WO2018190542A1 - Composition de lipolyse hypotonique et son procédé de préparation - Google Patents

Composition de lipolyse hypotonique et son procédé de préparation Download PDF

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WO2018190542A1
WO2018190542A1 PCT/KR2018/003786 KR2018003786W WO2018190542A1 WO 2018190542 A1 WO2018190542 A1 WO 2018190542A1 KR 2018003786 W KR2018003786 W KR 2018003786W WO 2018190542 A1 WO2018190542 A1 WO 2018190542A1
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hypotonic
composition
fat
lipolytic
hyaluronidase
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PCT/KR2018/003786
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English (en)
Korean (ko)
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이경락
강시하
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이경락
강시하
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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a hypotonic lipolytic composition and a method for preparing the same, and particularly to a hypotonic solution composed of distilled water and sodium chloride, sodium deoxycholate, hyaluronidase, a buffer, an additive, and the like. It relates to a hypotonic lipolysis composition for producing the hypolipidemic composition comprising the same and a method for producing the same.
  • PPC phosphatidylcholine
  • deoxycholine acid sodium deoxycholate
  • An object of the present invention is to provide a hypotonic lipolysis composition and a method for producing the hypolipidemic lipolysis composition comprising deoxycholic acid, hyaluronidase and the like in a hypotonic solution composed of distilled water and sodium chloride.
  • Another object of the present invention to provide a hypotonic lipolytic composition for producing a hypolipidemic lipolysis composition
  • a hypolipidemic lipolysis composition comprising deoxycholic acid, hyaluronidase, buffers, additives and the like in a hypotonic solution consisting of distilled water and sodium chloride There is.
  • the hypotonic lipolysis composition according to the embodiment of the present invention in the hypotonic lipolysis composition, comprises hyaluronidase 50 IU / ml ⁇ 3,000 IU / ml, and the hypotonic lipolysis to the total weight of the hypotonic lipolysis composition 0.01 wt% to 9.9 wt% of sodium deoxycholate, which selectively destroys fat cells to reduce fat volume upon subcutaneous fat layer injection of the composition, and the other is hypotonic to induce physical fat cell degradation due to osmotic pressure difference. It can consist of a solution.
  • the hypotonic lipolysis composition according to the embodiment of the present invention in the hypolipidemic lipolysis composition, comprises 50 IU / ml to 3,000 IU / ml of hyaluronidase, and the subcutaneous lipolysis composition of the hypotonic lipolysis composition to the total weight of the hypo storing lipolytic composition 0.01 wt% to 9.9 wt% of deoxycholic acid, which selectively destroys fat cells to reduce fat volume upon fat layer injection, and 0.01 wt% to 50 wt% of buffer for controlling acidity (pH) of the hypotonic lipolytic composition
  • 0.01 wt% to 50 wt% of the additive for maintaining the shelf life of the hypotonic lipolytic composition and the rest may be composed of a hypotonic solution that induces physical fat cell degradation due to osmotic pressure difference.
  • the storage solution may be prepared by adding 0.1 g to 8.9 g of sodium chloride to 1000 ml of distilled water and stirring the mixture.
  • the buffer may be lactose hydrate, succinate, acetate, phosphate, citrate, aconitate, malate ( malate) and carbonate (carbonate).
  • the additive may include at least one of a diluent, an adjuvant, an excipient, and a vehicle.
  • sodium chloride which induces physical fat cell degradation due to an osmotic pressure difference when subcutaneous fat layer injection of the hypotonic lipolysis composition into distilled water is performed.
  • Injecting and stirring to prepare a storage solution Preparing a mixed solution by injecting and stirring deoxycholic acid which selectively destroys fat cells to reduce fat volume when the subcutaneous fat layer injection of the hypotonic lipolytic composition is injected into the prepared storage solution; And hyaluronidase is added and stirred to increase the drug penetration of subcutaneous connective tissue to the prepared A mixed solution so that the deoxycholic acid disperses, delivers and effects fat cells. It may comprise the step of preparing a lipolysis composition.
  • the hypotonic lipolytic composition may include 50 IU / ml to 3,000 IU / ml of hyaluronidase, and 0.01 wt% to 9.9 wt% of the deoxycholic acid and the remaining storage solution. It can be configured as.
  • sodium chloride which induces physical fat cell degradation due to an osmotic pressure difference when subcutaneous fat layer injection of the hypotonic lipolysis composition into distilled water is performed.
  • Injecting and stirring to prepare a storage solution Preparing a mixed solution by injecting and stirring deoxycholic acid which selectively destroys fat cells to reduce fat volume when the subcutaneous fat layer injection of the hypotonic lipolytic composition is injected into the prepared storage solution; Hyaluronidase was added and stirred to increase the drug penetration of subcutaneous connective tissue to the prepared A mixed solution so that the deoxycholic acid diffuses, delivers, and effects fat cells.
  • Manufacturing step And preparing a hypotonic lipolytic composition by adding and stirring a buffer for controlling the acidity (pH) of the hypotonic lipolytic composition and an additive for maintaining the shelf life of the hypotonic lipolytic composition to the prepared B mixture. It may include.
  • the hypotonic lipolytic composition includes 50 IU / ml to 3,000 IU / ml of hyaluronidase, 0.01 wt% to 9.9 wt% of the deoxycholic acid, and 0.01 wt% of the buffer. ⁇ 50% by weight, 0.01% by weight to 50% by weight of the additive and the rest may be composed of a hypotonic solution that induces physical fat cell degradation by the osmotic pressure difference.
  • the present invention is to prepare a hypotonic lipolysis composition containing deoxycholic acid, hyaluronidase, etc. in a storage solution composed of distilled water and sodium chloride, thereby preventing the occurrence of consolidation phenomenon in the injection site according to the use of deoxycholic acid alone Reduce the effects on cells containing fat components other than fat cells (e.g., nerve cells, muscle cells, bone cells, etc.) compared to the use of deoxycholic acid alone. Reduce side effects, reduce side effects such as edema, swelling, erythema, and pain, and use hyaluronidase in combination with a hypotonic solution. Increasing the efficiency, there is an effect that can be used as a drug for reducing fat accumulated in the local area by subcutaneous administration.
  • a storage solution composed of distilled water and sodium chloride
  • the present invention is to prepare a hypotonic lipolysis composition containing deoxycholic acid, hyaluronidase, buffer, additives, etc. in a hypotonic solution consisting of distilled water and sodium chloride, tissue is injected into the hypotonic lipolytic composition
  • a hypotonic solution consisting of distilled water and sodium chloride
  • tissue is injected into the hypotonic lipolytic composition
  • Deoxycholine acid is effectively delivered to adipocytes, resulting in efficient lipolysis effect even with low concentrations of deoxycholic acid, edema of injection site caused by high concentration of deoxycholine acid, erythema, pain, callus, etc. It is effective to reduce the phenomenon.
  • FIG. 1 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a first embodiment of the present invention.
  • FIG. 2 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a second embodiment of the present invention.
  • Figure 3 is a graph showing the relative weight between the examples according to the hypotonic lipolytic composition according to the present invention and the comparative examples.
  • first and second used in the present invention may be used to describe components, but the components should not be limited by the terms. The terms are used only to distinguish one component from another.
  • first component may be referred to as the second component, and similarly, the second component may also be referred to as the first component.
  • FIG. 1 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a first embodiment of the present invention.
  • sodium chloride is added to distilled water and stirred to prepare (or prepare) a storage solution.
  • the sodium chloride is used to prepare a low osmotic solution (or hypotonic solution) (or the hypotonic solution).
  • the sodium chloride has an effect of inducing physical fat cell destruction (or degradation) due to the osmotic pressure difference during subcutaneous injection of the hypotonic lipolytic composition.
  • the distilled water is 1% to 99% by weight based on the total weight of the hypotonic lipolytic composition
  • the sodium chloride is 0.01% to 0.89% by weight (typically 0.45 weight based on the total weight of the hypotonic lipolytic composition %).
  • stirring conditions and time are stirred for about 5 minutes to 20 minutes (typically 10 minutes) in a stirrer (not shown) having a rotation speed of 250 rpm to 300 rpm, the pressure is atmospheric pressure and the temperature may be room temperature .
  • Such stirring conditions and time may be variously set according to the design of the designer.
  • a mixed solution may be prepared under the stirring environment (the stirring conditions and time) in all stirring steps (S110).
  • deoxycholine acid sodium deoxycholate
  • a mixed solution sodium deoxycholate
  • the deoxycholic acid has the effect of selectively destroying fat cells upon subcutaneous injection of the hypotonic lipolytic composition, thereby reducing fat volume. Fat cells thus destroyed are unable to accumulate fat again and cause permanent fat volume reduction.
  • the deoxycholic acid may be 0.01% to 9.9% by weight (generally 0.075% by weight) based on the total weight of the hypotonic lipolytic composition (S120).
  • hypotonic lipolytic composition is prepared. Then, hyaluronidase is added to the prepared A mixed solution and stirred to prepare (or prepare / complete) the hypotonic lipolytic composition.
  • the hyaluronidase is a huge family of enzymes that degrade hyaluronic acid.
  • the hyaluronic acid is a key component of the cell's extracelluar matrix and is a major member of the interstitial barrier.
  • the hyaluronidase catalyzes the hydrolysis of hyaluronic acid, thereby lowering the viscosity of the hyaluronic acid, thereby increasing tissue permeability and diffusion.
  • the hyaluronidase is used as an electrodeposition or dispersant along with other reagents, drugs, proteins, etc., to enhance dispersibility and deliverability.
  • the hyaluronidase promotes (or catalyzes) the hydrolysis of the hyaluronic acid, thereby increasing drug penetration of subcutaneous connective tissue, so that deoxycholic acid contained in the hypotonic lipolytic composition effectively disperses into fat cells. ), Delivery, and effect.
  • hyaluronidase is a hyaluronidase (EC 4.2.99.1), leech, other parasites and hyaluronidase derived from crustaceans (EC 3.2.1.36), mammalian-type hyaluronidase according to the mechanism of action (EC 3.2.1.35), etc.
  • hyaluronidase described in the present invention is not limited thereto, and may include any non-human hyaluronidase, human hyaluronidase, and the like.
  • hyaluronidase of any of the above non-human origins such as rats, dogs, cats, rabbits, birds, cattle, sheep, pigs, horses, fishes, frogs, fungi, leeches, other parasites, crustaceans, etc. It may include.
  • hyaluronidase of non-human origin includes cattle, wasps, bees, white-faced bumblebees, wasps, rats, pigs, rats (rabbits), rabbits, sheep, orangutans, Philippine monkeys, guinea pigs, Staphylococcus aureus, Streptococcus, hyaluronidase from clostridium perfringens.
  • hyaluronidase of human origin includes HYAL1, HYAL2, HYAL3, HYAL4, PH20 and the like.
  • the hyaluronidase also includes sheep and bovine PH20, soluble human PH20, soluble rHuPH20 and the like.
  • the hyaluronidase having a biological activity of 50 I.U / ml to 3,000 I.U / ml (typically 90 I.U / ml) at room temperature may be added to the A mixture.
  • hypotonic lipolytic composition may be prepared by stirring the distilled water, the sodium chloride, the deoxycholic acid, the hyaluronidase, and the like.
  • ingredient Composition ratio (wt%) Distilled water 1 to 99 Sodium chloride 0.01 to 0.89 Deoxycholic acid 0.01 to 9.9 Hyaluronidase 50 to 3,000 I.U / ml
  • hypotonic lipolytic composition may be composed of a composition ratio (% by weight) as shown in [Table 1].
  • the hypotonic lipolysis composition comprises the hyaluronidase in a unit of 50 IU / ml to 3,000 IU / ml, and 0.01 wt% to 9.9 wt% of the deoxycholic acid relative to the total weight of the hypotonic lipolytic composition and the rest. It consists of the hypotonic solution.
  • the hypotonic solution is intended to induce physical fat cell destruction (or degradation) due to the osmotic pressure difference during subcutaneous injection of the hypotonic lipolytic composition, and 0.1 g to 8.9 g of sodium chloride (generally, based on 1000 ml of the hypotonic solution) 4.5 g) and the remaining distilled water.
  • hypotonic lipolytic composition is administered (or composed / manufactured / prepared) in the form of a solution or a lyophilized formulation.
  • the depotable lipolytic composition when it is a lyophilized formulation, it may be prepared in a liquid state by dilution (S130).
  • the prepared (or prepared) hypotonic lipolytic composition is packaged by use (or unit) in a predetermined container (not shown).
  • the hypotonic lipolytic composition comprising the packaged pharmaceutically active compound should be sterile.
  • the prepared (or prepared) depot lipolytic composition is packaged in ampules, vials, syringes with needles and the like.
  • the packaged hypotonic lipolytic composition can be injected directly into the subcutaneous fat layer of the user's body, thereby selectively destroying fat cells, causing fat volume reduction, and reducing and correcting facial and body shape.
  • the hypotonic lipolytic composition may be injected into the subcutaneous fat layer, such as the user's double chin area.
  • hypotonic lipolytic composition when the hypotonic lipolytic composition is injected into human tissue, cells of the tissue into which the hypotonic lipolytic composition is injected (for example, fat cells, etc.) are inflated by an osmotic pressure difference, and the osmotic pressure difference The swollen cells make the destruction of fat cells by the deoxycholic acid more effective.
  • the lipolytic effect can be maximized and side effects due to permanent damage of the motor nerves can be reduced.
  • hypotonic lipolytic composition injected into the subcutaneous fat layer destroys the fat cell membrane and changes the fat to water-soluble. Thereafter, the fat changed to water solubility may be discharged to the body in urine or sweat (S140).
  • the embodiment of the present invention did not include phosphatidylcholine, which is associated with the occurrence of side effects in the hypotonic lipolytic composition.
  • hypotonic lipolytic composition contained deoxycholic acid, the effect of lipolysis has been demonstrated.
  • hypotonic lipolytic composition includes the hyaluronidase based on the hypotonic solution to maximize the lipolytic effect of the deoxycholic acid and reduce discomfort such as edema, erythema, pain, and skin callus. have.
  • FIG. 2 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a second embodiment of the present invention.
  • sodium chloride is added to distilled water and stirred to prepare (or prepare) a storage solution.
  • the sodium chloride is used to prepare a low osmotic solution (or the hypotonic solution).
  • the sodium chloride has an effect of inducing physical fat cell destruction (or degradation) due to the osmotic pressure difference during subcutaneous injection of the hypotonic lipolytic composition.
  • the distilled water is 1% to 99% by weight based on the total weight of the hypotonic lipolytic composition
  • the sodium chloride is 0.01% to 0.89% by weight (typically 0.45 weight based on the total weight of the hypotonic lipolytic composition %).
  • stirring conditions and time are stirred for about 5 minutes to 20 minutes (typically 10 minutes) in a stirrer (not shown) having a rotation speed of 250 rpm to 300 rpm, the pressure is atmospheric pressure and the temperature may be room temperature .
  • Such stirring conditions and time may be variously set according to the design of the designer.
  • a mixed solution may be prepared under the stirring environment (the stirring conditions and time) in all stirring steps (S210).
  • deoxycholic acid is added to the prepared storage solution and stirred to prepare (or prepare) A mixed solution.
  • the deoxycholic acid has the effect of selectively destroying fat cells upon subcutaneous injection of the hypotonic lipolytic composition, thereby reducing fat volume. Fat cells thus destroyed are unable to accumulate fat again and cause permanent fat volume reduction.
  • the deoxycholic acid may be 0.01% to 9.9% by weight (generally 0.075% by weight) based on the total weight of the hypotonic lipolytic composition (S220).
  • hyaluronidase is added to the prepared A mixed solution and stirred to prepare (or prepare) the B mixed solution.
  • the hyaluronidase having a biological activity of 50 I.U / ml to 3,000 I.U / ml (typically 90 I.U / ml) at room temperature may be added to the A mixture (S230).
  • a buffer and other additives are added to the prepared B mixture, followed by stirring to prepare (or prepare / complete) the hypotonic lipolysis composition.
  • the buffer is used to control the acidity (pH) of the hypotonic lipolytic composition, lactose hydrate (succinate), succinate (acetate), phosphate (phosphate), citrate, Aconate, malate, carbonate and the like.
  • various buffers may also be used that provide acceptable pH stability or meet buffer capacity within the indicated (or preset) range.
  • the additive is for maintaining the shelf life of the hypotonic lipolytic composition, and includes a carrier such as a diluent, an adjuvant, an excipient, a vehicle, and the like.
  • the pharmaceutical carrier may be an oil including a sterile liquid, water and petroleum, animal, peanut oil, soybean oil, mineral oil and carrier of plant or synthetic origin such as sesame oil.
  • liquid carrier saline solution, aqueous dextrose, glycerol solution and the like can be used as the liquid carrier.
  • pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, tonicity agents, antioxidants, local anesthetics, suspensions and dispersants, emulsifiers, metal blockades. Or chelating agents, other pharmaceutically acceptable substances, and the like.
  • Such aqueous vehicles include sodium chloride injections, Ringer's injections, isotonic dextrose injections, sterile water injections, dextrose and lactated Ringer's injections, and the like.
  • non-aqueous vehicles include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil, peanut oil and the like.
  • the antimicrobial agents in bacteriostatic or fungal concentrates are phenol or cresol, benzyl alcohol, chlorobutanol, methyl and propyl p-Hydroxybenzoic esters ), Thimerosal, benzalkonium chloride, benzthonium chloride, and the like.
  • the tonicity agent includes sodium chloride, dextrose and the like.
  • the antioxidant includes sodium bisulfate and the like.
  • the local anesthetics include lidocaine hydrochloride, procaine hydrochloride, and the like.
  • the suspending agent and dispersing agent include sodium carboxymethyl cellulose (Sodium Carboxymethylcellulose), hydroxypropyl methylcellulose (Hydroxypropylmethylcellulose), polyvinylpyrollidon (Polyvinylpyrollidon) and the like.
  • the emulsifying agent includes polysorbate 80 (TWEENs 80) and the like.
  • the metal blocking agent or chelating agent of the metal ion includes EDTA (ethylenediaminetertraacetic acid).
  • the pharmaceutical carrier may include ethyl alcohol, polyethylene glycol, propylene glycol, sodium hydroxide for pH adjustment, hydrochloric acid, citric acid, lactic acid, and the like for water miscible vehicles.
  • the additive may include a diluent (e.g., lactose, sucrose, dicalcium phosphate, carboxymethylcellulose, etc.), a lubricant (e.g., magnesium stearate ), Calcium stearate, talc, etc.), binders (including starch, natural gums, etc.) and the like.
  • a diluent e.g., lactose, sucrose, dicalcium phosphate, carboxymethylcellulose, etc.
  • a lubricant e.g., magnesium stearate ), Calcium stearate, talc, etc.
  • binders including starch, natural gums, etc.
  • the additives may also be used in trace amounts of wetting or emulsifying agents, pH buffers (e.g. acetates, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, Triethanolamino oleate (including triethanolaminolate) and the like.
  • pH buffers e.g. acetates, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, Triethanolamino oleate (including triethanolaminolate) and the like.
  • the buffer is 0.01% to 50% by weight based on the total weight of the hypotonic lipolytic composition
  • the additive is 0.01% to 50% by weight based on the total weight of the hypotonic lipolytic composition.
  • hypotonic lipolytic composition may be prepared by stirring the distilled water, the sodium chloride, the deoxycholic acid, the hyaluronidase, the buffer, the additive, and the like.
  • ingredient Composition ratio (wt%) Distilled water 1 to 99 Sodium chloride 0.01 to 0.89 Deoxycholic acid 0.01 to 9.9 Hyaluronidase 50 to 3,000 I.U / ml Buffer 0.01 to 50 additive 0.01 to 50
  • hypotonic lipolytic composition may be composed of the composition ratio (% by weight) as shown in the [Table 2].
  • the hypotonic lipolytic composition comprises the hyaluronidase in a unit of 50 IU / ml ⁇ 3,000 IU / ml, 0.01 wt% to 9.9 wt% of the deoxycholic acid relative to the total weight of the hypotonic lipolytic composition, 0.01 wt% to 50 wt% of a buffer for controlling acidity of the hypotonic lipolytic composition, 0.01 wt% to 50 wt% of an additive for maintaining the shelf life of the hypotonic lipolytic composition, and the remaining hypotonic solution.
  • hypotonic solution is intended to induce physical fat cell destruction (or degradation) due to the osmotic pressure difference during subcutaneous injection of the hypotonic lipolytic composition, and 0.1 g to 8.9 g of sodium chloride (generally, based on 1000 ml of the hypotonic solution) 4.5 g) and the remaining distilled water.
  • hypotonic lipolytic composition is administered (or composed / manufactured / prepared) in the form of a solution or a lyophilized formulation.
  • the depotable lipolytic composition when it is a lyophilized formulation, it may be prepared in a liquid state by dilution (S240).
  • the prepared (or prepared) hypotonic lipolytic composition is packaged by use (or unit) in a predetermined container (not shown).
  • the hypotonic lipolytic composition comprising the packaged pharmaceutically active compound should be sterile.
  • the prepared (or prepared) hypotonic lipolytic composition is packaged in ampoules, vials, syringes with needles and the like.
  • the packaged hypotonic lipolytic composition can be injected directly into the subcutaneous fat layer of the user's body, thereby selectively destroying fat cells, causing fat volume reduction, and reducing and correcting facial and body shape.
  • the hypotonic lipolytic composition may be injected into the subcutaneous fat layer, such as the user's double chin area.
  • hypotonic lipolytic composition when the hypotonic lipolytic composition is injected into human tissue, cells of the tissue into which the hypotonic lipolytic composition is injected (for example, fat cells, etc.) are inflated by an osmotic pressure difference, and the osmotic pressure difference The swollen cells make the destruction of fat cells by the deoxycholic acid more effective.
  • the lipolytic effect can be maximized and side effects due to permanent damage of the motor nerves can be reduced.
  • hypotonic lipolytic composition injected into the subcutaneous fat layer destroys the fat cell membrane and changes the fat to water-soluble. Thereafter, the fat changed to water solubility may be discharged to the body in urine or sweat (S250).
  • hypotonic lipolytic composition (or injectable composition) according to the embodiment of the present invention used hyaluronidase 9000 I.U, 75 mg deoxycholic acid, 450 mg sodium chloride and the remaining distilled water based on 100 ml of the total solution.
  • a high dose of 1000 mg of deoxycholic acid was used for the saline solution.
  • Hyaluronidase 9000 I.U was used for physiological saline.
  • hypotonic solution was used alone.
  • Hyaluronidase 9000 I.U and 75 mg of deoxycholic acid were used for the saline solution.
  • composition of the injection composition according to the embodiment of the present invention and the injection composition according to Comparative Examples 1 to 6 may be represented as shown in Table 3 below.
  • injectable compositions were prepared in 100 ml.
  • the hyaluronidase was used as a hyalponic strain (1 vial 1500 I.U) of Woori Pharmaceutical Co., Ltd.
  • the composition of the injectable composition is determined by measuring the deoxycholine acid (manufacturer: Sigma-Aldrich) with a microbalance in accordance with the corresponding content, and then saline solution (manufacturer: Korea Pharmaceutical Industry) or saline and distilled water (manufacturer: Korea Pharmaceutical Industry) ) Was dissolved in the mixed storage solution to prepare the corresponding respective contents.
  • mice Male 5-week-old Sprague Dawley rat, an experimental animal used in this test, was purchased from Orient Bio. In addition, the breeding environmental conditions of rats were set to 22 °C ⁇ 24 °C, relative humidity 30% to 50%, and two dogs per breeding box. From 7 am to 7 pm, the lights were illuminated from 150 Lux to 300 Lux and lit 12 hours a day, 12 hours off. Feed was freely consumed using a high fat diet (45% fat content, 2018, manufactured by Research Diet Inc, USA).
  • the animals that caused obesity for 8 weeks in a high-fat diet was separated from the group based on the weight, and after the group separation, the injection of the present invention (or Example) and the comparative examples 1 to 6 of the right subcutaneous inguinal fat of the animal Injections were injected subcutaneously once a week for four weeks.
  • Injection composition group feed Dosage (ml) Number of individuals Comparative Example 1 Normal control General feed 500 8 Comparative Example 1 Obesity-induced Control High Fat Feed 500 8 Comparative Example 2 Experiment group 1 High Fat Feed 500 8 Comparative Example 3 Experiment group 2 High Fat Feed 500 8 Comparative Example 4 Experiment group 3 High Fat Feed 500 8 Comparative Example 5 Experimental Group 4 High Fat Feed 500 8 Comparative Example 6 Experimental group 5 High Fat Feed 500 8 Example Experimental Group 6 High Fat Feed 500 8
  • the relative weight of the inguinal fat of the obesity-induced control group was significantly higher than that of the normal control group.
  • Comparative Example 2 Comparative Example 6 and the injection according to the embodiment of the present invention showed a significantly lower relative weight in comparison with the relative weight of the right inguinal fat of the obesity-induced control.
  • the relative weight of the right inguinal fat of the group administered the injection according to the embodiment of the present invention is 0.0120 ⁇ 0.0019 relative to the weight of the right inguinal fat 0.0167 ⁇ 0.0026 of the obesity-induced control group It was reduced by about 28.1% compared to the lowest relative weight.
  • a storage solution according to an embodiment of the present invention as compared to the case of using a high dose of deoxycholic acid or hyaluronidase alone in physiological saline, or using deoxycholic acid and hyaluronidase in physiological saline.
  • deoxycholic acid and hyaluronidase it can be seen that local lipolytic effect is better.
  • the hypotonic lipolytic composition in order to maximize the lipolytic effect of the hypotonic lipolytic composition, and to reduce the side effects due to permanent damage of the motor nerve, it is described that the hypotonic lipolytic composition is directly injected into the double chin of the user
  • the present invention is not limited thereto, and the above-described hypotonic lipolytic composition may also be applied to the face part (including the clown, cheeks, orbital fat, etc.), the body part (eg, the abdomen, back, side, upper arm, thigh, calf, etc.)
  • the hypotonic lipolytic composition may also be injected into the face, body and the like.
  • an embodiment of the present invention prepares a hypotonic lipolytic composition including deoxycholic acid, hyaluronidase, and the like in a hypotonic solution composed of distilled water and sodium chloride, and thus has a high concentration (for example, the total weight of the composition).
  • 10% to 95% by weight of deoxycholine acid alone reduces the incidence of consolidation in the injection site, and cells containing other fat components other than fat cells (eg For example, it reduces the effects on nerve cells, muscle cells, bone cells, etc.) to reduce the occurrence of side effects such as nerve palsy, muscle atrophy, bone atrophy, edema (swelling), erythema, pain (pain), etc.
  • side effects of the drug increase the efficiency of fat cell destruction by using hyaluronidase in combination with a hypotonic solution, and reduce localized fat accumulation by subcutaneous administration. Can be used as a medicament.
  • an embodiment of the present invention in the storage solution consisting of distilled water and sodium chloride, deoxycholine acid, hyaluronidase, buffers, additives and the like to prepare a storage fat decomposing composition, storage fat Deoxycholine acid is effectively delivered to adipocytes in tissues in which the degradation composition is injected so that even at low concentrations (e.g., 0.01% to 9.9% by weight of the total weight of the hypotonic lipolytic composition), Decomposition effects can be obtained, and phenomena such as edema, erythema, pain, and callus caused by injection of high concentrations of deoxycholic acid can be reduced.
  • low concentrations e.g., 0.01% to 9.9% by weight of the total weight of the hypotonic lipolytic composition
  • the present invention is to prepare a hypotonic lipolysis composition containing deoxycholic acid, hyaluronidase, etc. in a storage solution composed of distilled water and sodium chloride, thereby preventing the occurrence of consolidation phenomenon in the injection site according to the use of deoxycholic acid alone
  • a storage solution composed of distilled water and sodium chloride

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Abstract

L'invention concerne une composition de lipolyse hypotonique et son procédé de préparation. À savoir, la présente invention concerne un procédé de préparation d'une composition de lipolyse hypotonique contenant de l'acide désoxycholique, de l'hyaluronidase et autres dans une solution hypotonique constituée d'eau distillée et de chlorure de sodium, pour ainsi : réduire l'apparition, en un point d'injection, d'un phénomène de consolidation provoqué par l'utilisation d'acide désoxycholique seul ; réduire les effets secondaires tels que la paralysie nerveuse, l'atrophie musculaire et l'atrophie osseuse par réduction de l'influence sur les cellules (comprenant, par exemple, les cellules nerveuses, les cellules musculaires, les cellules osseuses et autres), à l'exclusion des adipocytes, et contenant des composants gras, comparativement à l'utilisation de l'acide désoxycholique seul ; réduire les effets secondaires tels que l'œdème/le gonflement, l'érythème et la douleur ; augmenter l'efficacité de rupture des adipocytes grâce à une utilisation combinée de l'hyaluronidase sur la base d'une solution hypotonique ; et permettre l'utilisation d'un médicament destiné à réduire la graisse qui s'est accumulée localement par l'intermédiaire d'une administration par voie sous-cutanée.
PCT/KR2018/003786 2016-09-22 2018-03-30 Composition de lipolyse hypotonique et son procédé de préparation WO2018190542A1 (fr)

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KR20180072638A (ko) 2018-06-29
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KR20180071232A (ko) 2018-06-27
KR101883903B1 (ko) 2018-08-01
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