correspond to the sample numbers shown in Table 2 of Table 1 below.

<i3i> FIG. 3 shows a comparison of appearance between compositions for solubilizing phosphatidylcholine, and the numbers shown in FIG. 3 correspond to the sample numbers shown in Table 3 of Table 1 below.

<132>

[Mode for Invention]

<i33> Hereinafter, the present invention will be described in detail with reference to following Examples.

<i34> However, the following Examples are only for illustrative purposes and are not intended to limit the scope of the invention.

<135> <136> Comparative Example 1

<137> Experiment on stability of simple dilution of conventional formulation <138> A conventional injectable formulation comprising phosphat idyl chol ine(sam le No. Al) consisting of a mixture of 287.5 mg of phosphatidylcholine, 120 mg of sodium deoxycholate, 45 mg of benzyl alcohol, 12 mg of NaCl, 50 mg of ethanol , 5.75 mg of NaOHand 5 ml of water was added to and mixed with 5 ml of water to obtain a solution (sample No. A2)which was then allowed to stand at room temperature for 1 hour, after which the appearance thereof was observed.

<139> As a result, as can be seen in FIG. 1, the dilution of the conventional formulation in injectable water was initially maintained in a clear state, but formed a visible precipitate after a certain amount of time.

<140>

<141> [Table 1]

<142> Compositions of conventional formulations

<143>

<144> Example l: Compar i son of stabi 1 ity for select ion of suitable solubilizer from surfactants

<145> In the case of formulations for intravenous injection, the kind and content of excipient are very limited. This is because the excipient is likely to be mixed directly with a blood flow to cause hemolysis, redness, hypersensitivity and the like. Surfactants which can be injected intravenously in a relatively safe manner include polyethoxylated castor oil, polysorbate 80, polysorbate 20, macrogol 15 hydroxystearate, pegylated castor oil, sodium deoxycholate and the like, and among them, polysorbate 80 and macrogol 15 hydroxystearate. Thus, the properties of macrogol 15 hydroxystearate and polysorbate 80 as solubilizers were compared.

<i46> 120 mg of sodium deoxycholate and 45 mg of benzyl alcohol and optionally 12 mg of an isotonic agent (NaCl) were added to injectable water and stirred under the 1 ight-shieldedand closed conditions at 30 ^°Cat 300 RPM for 30 minutes. Then, phosphatidylcholine (essential phospholipid substance), ethanol, macrogol 15 hydroxystearate, polysorbate and a pH adjusting agent were added to the mixture in the amounts shown in Table 2 below, and the mixtures were stirred under the 1 ight-shieldedand closed conditions at 30 ^°C at 280 RPM for 23 hours. After stirring, injectable water was added to the mixturesto reach a total volume of 10 ml, and the resulting mixtures were allowed to stand at room temperature for 1 hour, after the appearances thereof were comparatively observed.

<i47> As a result, as can be seen in FIG. 2, sample No. All consisting of a conventional formulation comprising polysorbate 80 was initially maintained in a clear state, but formed a visible precipitate. It could also be observed that sample No. A10 formed a visible precipitate. However, it was observed that sample No. A9 obtained by adding 2 wt% of macrogol 15 hydroxystearate to the conventional formulation did not form a precipitate and maintained in a clear state even after 48 hours. Meanwhile, it could be observed that sample No. A6 containing 1 wt% of macrogol 15 hydroxystearate formed a visible precipitate.

<148> In order to examine whether the isotonic agent and the pH adjusting agent influence the appearance of sample No. A9, sample Nos. A9-1, A9-2 and A9-3 were prepared and the appearances thereof were compared with that of sample No. A9. As a result, it was observed that the samples were maintained in a clear state regardless of the presence or absence of the isotonic agent and the pH adjusting agent.

<149>

<i50> [Table 2]

<i5i> Solubilities in various solubilizers

<i54> Example 2: Comparison of solubility between various ethanol contents

<i55> Injectable compositions containing phosphatidylcholine were prepared according to the components and contents shown in Table 3 below. Specifically, 120 mg of sodium deoxycholate, 12 mg of sodium chloride and 45 mg of benzyl alcohol were added to injectable water and stirred under the light-shielded and closed conditions at 30 ^°C at 300 RPM for about 30 minutes until they were completely dissolved. Then, 287.5 mg of an essential phospholipid substance and ethanol and macrogol 15 hydroxystearate in the amounts shown in Table 3 below were added to the mixture and stirred under the 1 ight-shielded and closed conditions at 30 "Cat 280 RPM for about 23 hours until they were completely dissolved. Then, 5.75 mg of sodium hydroxide was added to each mixture, after which the mixtures were stirred under the light-shielded and closed conditions at 30 ^°Ct 280 RPM and adjusted to a pH of 8. Then, injectable water was added to each mixture to reach a total volume of 10 ml, and each mixture was stirred to be homogenized. The compositions prepared as described above were visually observed to determine whether suspension, precipitation and layer separation occurred.

<i 56> As a result, as can be seen in Table below and FIG. 3, it was observed that compositions of sample Nos. A3 to A5 containing no macrogol 15 hydroxystearate formed a precipitate. Further, compositions of sample Nos. A6 to A8 containing macrogol 15 hydroxystearate also formed a precipitate. However, compositions of sample Nos. A9 and A12 were maintained in a clear state (the sample at the end of the right side of FIG. 3 is A12).

<157>

<i58> [Table 3]

<i59> Solubilities at various macrogol 15 hydroxystearate contents

[Industrial Applicability]

As can be seen foregoing, the present invention provides an injectable composition comprising phosphatidylcholine which comprises phosphatidylcholine, sodium deoxycholate, benzyl alcohol, ethanol, macrogol 15 hydroxystearate and water or injectable water. The injectable composition of the present invention does not pose problems, such as precipitation occurring during dilution, unlike conventional formulations, and can be injected without any additional operation. Thus, the composition of the present invention is convenient to use and is easily maintained in a sterile state to ensure safety. And the composition is useful for treating or reducing localized accumulations of fat.

Claims

[CLAIMS]

[Claim 1]

<178> An injectable composition comprising phosphatidylcholine which comprises :

<i79> 2-3% (w/v) of phosphatidylcholine;

<i8o> 0.5-2% (w/v) of sodium deoxycholate;

<i8i> 0.1-1% (w/v) of benzyl alcohol;

<182> 1-10% (w/v) of ethanol

<i83> 1.1-5% (w/v) of macrogol 15 hydroxystearate and

<184> a balance of water or injectable water.

<185>

[Claim 2]

<186> The composition of claim 1, wherein the composition further comprisies

0.05-0.2% (w/v) of an isotonic agent or 0.01-0.1% (w/v) of a pH adjusting agent .

<187>

[Claim 3]

<i88> The composition of claim 1, wherein the composition further comprisies

0.001-0.005 parts by weight of riboflavin based on 100 parts by weight of the composition.

<189>

[Claim 4]

<190> The composition of claim 1, wherein the composition comprises 1-5%

(w/v) of ethanol, 1.1-2% (w/v) of macrogol 15 hydroxystearate.

<19I>

[Claim 5]

<i92> The composition of any one of claims 1-4, wherein the pH of the injectable composition ranges from 8 to 10.

<193>

[Claim 6]

<i94> A method for preparing an injectable composition comprising phosphatidylcholine, the method comprising the steps of: <195> a) mixing, based on the total volume of the composition, 0.5-2% (w/w) of sodium deoxycholate and 0.1-1% (w/v) of benzyl alcohol and stirring the mixture until a clear solution is formed;

<i96> (b) adding 2-3% (w/v) of phosphatidylcholine, 1.1-5% (w/v) of macrogol

<i97> (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.

<198>

[Claim 7]

<i99> The method of claim 6, wherein the step (a) is mixing, based on the total volume of the composition, 0.5-2% (w/v) of sodium deoxycholate, 0.1-1% (w/v) of benzyl alcohol and 0.05-0.2% (w/v)of an isotonic agent and stirring the mixture until a clear solution is formed,

<2oo> the step (c) is adding 0.01- 0.1% (w/v) of a pH adjusting agent to the solution of step (b) to adjust pH 8-10, adding water or injectable water to reach a predetermined total volume and homogenizing the resulting solution.

<201>

[Claim 8]

<202> The method of claim 6 or 7, wherein the step (b) is characterized by adding 1.1-2% (w/v) of macrogol 15 hydroxystearate and 1-5% (w/v) of ethanol .

<203>

[Claim 9]

<204> A method for reducing a localized fat deposit in a subject having such a deposit, the method comprising administering to subject in need thereof an effective amount of the composition of claim 1.