WO2013151341A1 - Composition injectable comprenant de la phosphatidylcholine et procédé pour sa préparation - Google Patents

Composition injectable comprenant de la phosphatidylcholine et procédé pour sa préparation Download PDF

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Publication number
WO2013151341A1
WO2013151341A1 PCT/KR2013/002794 KR2013002794W WO2013151341A1 WO 2013151341 A1 WO2013151341 A1 WO 2013151341A1 KR 2013002794 W KR2013002794 W KR 2013002794W WO 2013151341 A1 WO2013151341 A1 WO 2013151341A1
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Prior art keywords
composition
phosphatidylcholine
injectable
water
present
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PCT/KR2013/002794
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English (en)
Inventor
Ki Teak Lee
Jong Hyuk Lee
Ilkyeong SEONG
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Ami Pharm Co., Ltd.
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Publication of WO2013151341A1 publication Critical patent/WO2013151341A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • 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 .
  • 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 .
  • 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.
  • a damagedliver has a significantly reduced ability to synthesize phospholi ids, and a significant amount of energy is consumed to produce new phospholipids.
  • ⁇ 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).
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • ⁇ 28> a balance of water or injectable water.
  • 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;
  • step (a) 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
  • step (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.
  • 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.
  • the present invention provides an injectable composition comprising phosphatidylcholine which comprises;
  • ⁇ 43> a balance of water or injectable water.
  • 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;
  • step (a) 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
  • step (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.
  • 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.
  • the injectable composition of the present invention is characterized by consisting 2-3% (w/v) of phosphatidylcholine;
  • 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.
  • the concentration of phosphatidylcholine is preferably 2-3% (w/v).
  • 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.
  • the concentration of sodium deoxycholate is preferably 0.5-2% (w/v).
  • 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).
  • 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.
  • concentration of ethanol in the composition according to the present invention is preferably 1-10% (w/v) and more preferably l-5%(w/v).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • the isotonic agent may be sodium chloride.
  • 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.
  • 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.
  • the pH adjusting agent may be a basic substance.
  • the basic substance examples 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).
  • inorganic bases e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite, etc.
  • organic bases e.g., basic amino acids such as lysine or arginine, meglumine, etc.
  • the pH adjusting agent in the present invention may be sodium hydroxide.
  • 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.
  • 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;
  • step (c) adding water or injectable water to the solution of step (b) to reach a predetermined total volume and homogenizing the resulting solution.
  • 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.
  • 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.
  • an isotonic agent may further be added in step (a).
  • 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.
  • step (a) The kind and concentration of isotonic agent in step (a) are as described for the injectable composition.
  • 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.
  • 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.
  • 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
  • until the phosphatidylcholine is solubilized means that the phosphatidylcholine is dissolved in the injectable solution to form a clear solution
  • 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.
  • step (c) water or injectable water is added to the solution of step
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a composition for local lipolysis containing the inventive injectable composition as an active ingredient .
  • 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".
  • the inventive composition for local lipolysis may further comprise, in addition to the inventive injectable composition, other components known to have local lypolytic effects.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition of the present invention may comprise a pharmaceutically acceptable composition alone or further comprise one or more pharmaceutically acceptable carriers.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • treatment refers improvement, relief or complete recoyery of a symptom.
  • subject As used herein, the “subject” refers to mammals, particularly, patients having localized fat deposit.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 1 shows a comparison of stability between a conventional formulation (Al) and a dilution (A2) of the conventional formulation.
  • 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.
  • 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.
  • 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.
  • Example l Compar i son of stabi 1 ity for select ion of suitable solubilizer from surfactants
  • sodium deoxycholate and 45 mg of benzyl alcohol and optionally 12 mg of an isotonic agent (NaCl) were added to injectable water and
  • 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.
  • sample No. A9 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.
  • 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.
  • 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).
  • the present invention provides an injectable composition
  • 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.
  • 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.

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Abstract

La présente invention concerne une nouvelle composition injectable comprenant de la phosphatidylcholine et plus particulièrement elle se rapporte à une nouvelle composition injectable comprenant de la phosphatidylcholine et un procédé de préparation de celle-ci et à une composition injectable comprenant de la phosphatidylcholine, qui comprend de la phosphatidylcholine du désoxycholate de sodium, de l'alcool benzylique, de l'éthanol, de l'hydroxystéarate de macrogol 15, et de l'eau ou de l'eau injectable, et un procédé de préparation de celle-ci. La composition injectable selon la présente invention ne pose pas de problèmes, tels que la précipitation se produisant pendant la dilution, contrairement aux formulations classiques, et peut être injectée sans opération supplémentaire. Par conséquent, la composition de la présente invention est pratique à utiliser et est facilement maintenue dans un état stérile afin de garantir la sécurité. La composition est utile pour traiter ou réduire des accumulations localisées de graisse.
PCT/KR2013/002794 2012-04-04 2013-04-04 Composition injectable comprenant de la phosphatidylcholine et procédé pour sa préparation WO2013151341A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2012-0035135 2012-04-04
KR1020120035135A KR101365252B1 (ko) 2012-04-04 2012-04-04 포스파티딜콜린 함유 주사용 조성물 및 이의 제조방법

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WO2013151341A1 true WO2013151341A1 (fr) 2013-10-10

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WO2016030876A1 (fr) * 2014-08-25 2016-03-03 Yaron Ilan Extraits de soja et combinaisons de ceux-ci avec de l'huile de ricin polyéthoxylée et d'autres adjuvants pour contrôler les taux de sucre dans le sang et pour l'hépatoprotection
EP3260138A1 (fr) * 2016-06-20 2017-12-27 Oh Young Yeo Composition anticancéreuse injectable pour administration locale contenant une suspension de sel de quinine
WO2020081590A1 (fr) 2018-10-16 2020-04-23 Rotunda Adam M Compositions à base d'alcool et leurs utilisations
US20210000760A1 (en) * 2018-10-16 2021-01-07 Polithera, Inc. Alcohol-based compositions and uses thereof
CN114945373A (zh) * 2020-11-06 2022-08-26 德国生物分子研究公司 肠外营养制剂及其制备方法

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KR101713219B1 (ko) 2015-04-01 2017-03-07 문정선 포스파티딜콜린 및 리소포스파티딜콜린을 포함하는 주사제용 조성물 및 이의 제조방법
WO2019203511A1 (fr) * 2018-04-16 2019-10-24 주식회사 펜믹스 Composition pharmaceutique d'acide désoxycholique
KR102111346B1 (ko) * 2019-08-20 2020-05-22 아영창 침전으로부터 안정한 소듐디옥시콜레이트를 포함하는 수용액상 조성물

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WO2006086038A1 (fr) * 2005-02-08 2006-08-17 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Methodes et compositions associees permettant de reduire des depots graisseux et de retendre la peau
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030876A1 (fr) * 2014-08-25 2016-03-03 Yaron Ilan Extraits de soja et combinaisons de ceux-ci avec de l'huile de ricin polyéthoxylée et d'autres adjuvants pour contrôler les taux de sucre dans le sang et pour l'hépatoprotection
EP3260138A1 (fr) * 2016-06-20 2017-12-27 Oh Young Yeo Composition anticancéreuse injectable pour administration locale contenant une suspension de sel de quinine
TWI650141B (zh) * 2016-06-20 2019-02-11 呂旿榮 包含奎寧鹽懸浮液的用於抗癌治療的局部給藥用注射劑組合物
WO2020081590A1 (fr) 2018-10-16 2020-04-23 Rotunda Adam M Compositions à base d'alcool et leurs utilisations
US10835502B2 (en) * 2018-10-16 2020-11-17 Polithera, Inc. Alcohol-based compositions and uses thereof
US20210000760A1 (en) * 2018-10-16 2021-01-07 Polithera, Inc. Alcohol-based compositions and uses thereof
CN114945373A (zh) * 2020-11-06 2022-08-26 德国生物分子研究公司 肠外营养制剂及其制备方法
CN114945373B (zh) * 2020-11-06 2024-02-06 德国生物分子研究公司 肠外营养制剂及其制备方法

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KR101365252B1 (ko) 2014-02-21

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