WO2018190542A1 - Hypotonic lipolysis composition and preparation method therefor - Google Patents

Hypotonic lipolysis composition and preparation method therefor Download PDF

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Publication number
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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French (fr)
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

A hypotonic lipolysis composition and a preparation method therefor are disclosed. That is, the present invention prepares a hypotonic lipolysis composition in which deoxycholic acid, hyaluronidase, and the like are contained in a hypotonic solution comprising distilled water and sodium chloride, thereby: reducing the occurrence, at an injection site, of a consolidation phenomenon caused by using deoxycholic acid alone; reducing adverse effects such as nerve palsy, muscle atrophy, and bone atrophy by reducing influence on cells (for example, including nerve cells, muscle cells, bone cells and the like), excluding adipocytes, and containing fat components, in comparison to the use of deoxycholic acid alone; reducing adverse effects such as edema/swelling, erythema, and pain; increasing adipocyte disruption efficiency according to a combined use of hyaluronidase on the basis of a hypotonic solution; and enabling a medicine for reducing the fat accumulated at a local site to be used through subcutaneous administration.

Description

저장성 지방 분해 조성물 및 그의 제조 방법Hypotonic lipolytic composition and method for preparing the same
본 발명은 저장성 지방 분해 조성물 및 그의 제조 방법에 관한 것으로, 특히 증류수와 염화나트륨(sodium chloride)으로 구성된 저장성 용액에, 데옥시콜린산(sodium deoxycholate), 히알루로니다아제(hyaluronidase), 완충제, 첨가제 등이 포함된 저장성 지방 분해 조성물을 제조하는 저장성 지방 분해 조성물 및 그의 제조 방법에 관한 것이다.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.
일반적으로, 지방성형(lipoplasty)을 목적으로 포스파티딜콜린(Phosphatidylcholine, PPC라 함)과 데옥시콜린산(sodium deoxycholate)을 이용한 복합제제 주사제가 국소비만에 많이 이용되어 왔다.In general, a combination injection using phosphatidylcholine (PPC) and deoxycholine acid (sodium deoxycholate) for lipolasty has been widely used for local obesity.
하지만, 이러한 포스파티딜콜린과 데옥시콜린산을 이용한 복합제제 주사제에 의한 지방괴사 덩어리 발생으로 인해, 포스파티딜콜린을 제외한 데옥시콜린산 단독 제제를 이용한 지방분해 조성물을 개발하고 있으나, 데옥시콜린산 단독 제제를 이용한 지방분해 조성물의 경우 부종, 홍반, 통증, 피부경결 등의 부작용이 빈번하게 발생하는 문제점이 있다.However, due to the generation of fat necrosis by the injection of a combination preparation using phosphatidylcholine and deoxycholic acid, a lipolytic composition using deoxycholine acid alone except phosphatidylcholine has been developed. In the case of lipolytic compositions, side effects such as edema, erythema, pain, and callus frequently occur.
본 발명의 목적은 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제 등이 포함된 저장성 지방 분해 조성물을 제조하는 저장성 지방 분해 조성물 및 그의 제조 방법을 제공하는 데 있다.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.
본 발명의 다른 목적은 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제, 완충제, 첨가제 등이 포함된 저장성 지방 분해 조성물을 제조하는 저장성 지방 분해 조성물 및 그의 제조 방법을 제공하는 데 있다.Another object of the present invention to provide a hypotonic lipolytic composition for producing 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.
본 발명의 실시예에 따른 저장성 지방 분해 조성물은 저장성 지방 분해 조성물에 있어서, 히알루로니다아제(hyaluronidase) 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 저장성 지방 분해 조성물 총중량 대비 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산(sodium deoxycholate)을 0.01 중량% ~ 9.9 중량% 및 나머지는 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 저장성 용액으로 구성할 수 있다.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.
본 발명의 실시예에 따른 저장성 지방 분해 조성물은 저장성 지방 분해 조성물에 있어서, 히알루로니다아제 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 저장성 지방 분해 조성물 총중량 대비 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산을 0.01 중량% ~ 9.9 중량%, 상기 저장성 지방 분해 조성물의 산도(pH)를 조절하기 위한 완충제 0.01 중량% ~ 50 중량%, 상기 저장성 지방 분해 조성물의 약효 기간을 유지하기 위한 첨가제 0.01 중량% ~ 50 중량% 및 나머지는 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 저장성 용액으로 구성할 수 있다.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 In addition, 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.
본 발명과 관련된 일 예로서 상기 저장성 용액은, 증류수 1000ml에 염화나트륨(sodium chloride) 0.1g ~ 8.9g을 투입하고 교반하여 준비할 수 있다.As an example related to the present invention, 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.
본 발명과 관련된 일 예로서 상기 완충제는, 유당 수화물(lactose hydrate), 석시네이트(succinate), 아세테이트(acetate), 포스페이트(phosphate), 시트레이트(citrate), 아코니테이트(aconitate), 말레이트(malate) 및 카보네이트(carbonate) 중 적어도 하나를 포함할 수 있다.As an example related to the present invention, the buffer may be lactose hydrate, succinate, acetate, phosphate, citrate, aconitate, malate ( malate) and carbonate (carbonate).
본 발명과 관련된 일 예로서 상기 첨가제는, 희석제, 아쥬반트(adjuvant), 부형제(excipient) 및 비히클(vehicle) 중 적어도 하나를 포함할 수 있다.As an example related to the present invention, the additive may include at least one of a diluent, an adjuvant, an excipient, and a vehicle.
본 발명의 실시예에 따른 저장성 지방 분해 조성물의 제조 방법은 저장성 지방 분해 조성물의 제조 방법에 있어서, 증류수에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 염화나트륨을 투입하고 교반하여 저장성 용액을 제조하는 단계; 상기 제조된 저장성 용액에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산을 투입하고 교반하여 A 혼합액을 제조하는 단계; 및 상기 제조된 A 혼합액에 피하 결합 조직의 약물 침투력을 증가시켜 상기 데옥시콜린산이 지방 세포에 확산(dispersion), 전달(delivery) 및 작용(effect)하도록 히알루로니다아제를 투입하고 교반하여 상기 저장성 지방 분해 조성물을 제조하는 단계를 포함할 수 있다.In the method for preparing a hypotonic lipolysis composition according to an embodiment of the present invention, in the method of preparing a hypotonic lipolysis composition, 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.
본 발명과 관련된 일 예로서 상기 저장성 지방 분해 조성물은, 히알루로니다아제 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 데옥시콜린산을 0.01 중량% ~ 9.9 중량% 및 나머지는 상기 저장성 용액으로 구성할 수 있다.As an example related to the present invention, 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.
본 발명의 실시예에 따른 저장성 지방 분해 조성물의 제조 방법은 저장성 지방 분해 조성물의 제조 방법에 있어서, 증류수에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 염화나트륨을 투입하고 교반하여 저장성 용액을 제조하는 단계; 상기 제조된 저장성 용액에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산을 투입하고 교반하여 A 혼합액을 제조하는 단계; 상기 제조된 A 혼합액에 피하 결합 조직의 약물 침투력을 증가시켜 상기 데옥시콜린산이 지방 세포에 확산(dispersion), 전달(delivery) 및 작용(effect)하도록 히알루로니다아제를 투입하고 교반하여 B 혼합액을 제조하는 단계; 및 상기 제조된 B 혼합액에 상기 저장성 지방 분해 조성물의 산도(pH)를 조절하기 위한 완충제 및 상기 저장성 지방 분해 조성물의 약효 기간을 유지하기 위한 첨가제를 투입하고 교반하여 상기 저장성 지방 분해 조성물을 제조하는 단계를 포함할 수 있다.In the method for preparing a hypotonic lipolysis composition according to an embodiment of the present invention, in the method of preparing a hypotonic lipolysis composition, 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.
본 발명과 관련된 일 예로서 상기 저장성 지방 분해 조성물은, 히알루로니다아제 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 데옥시콜린산을 0.01 중량% ~ 9.9 중량%, 상기 완충제 0.01 중량% ~ 50 중량%, 상기 첨가제 0.01 중량% ~ 50 중량% 및 나머지는 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 저장성 용액으로 구성할 수 있다.As an example related to the present invention, 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.
본 발명은 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제 등이 포함된 저장성 지방 분해 조성물을 제조함으로써, 데옥시콜린산 단독 사용에 따른 주입 부위 경결(consolidation) 현상 발생을 줄이고, 데옥시콜린산 단독 사용에 비해 지방 세포 외 다른 지방 성분을 함유하는 세포들(예를 들어 신경 세포, 근육 세포, 골 세포 등 포함)에 대한 영향을 줄여 신경마비, 근육위축, 골위축 등의 부작용 발생을 줄이며, 부종(edema, swelling), 홍반(erythema), 통증(pain) 등의 부작용(adverse effect)을 줄이며, 저장성 용액을 바탕으로 히알루로니다아제를 복합 사용함에 따라 지방 세포 파괴의 효율을 증가시키고, 피하 내 투여로써 국소부위 축적된 지방감소용 약제로 사용할 수 있는 효과가 있다.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.
또한, 본 발명은 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제, 완충제, 첨가제 등이 포함된 저장성 지방 분해 조성물을 제조함으로써, 저장성 지방 분해 조성물이 주입된 조직(tissue)에서 데옥시콜린산이 지방 세포에 효과적으로 전달되어, 저농도의 데옥시콜린산으로도 효율적인 지방분해의 효과를 얻을 수 있으며, 고농도의 데옥시콜린산 주입으로 인한 주입부 부종, 홍반, 통증, 피부경결 등의 현상을 줄일 수 있는 효과가 있다.In addition, 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 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.
도 1은 본 발명의 제 1 실시예에 따른 저장성 지방 분해 조성물의 제조 방법을 나타낸 흐름도이다.1 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a first embodiment of the present invention.
도 2는 본 발명의 제 2 실시예에 따른 저장성 지방 분해 조성물의 제조 방법을 나타낸 흐름도이다.2 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a second embodiment of the present invention.
도 3은 본 발명의 실시예에 따른 저장성 지방 분해 조성물에 따른 실시예와 비교예들 간의 상대 중량을 나타낸 그래프이다.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.
본 발명에서 사용되는 기술적 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로, 본 발명을 한정하려는 의도가 아님을 유의해야 한다. 또한, 본 발명에서 사용되는 기술적 용어는 본 발명에서 특별히 다른 의미로 정의되지 않는 한, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 의미로 해석되어야 하며, 과도하게 포괄적인 의미로 해석되거나, 과도하게 축소된 의미로 해석되지 않아야 한다. 또한, 본 발명에서 사용되는 기술적인 용어가 본 발명의 사상을 정확하게 표현하지 못하는 잘못된 기술적 용어일 때에는 당업자가 올바르게 이해할 수 있는 기술적 용어로 대체되어 이해되어야 할 것이다. 또한, 본 발명에서 사용되는 일반적인 용어는 사전에 정의되어 있는 바에 따라, 또는 전후 문맥상에 따라 해석되어야 하며, 과도하게 축소된 의미로 해석되지 않아야 한다.It should be noted that the technical terms used in the present invention are merely used to describe specific embodiments, and are not intended to limit the present invention. In addition, the technical terms used in the present invention should be interpreted as meanings generally understood by those skilled in the art unless the present invention has a special meaning defined in the present invention, and is excessively comprehensive. It should not be interpreted in the sense of or in the sense of being excessively reduced. In addition, when a technical term used in the present invention is an incorrect technical term that does not accurately express the spirit of the present invention, it should be replaced with a technical term that can be understood by those skilled in the art. In addition, the general terms used in the present invention should be interpreted as defined in the dictionary or according to the context before and after, and should not be interpreted in an excessively reduced sense.
또한, 본 발명에서 사용되는 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한 복수의 표현을 포함한다. 본 발명에서 "구성된다" 또는 "포함한다" 등의 용어는 발명에 기재된 여러 구성 요소들 또는 여러 단계를 반드시 모두 포함하는 것으로 해석되지 않아야 하며, 그 중 일부 구성 요소들 또는 일부 단계들은 포함되지 않을 수도 있고, 또는 추가적인 구성 요소 또는 단계들을 더 포함할 수 있는 것으로 해석되어야 한다.Also, the singular forms used in the present invention include plural forms unless the context clearly indicates otherwise. Terms such as “consisting of” or “comprising” in the present invention should not be construed as necessarily including all of the various components or steps described in the present invention, and some of the components or some steps may not be included. It should be construed that it may further include, or further include, additional components or steps.
또한, 본 발명에서 사용되는 제 1, 제 2 등과 같이 서수를 포함하는 용어는 구성 요소들을 설명하는데 사용될 수 있지만, 구성 요소들은 용어들에 의해 한정되어서는 안 된다. 용어들은 하나의 구성 요소를 다른 구성 요소로부터 구별하는 목적으로만 사용된다. 예를 들어, 본 발명의 권리 범위를 벗어나지 않으면서 제 1 구성 요소는 제 2 구성 요소로 명명될 수 있고, 유사하게 제 2 구성 요소도 제 1 구성 요소로 명명될 수 있다.In addition, terms including ordinal numbers such as 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. For example, without departing from the scope of the present invention, the first component may be referred to as the second component, and similarly, the second component may also be referred to as the first component.
이하, 첨부된 도면을 참조하여 본 발명에 따른 바람직한 실시예를 상세히 설명하되, 도면 부호에 관계없이 동일하거나 유사한 구성 요소는 동일한 참조 번호를 부여하고 이에 대한 중복되는 설명은 생략하기로 한다.Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings, and the same or similar components will be given the same reference numerals regardless of the reference numerals, and redundant description thereof will be omitted.
또한, 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다. 또한, 첨부된 도면은 본 발명의 사상을 쉽게 이해할 수 있도록 하기 위한 것일 뿐, 첨부된 도면에 의해 본 발명의 사상이 제한되는 것으로 해석되어서는 아니 됨을 유의해야 한다.In addition, in describing the present invention, when it is determined that the detailed description of the related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted. In addition, it should be noted that the accompanying drawings are only for easily understanding the spirit of the present invention and should not be construed as limiting the spirit of the present invention by the accompanying drawings.
이하에서는, 본 발명에 따른 저장성 지방 분해 조성물의 제조 방법을 도 1 내지 도 3을 참조하여 상세히 설명한다.Hereinafter, a method for preparing a hypotonic lipolytic composition according to the present invention will be described in detail with reference to FIGS. 1 to 3.
도 1은 본 발명의 제 1 실시예에 따른 저장성 지방 분해 조성물의 제조 방법을 나타낸 흐름도이다.1 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a first embodiment of the present invention.
먼저, 증류수에 염화나트륨(sodium chloride)을 투입하고 교반하여 저장성 용액을 제조(또는 준비)한다.First, sodium chloride is added to distilled water and stirred to prepare (or prepare) a storage solution.
상기 염화나트륨은 낮은 삼투압 용액(또는 hypotonic solution)(또는 상기 저장성 용액)을 제조하기 위한 용도로 사용한다.The sodium chloride is used to prepare a low osmotic solution (or hypotonic solution) (or the hypotonic solution).
즉, 상기 염화나트륨은 저장성 지방 분해 조성물의 피하 주입 시, 삼투압 차이에 의한 물리적인 지방 세포 파괴(또는 분해)를 유도하는 효과가 있다.That is, 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.
이때, 상기 증류수는 저장성 지방 분해 조성물의 총 중량을 기준으로 1 중량% ~ 99 중량%이고, 상기 염화나트륨은 상기 저장성 지방 분해 조성물의 총 중량을 기준으로 0.01 중량% ~ 0.89 중량%(일반적으로 0.45 중량%)일 수 있다.At this time, 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 %).
여기서, 상기 교반 조건 및 시간은 250 rpm ~ 300 rpm 회전 속도를 갖는 교반기(미도시)에서 5분 ~ 20분(일반적으로 10분) 정도 교반하며, 이때의 압력은 대기압이고 온도는 상온일 수 있다. 이러한 상기 교반 조건 및 시간은 설계자의 설계에 따라 다양하게 설정할 수도 있다. 또한, 이하 모든 교반 단계에서 상기 교반 환경(상기 교반 조건 및 시간) 하에서 혼합액이 제조될 수 있다(S110).Here, the 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. In addition, a mixed solution may be prepared under the stirring environment (the stirring conditions and time) in all stirring steps (S110).
이후, 상기 제조된 저장성 용액에 데옥시콜린산(sodium deoxycholate)을 투입하고 교반하여 A 혼합액을 제조(또는 준비)한다.Then, deoxycholine acid (sodium deoxycholate) is added to the prepared storage solution and stirred to prepare (or prepare) A mixed solution.
상기 데옥시콜린산은 상기 저장성 지방 분해 조성물의 피하 주입 시, 지방 세포를 선택적으로 파괴하여, 지방 부피를 감소시키는 효과가 있다. 이와 같이 파괴된 지방 세포는 재차 지방 축적을 할 수 없으며, 영구적인 지방 부피의 감소를 유발한다.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.
이때, 상기 데옥시콜린산은 상기 저장성 지방 분해 조성물의 총 중량을 기준으로 0.01 중량% ~ 9.9 중량%(일반적으로 0.075 중량%)일 수 있다(S120).In this case, 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).
이후, 상기 제조된 A 혼합액에 히알루로니다아제(hyaluronidase)를 투입하고 교반하여 상기 저장성 지방 분해 조성물을 제조(또는 준비/완성)한다.Then, hyaluronidase is added to the prepared A mixed solution and stirred to prepare (or prepare / complete) the hypotonic lipolytic composition.
상기 히알루로니다아제는 히아루론산(hyaluronic acid)을 분해하는 효소(enzyme)들의 거대한 패밀리이다. 상기 히아루론산은 세포의 기질(extracelluar matrix)의 핵심적인 성분이며, 세포간질장벽(interstitial barrier)의 주된 구성원이다. 상기 히알루로니다아제는 상기 히알루로산의 가수 분해를 촉매함으로써, 상기 히알루론산의 점도를 낮추고, 그로 인해 조직 투과성(tissue permeability) 및 확산(diffusion)을 증가시킨다. 따라서, 상기 히알루로니다아제는 다른 시약들, 약물들, 단백질들 등과 함께 전착제 또는 분산제로 사용되어, 분산성 및 전달성을 증강한다.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. Thus, the hyaluronidase is used as an electrodeposition or dispersant along with other reagents, drugs, proteins, etc., to enhance dispersibility and deliverability.
즉, 상기 히알루로니다아제는 상기 히아루론산의 가수 분해를 촉진(또는 촉매)함으로써, 피하 결합 조직의 약물 침투력을 증가시켜, 상기 저장성 지방 분해 조성물에 포함된 데옥시콜린산이 지방 세포에 효과적으로 확산(dispersion), 전달(delivery), 작용(effect)할 수 있도록 도와주는 효과가 있다.That is, 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.
또한, 상기 히알루로니다아제는 작용기전에 따라 박테리아의 히알루로니다아제(EC 4.2.99.1), 거머리, 기타 기생충 및 갑각류 유래의 히알루로니다아제(EC 3.2.1.36), 포유류-타입 히알루로니다아제(EC 3.2.1.35) 등을 포함한다.In addition, the 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.
또한, 본 발명에서 설명하고 있는 상기 히알루로니다아제는 이에 한정되는 것이 아니며, 임의의 비인간 기원의 히알루로니다아제, 인간 기원의 히알루로니다아제 등을 포함할 수 있다.In addition, the hyaluronidase described in the present invention is not limited thereto, and may include any non-human hyaluronidase, human hyaluronidase, and the like.
즉, 쥐과 동물, 개, 고양이, 토끼류, 조류, 소, 양, 돼지, 말, 물고기류, 개구리류, 균류, 거머리류, 기타 기생충류, 갑각류 등의 상기 임의의 비인간 기원의 히알루로니다아제를 포함할 수 있다.That is, 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.
예를 들어, 비인간 기원의 히알루로니다아제는 소, 말벌, 꿀벌, 흰얼굴 호박벌, 장수말벌, 쥐, 돼지, 랫트(백쥐), 토끼, 양, 오랑우탄, 필리핀 원숭이, 기니 피그, 황색포도상구균, 연쇄상구균, 클로스트리디움 페르프린겐스(clostridium perfringens) 유래의 히알루로니다아제를 포함한다.For example, 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.
또한, 인간 기원의 히알루로니다아제는 HYAL1, HYAL2, HYAL3, HYAL4, PH20 등을 포함한다.In addition, hyaluronidase of human origin includes HYAL1, HYAL2, HYAL3, HYAL4, PH20 and the like.
또한, 상기 히알루로니다아제는 양 및 소의 PH20, 가용성 인간 PH20, 가용성 rHuPH20 등을 포함한다.The hyaluronidase also includes sheep and bovine PH20, soluble human PH20, soluble rHuPH20 and the like.
또한, 상온에서 히알루로니다아제의 생물학적 활성이 50 I.U/ml ~ 3,000 I.U/ml(일반적으로 90 I.U/ml)인 상기 히알루로니다아제가 상기 A 혼합액에 투입될 수 있다.In addition, 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.
이와 같이, 상기 저장성 지방 분해 조성물은 상기 증류수, 상기 염화나트륨, 상기 데옥시콜린산, 상기 히알루로니다아제 등을 교반하여 제조할 수 있다.As such, the hypotonic lipolytic composition may be prepared by stirring the distilled water, the sodium chloride, the deoxycholic acid, the hyaluronidase, and the like.
성 분ingredient 조성비(중량%)Composition ratio (wt%)
증류수Distilled water 1 ~ 991 to 99
염화나트륨Sodium chloride 0.01 ~ 0.890.01 to 0.89
데옥시콜린산Deoxycholic acid 0.01 ~ 9.90.01 to 9.9
히알루로니다아제Hyaluronidase 50 ~ 3,000 I.U/ml50 to 3,000 I.U / ml
또한, 상기 저장성 지방 분해 조성물은 상기 [표 1]에서와 같은 조성비(중량%)로 구성할 수 있다.In addition, the hypotonic lipolytic composition may be composed of a composition ratio (% by weight) as shown in [Table 1].
또한, 상기 저장성 지방 분해 조성물은 상기 히알루로니다아제를 50 I.U/ml ~ 3,000 I.U/ml 단위로 포함하고, 상기 저장성 지방 분해 조성물 총중량 대비 상기 데옥시콜린산을 0.01 중량% ~ 9.9 중량% 및 나머지 상기 저장성 용액으로 구성한다. 여기서, 상기 저장성 용액은 상기 저장성 지방 분해 조성물의 피하 주입 시 삼투압 차이에 의한 물리적인 지방 세포 파괴(또는 분해)를 유도하기 위한 것으로, 상기 저장성 용액 1000ml를 기준으로 염화나트륨 0.1g ~ 8.9g(일반적으로 4.5g) 및 나머지 증류수로 구성한다.In addition, 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. Here, 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.
또한, 상기 저장성 지방 분해 조성물은 용액의 제형이거나 동결건조된 제형으로 관리(또는 구성/제조/준비)한다.In addition, the hypotonic lipolytic composition is administered (or composed / manufactured / prepared) in the form of a solution or a lyophilized formulation.
또한, 상기 저장성 지방 분해 조성물이 동결건조된 제형인 경우, 희석액에 의해 액체 상태로 준비할 수도 있다(S130).In addition, when the depotable lipolytic composition is a lyophilized formulation, it may be prepared in a liquid state by dilution (S130).
이후, 상기 제조된(또는 준비된) 저장성 지방 분해 조성물은 미리 설정된 용기(미도시)에 용도별(또는 단위별)로 포장된다. 여기서, 상기 포장되는 약제학적 활성화합물을 포함하는 저장성 지방 분해 조성물은 멸균성이 보장되어야 한다.Thereafter, the prepared (or prepared) hypotonic lipolytic composition is packaged by use (or unit) in a predetermined container (not shown). Here, the hypotonic lipolytic composition comprising the packaged pharmaceutically active compound should be sterile.
즉, 상기 제조된(또는 준비된) 저장성 지방 분해 조성물은 앰플(ample), 바이알(vial), 바늘이 있는 주사기 등에 포장된다.That is, the prepared (or prepared) depot lipolytic composition is packaged in ampules, vials, syringes with needles and the like.
또한, 상기 포장된 저장성 지방 분해 조성물은 사용자의 신체 피하 지방층에 직접 주입되어, 지방 세포를 선택적으로 파괴함으로써 지방 부피 감소를 유발하며, 안면 및 체형을 축소 및 교정할 수 있다. 이때, 상기 저장성 지방 분해 조성물은 사용자의 이중턱 부위 등의 피하 지방층에 주입될 수 있다.In addition, 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. At this time, the hypotonic lipolytic composition may be injected into the subcutaneous fat layer, such as the user's double chin area.
즉, 상기 저장성 지방 분해 조성물을 인체 조직에 주입하게 되면, 상기 저장성 지방 분해 조성물이 주입된 조직의 세포들(예를 들어 지방 세포 등 포함)이 삼투압 차이에 의해 부풀어 오르게 되며, 상기 삼투압 차이에 의해 부풀어 오르게 된 세포들로 인해 상기 데옥시콜린산에 의한 지방 세포의 파괴를 더욱 효과적으로 만들어주게 된다.That is, 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.
이와 같이, 운동 신경이 상대적으로 적은 사용자의 이중턱 부위에 상기 저장성 지방 분해 조성물을 직접 주입하여, 지방 분해 효과를 극대화하고, 운동 신경의 영구 손상에 따른 부작용을 줄일 수 있다.As such, by directly injecting the hypotonic lipolytic composition into the user's double chin area with relatively few motor nerves, the lipolytic effect can be maximized and side effects due to permanent damage of the motor nerves can be reduced.
상기 피하 지방층에 주입된 저장성 지방 분해 조성물의 작용에 의해 지방 세포막을 파괴하며, 지방질을 수용성으로 변화시킨다. 이후, 상기 수용성으로 변화된 지방질은 소변이나 땀으로 체외로 배출될 수 있다(S140).The action of the 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).
이와 같이, 본 발명의 실시예에서는 저장성 지방 분해 조성물에 부작용 발생과 관련이 있는 포스파티딜콜린을 포함하지 않았다.As such, the embodiment of the present invention did not include phosphatidylcholine, which is associated with the occurrence of side effects in the hypotonic lipolytic composition.
반면에, 상기 저장성 지방 분해 조성물은 지방분해의 효과가 입증된 데옥시콜린산을 포함하였다.On the other hand, the hypotonic lipolytic composition contained deoxycholic acid, the effect of lipolysis has been demonstrated.
또한, 상기 저장성 지방 분해 조성물은 저장성 용액을 바탕으로 상기 히알루로니다아제를 포함하여, 상기 데옥시콜린산의 지방분해 효과를 극대화하였으며, 부종, 홍반, 통증, 피부경결 등의 불편함을 줄일 수 있다.In addition, the 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.
도 2는 본 발명의 제 2 실시예에 따른 저장성 지방 분해 조성물의 제조 방법을 나타낸 흐름도이다.2 is a flowchart illustrating a method of preparing a hypotonic lipolytic composition according to a second embodiment of the present invention.
먼저, 증류수에 염화나트륨을 투입하고 교반하여 저장성 용액을 제조(또는 준비)한다.First, sodium chloride is added to distilled water and stirred to prepare (or prepare) a storage solution.
상기 염화나트륨은 낮은 삼투압 용액(또는 상기 저장성 용액)을 제조하기 위한 용도로 사용한다.The sodium chloride is used to prepare a low osmotic solution (or the hypotonic solution).
즉, 상기 염화나트륨은 저장성 지방 분해 조성물의 피하 주입 시, 삼투압 차이에 의한 물리적인 지방 세포 파괴(또는 분해)를 유도하는 효과가 있다.That is, 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.
이때, 상기 증류수는 저장성 지방 분해 조성물의 총 중량을 기준으로 1 중량% ~ 99 중량%이고, 상기 염화나트륨은 상기 저장성 지방 분해 조성물의 총 중량을 기준으로 0.01 중량% ~ 0.89 중량%(일반적으로 0.45 중량%)일 수 있다.At this time, 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 %).
여기서, 상기 교반 조건 및 시간은 250 rpm ~ 300 rpm 회전 속도를 갖는 교반기(미도시)에서 5분 ~ 20분(일반적으로 10분) 정도 교반하며, 이때의 압력은 대기압이고 온도는 상온일 수 있다. 이러한 상기 교반 조건 및 시간은 설계자의 설계에 따라 다양하게 설정할 수도 있다. 또한, 이하 모든 교반 단계에서 상기 교반 환경(상기 교반 조건 및 시간) 하에서 혼합액이 제조될 수 있다(S210).Here, the 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. In addition, a mixed solution may be prepared under the stirring environment (the stirring conditions and time) in all stirring steps (S210).
이후, 상기 제조된 저장성 용액에 데옥시콜린산을 투입하고 교반하여 A 혼합액을 제조(또는 준비)한다.Thereafter, deoxycholic acid is added to the prepared storage solution and stirred to prepare (or prepare) A mixed solution.
상기 데옥시콜린산은 상기 저장성 지방 분해 조성물의 피하 주입 시, 지방 세포를 선택적으로 파괴하여, 지방 부피를 감소시키는 효과가 있다. 이와 같이 파괴된 지방 세포는 재차 지방 축적을 할 수 없으며, 영구적인 지방 부피의 감소를 유발한다.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.
이때, 상기 데옥시콜린산은 상기 저장성 지방 분해 조성물의 총 중량을 기준으로 0.01 중량% ~ 9.9 중량%(일반적으로 0.075 중량%)일 수 있다(S220).In this case, 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).
이후, 상기 제조된 A 혼합액에 히알루로니다아제를 투입하고 교반하여 B 혼합액을 제조(또는 준비)한다.Then, hyaluronidase is added to the prepared A mixed solution and stirred to prepare (or prepare) the B mixed solution.
또한, 상온에서 히알루로니다아제의 생물학적 활성이 50 I.U/ml ~ 3,000 I.U/ml(일반적으로 90 I.U/ml)인 상기 히알루로니다아제가 상기 A 혼합액에 투입될 수 있다(S230).In addition, 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).
이후, 상기 제조된 B 혼합액에 완충제 및 기타 첨가제를 투입하고 교반하여 상기 저장성 지방 분해 조성물을 제조(또는 준비/완성)한다.Thereafter, a buffer and other additives are added to the prepared B mixture, followed by stirring to prepare (or prepare / complete) the hypotonic lipolysis composition.
상기 완충제는 상기 저장성 지방 분해 조성물의 산도(pH)를 조절하기 위한 용도이며, 유당 수화물(lactose hydrate), 석시네이트(succinate), 아세테이트(acetate), 포스페이트(phosphate), 시트레이트(citrate), 아코니테이트(aconitate), 말레이트(malate), 카보네이트(carbonate) 등을 포함한다.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.
또한, 상기 본 발명의 실시예에서 설명하고 있는 완충제 이외에도, 수용 가능한 pH 안정성을 제공하거나 지시된(또는 미리 설정된) 범위 내의 완충 용량(buffer capacity)을 충족하는 다양한 완충제가 사용될 수도 있다.In addition to the buffers described in the embodiments of the present invention, various buffers may also be used that provide acceptable pH stability or meet buffer capacity within the indicated (or preset) range.
상기 첨가제는 상기 저장성 지방 분해 조성물의 약효 기간을 유지하기 위한 용도이며, 희석제, 아쥬반트(adjuvant), 부형제(excipient), 비히클(vehicle: 매체/매개물) 등의 담체(擔體)를 포함한다.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.
이때, 약제학적 담체는 멸균 액체, 물 및 석유, 동물, 땅콩 오일, 대두 오일, 미네랄 오일 및 참기름과 같은 식물 또는 합성 기원의 담체를 포함하는 오일일 수 있다.At this time, 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.
또한, 식염수 용액, 수성 덱스트로스, 클리세롤 용액 등은 액체 담체로 사용될 수 있다.In addition, saline solution, aqueous dextrose, glycerol solution and the like can be used as the liquid carrier.
예를 들어, 비경구용 제제에 사용되는 약제학적으로 허용되는 담체에는 수성 비히클, 비수성 비히클, 항미생물제, 등장화제(tonicity agent), 산화방지제, 국소 마취제, 현탁제 및 분산제, 에멀전화제, 금속봉쇄제 또는 킬러레이트화제, 기타 약제학적으로 허용되는 물질 등을 포함한다.For example, 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.
상기 수성 비히클은 염화나트륨 주사제, 링거 주사제, 등장성 덱스트로스 주사제, 멸균수 주사제, 덱스트로스 및 락테이트화 링거 주사제 등을 포함한다.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.
상기 비수성 비히클(또는 비수성 비경구 비히클)은 식물 기원의 고정된 오일, 면실유, 옥수수유, 참기름, 땅콩 오일 등을 포함한다.Such non-aqueous vehicles (or non-aqueous parenteral vehicles) include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil, peanut oil and the like.
정균 또는 정진균 농축물 중의 상기 항미생물제는 페놀(phenol) 또는 크레졸(cresol), 벤질 알코올(benzyl alcohol), 클로로부탄올(chlorobutanol), 메틸 및 프로필 p-히드록시벤조산 에스테르(methyl and propyl p-Hydroxybenzoic esters), 티메로살(thimerosal), 벤즈알코늄 클로라이드(benzalkonium chloride), 벤즈에토늄 클로라이드(benzethonium chloride) 등을 포함한다.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.
상기 등장화제는 염화나트륨, 덱스트로스(Dextrose) 등을 포함한다.The tonicity agent includes sodium chloride, dextrose and the like.
상기 산화방지제는 나트륨 비설페이트(sodium bisulfate) 등을 포함한다.The antioxidant includes sodium bisulfate and the like.
상기 국소 마취제는 리도케인 히드로클로라이드(lidocaine hydrochloride), 프로케인 히드로클로라이드(procaine hydrochloride) 등을 포함한다.The local anesthetics include lidocaine hydrochloride, procaine hydrochloride, and the like.
상기 현탁제 및 분산제는 나트륨 카르복시메틸셀룰로스(Sodium Carboxymethylcellulose), 히드록시프로필 메틸셀룰로스(Hydroxypropylmethylcellulose), 폴리비닐피롤리돈(Polyvinylpyrollidon) 등을 포함한다.The suspending agent and dispersing agent include sodium carboxymethyl cellulose (Sodium Carboxymethylcellulose), hydroxypropyl methylcellulose (Hydroxypropylmethylcellulose), polyvinylpyrollidon (Polyvinylpyrollidon) and the like.
상기 에멀전화제는 폴리소르베이트 80(TWEENs 80) 등을 포함한다.The emulsifying agent includes polysorbate 80 (TWEENs 80) and the like.
상기 금속 이온의 금속봉쇄제 또는 킬러레이트화제는 EDTA(ethylenediaminetertraacetic acid) 등을 포함한다.The metal blocking agent or chelating agent of the metal ion includes EDTA (ethylenediaminetertraacetic acid).
상기 약제학적 담체는 수혼화성 비히클용의 에틸 알콜, 폴리에틸렌 글리콜, 프로필렌 글리콜, pH 조정용의 수산화나트륨, 염산, 시트르산, 락트산 등을 포함할 수 있다.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.
또한, 상기 첨가제는 희석제(예를 들어 락토오스(lactose), 수크로스(sucrose), 디칼슘 포스페이트(dicalcium phosphate), 카르복시메틸셀룰로스(Carboxymethylcellulose) 등 포함), 윤활제(예를 들어 마그네슘 스테아레이트(magnesium stearate), 칼슘 스테아레이트(calcium stearate), 탈크(talc) 등 포함), 결합제(예를 들어 전분, 천연 검 등 포함) 등을 포함할 수도 있다.In addition, 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.
또한, 상기 첨가제는 미량의 습윤제 또는 에멀전화제, pH 완충제(예를 들어 아세테이트, 나트륨 시트레이트, 시클로덱스트린 유도체(cyclodextrin derivative), 소르비탄 모노라우레이트(SorbitanMonooleate), 트리에탄올아민 나트륨 아세테이트(triethanolamine acetate), 트리에탄올아미노 올레에이트(triethanolaminolate) 등 포함) 등을 포함할 수도 있다.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.
이때, 상기 완충제는 상기 저장성 지방 분해 조성물의 총 중량을 기준으로 0.01 중량% ~ 50 중량%, 상기 첨가제(또는 기타 첨가제)는 상기 저장성 지방 분해 조성물의 총 중량을 기준으로 0.01 중량% ~ 50 중량%일 수 있다.In this case, the buffer is 0.01% to 50% by weight based on the total weight of the hypotonic lipolytic composition, and the additive (or other additives) is 0.01% to 50% by weight based on the total weight of the hypotonic lipolytic composition. Can be.
이와 같이, 상기 저장성 지방 분해 조성물은 상기 증류수, 상기 염화나트륨, 상기 데옥시콜린산, 상기 히알루로니다아제, 상기 완충제, 상기 첨가제 등을 교반하여 제조할 수 있다.As such, the 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.
성 분ingredient 조성비(중량%)Composition ratio (wt%)
증류수Distilled water 1 ~ 991 to 99
염화나트륨Sodium chloride 0.01 ~ 0.890.01 to 0.89
데옥시콜린산Deoxycholic acid 0.01 ~ 9.90.01 to 9.9
히알루로니다아제Hyaluronidase 50 ~ 3,000 I.U/ml50 to 3,000 I.U / ml
완충제Buffer 0.01 ~ 500.01 to 50
첨가제additive 0.01 ~ 500.01 to 50
또한, 상기 저장성 지방 분해 조성물은 상기 [표 2]에서와 같은 조성비(중량%)로 구성할 수 있다.In addition, the hypotonic lipolytic composition may be composed of the composition ratio (% by weight) as shown in the [Table 2].
또한, 상기 저장성 지방 분해 조성물은 상기 히알루로니다아제를 50 I.U/ml ~ 3,000 I.U/ml 단위로 포함하고, 상기 저장성 지방 분해 조성물 총중량 대비 상기 데옥시콜린산을 0.01 중량% ~ 9.9 중량%, 상기 저장성 지방 분해 조성물의 산도를 조절하기 위한 완충제 0.01 중량% ~ 50 중량%, 상기 저장성 지방 분해 조성물의 약효 기간을 유지하기 위한 첨가제 0.01 중량% ~ 50 중량% 및 나머지 상기 저장성 용액으로 구성한다. 여기서, 상기 저장성 용액은 상기 저장성 지방 분해 조성물의 피하 주입 시 삼투압 차이에 의한 물리적인 지방 세포 파괴(또는 분해)를 유도하기 위한 것으로, 상기 저장성 용액 1000ml를 기준으로 염화나트륨 0.1g ~ 8.9g(일반적으로 4.5g) 및 나머지 증류수로 구성한다.In addition, 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. Here, 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.
또한, 상기 저장성 지방 분해 조성물은 용액의 제형이거나 동결건조된 제형으로 관리(또는 구성/제조/준비)한다.In addition, the hypotonic lipolytic composition is administered (or composed / manufactured / prepared) in the form of a solution or a lyophilized formulation.
또한, 상기 저장성 지방 분해 조성물이 동결건조된 제형인 경우, 희석액에 의해 액체 상태로 준비할 수도 있다(S240).In addition, when the depotable lipolytic composition is a lyophilized formulation, it may be prepared in a liquid state by dilution (S240).
이후, 상기 제조된(또는 준비된) 저장성 지방 분해 조성물은 미리 설정된 용기(미도시)에 용도별(또는 단위별)로 포장된다. 여기서, 상기 포장되는 약제학적 활성화합물을 포함하는 저장성 지방 분해 조성물은 멸균성이 보장되어야 한다.Thereafter, the prepared (or prepared) hypotonic lipolytic composition is packaged by use (or unit) in a predetermined container (not shown). Here, the hypotonic lipolytic composition comprising the packaged pharmaceutically active compound should be sterile.
즉, 상기 제조된(또는 준비된) 저장성 지방 분해 조성물은 앰플, 바이알, 바늘이 있는 주사기 등에 포장된다.That is, the prepared (or prepared) hypotonic lipolytic composition is packaged in ampoules, vials, syringes with needles and the like.
또한, 상기 포장된 저장성 지방 분해 조성물은 사용자의 신체 피하 지방층에 직접 주입되어, 지방 세포를 선택적으로 파괴함으로써 지방 부피 감소를 유발하며, 안면 및 체형을 축소 및 교정할 수 있다. 이때, 상기 저장성 지방 분해 조성물은 사용자의 이중턱 부위 등의 피하 지방층에 주입될 수 있다.In addition, 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. At this time, the hypotonic lipolytic composition may be injected into the subcutaneous fat layer, such as the user's double chin area.
즉, 상기 저장성 지방 분해 조성물을 인체 조직에 주입하게 되면, 상기 저장성 지방 분해 조성물이 주입된 조직의 세포들(예를 들어 지방 세포 등 포함)이 삼투압 차이에 의해 부풀어 오르게 되며, 상기 삼투압 차이에 의해 부풀어 오르게 된 세포들로 인해 상기 데옥시콜린산에 의한 지방 세포의 파괴를 더욱 효과적으로 만들어주게 된다.That is, 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.
이와 같이, 운동 신경이 상대적으로 적은 사용자의 이중턱 부위에 상기 저장성 지방 분해 조성물을 직접 주입하여, 지방 분해 효과를 극대화하고, 운동 신경의 영구 손상에 따른 부작용을 줄일 수 있다.As such, by directly injecting the hypotonic lipolytic composition into the user's double chin area with relatively few motor nerves, the lipolytic effect can be maximized and side effects due to permanent damage of the motor nerves can be reduced.
상기 피하 지방층에 주입된 저장성 지방 분해 조성물의 작용에 의해 지방 세포막을 파괴하며, 지방질을 수용성으로 변화시킨다. 이후, 상기 수용성으로 변화된 지방질은 소변이나 땀으로 체외로 배출될 수 있다(S250).The action of the 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).
<실시예><Example>
본 발명의 실시예에 따른 상기 저장성 지방 분해 조성물(또는 주사제 조성물)은 총액 100ml를 기준으로 히알루로니다아제 9000I.U, 데옥시콜린산 75mg, 염화나트륨 450mg 및 나머지 증류수를 사용하였다.The 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.
<비교예 1>Comparative Example 1
생리식염수를 단독으로 사용하였다.Physiological saline was used alone.
<비교예 2>Comparative Example 2
생리식염수에 고용량의 데옥시콜린산 1000mg을 사용하였다.A high dose of 1000 mg of deoxycholic acid was used for the saline solution.
<비교예 3>Comparative Example 3
생리식염수에 데옥시콜린산 75mg을 사용하였다.75 mg of deoxycholic acid was used for the saline solution.
<비교예 4><Comparative Example 4>
생리식염수에 히알루로니다아제 9000I.U를 사용하였다.Hyaluronidase 9000 I.U was used for physiological saline.
<비교예 5>Comparative Example 5
저장성 용액을 단독으로 사용하였다.The hypotonic solution was used alone.
<비교예 6>Comparative Example 6
생리식염수에 히알루로니다아제 9000I.U, 데옥시콜린산 75mg을 사용하였다.Hyaluronidase 9000 I.U and 75 mg of deoxycholic acid were used for the saline solution.
이와 같은 본 발명의 실시예에 따른 주사제 조성물과 상기 비교예 1 내지 상기 비교예 6에 따른 주사제 조성물의 구성은 다음의 [표 3]과 같이 나타낼 수 있다.The 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.
성분ingredient 실시예Example 비교예1Comparative Example 1 비교예2Comparative Example 2 비교예3Comparative Example 3 비교예4Comparative Example 4 비교예5Comparative Example 5 비교예6Comparative Example 6
히알루로니다아제Hyaluronidase 9000I.U9000I.U -- -- -- 9000I.U9000I.U -- 9000I.U9000I.U
데옥시콜린산Deoxycholic acid 75mg(0.075%)75 mg (0.075%) -- 1000mg(1%)1000 mg (1%) 75mg(0.075%)75 mg (0.075%) -- -- 75mg(0.075%)75 mg (0.075%)
염화나트륨Sodium chloride 450mg(0.45%)450 mg (0.45%) 900mg(0.9%)900 mg (0.9%) 900mg(0.9%)900 mg (0.9%) 900mg(0.9%)900 mg (0.9%) 900mg(0.9%)900 mg (0.9%) 450mg(0.45%)450 mg (0.45%) 900mg(0.9%)900 mg (0.9%)
증류수Distilled water 잔량Remaining amount 잔량Remaining amount 잔량Remaining amount 잔량Remaining amount 잔량Remaining amount 잔량Remaining amount 잔량Remaining amount
총액Total amount 100ml100 ml 100ml100 ml 100ml100 ml 100ml100 ml 100ml100 ml 100ml100 ml 100ml100 ml
여기서, 모든 주사제 조성물은 100ml로 제조하였다. 이때, 상기 히알루로니다아제는 우리들제약(주)의 히알라프주(1 바이알 1500I.U)를 사용하였다. 상기 주사제 조성물의 조성은 데옥시콜린산(제조원: 시그마-알드리치)을 해당하는 함량에 맞게 미세저울로 측정한 후 생리식염수(제조원: 대한약품공업) 또는, 생리식염수와 증류수(제조원: 대한약품공업)를 혼합한 저장성 용액에 용해하여 상기 해당하는 각 함량으로 조제하였다.Here, all injectable compositions were prepared in 100 ml. At this time, 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.
또한, 상기 실시예, 상기 비교예 4 및 상기 비교예 6에서처럼 히알루로니다아제를 포함하는 주사제 조성물의 경우, 각각 조제된 용액을 히알라프주 바이알에 넣어 동결 건조된 히알루로니다아제를 녹인 후, 다시 회수하는 방법으로 주사제 조성물을 각각 제조하였다.In addition, in the case of the injectable composition containing hyaluronidase as in Example, Comparative Example 4 and Comparative Example 6, each of the prepared solution was put in a hyaluronic vial to dissolve lyophilized hyaluronidase, Injectable compositions were each prepared by the method of recovery again.
<시험예><Test Example>
본 시험에서 사용된 실험동물인 수컷 5주령 Sprague Dawley rat는 (주)오리엔트바이오에서 구입하였다. 또한, Rat의 사육 환경 조건은 22℃ ~ 24℃, 상대습도 30% ~ 50%로 설정하였고, 사육 상자당 2마리씩 사육하였다. 오전 7시 ~ 오후 7시까지 150룩스(Lux) ~ 300룩스의 조명을 주었고, 하루에 12시간 점등, 12시간 소등하였다. 사료는 고지방 식이(45% 지방함유, 2018, Research Diet Inc, USA 제조)를 사용하여 자유 섭취시켰다. 또한, 고지방 식이로 8주간 비만을 유발시킨 동물들을 체중을 기준으로 군 분리를 하였고, 군 분리 후 동물의 우측 피하 서혜부 지방에 본 발명(또는 실시예)의 주사제와 비교예 1 ~ 비교예 6의 주사제를 4주간 주 1회 피하 주사하였다.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 ℃ ~ 24 ℃, 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). In addition, 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.
주사제 조성Injection composition 그룹group 사료feed 투여량(ml)Dosage (ml) 개체수Number of individuals
비교예1Comparative Example 1 정상 대조군Normal control 일반사료General feed 500500 88
비교예1Comparative Example 1 비만유발 대조군Obesity-induced Control 고지방사료High Fat Feed 500500 88
비교예2Comparative Example 2 실험군 1Experiment group 1 고지방사료High Fat Feed 500500 88
비교예3Comparative Example 3 실험군 2Experiment group 2 고지방사료High Fat Feed 500500 88
비교예4Comparative Example 4 실험군 3Experiment group 3 고지방사료High Fat Feed 500500 88
비교예5Comparative Example 5 실험군 4Experimental Group 4 고지방사료High Fat Feed 500500 88
비교예6Comparative Example 6 실험군 5Experimental group 5 고지방사료High Fat Feed 500500 88
실시예Example 실험군 6Experimental Group 6 고지방사료High Fat Feed 500500 88
4주간 주 1회 주사제를 투여한 후, 최종 주사제 투여 후 2주 후 동물을 이소푸루란(isoflurane)으로 흡입 마취하여 희생한 후, 좌우측 서혜부 지방을 모두 적출하여 미세저울로 적출한 지방의 무게를 측정하고, 그 지방 무게를 해당 동물의 체중으로 나누어 지방 조직의 상대 중량을 산출하였다.After four weeks of injections, two weeks after the last injection, animals were inhaled with isophoran and anesthetized and sacrificed. The fat weight was divided by the weight of the animal to calculate the relative weight of the adipose tissue.
시험에서 얻어진 모든 시험 결과는 평균치 ± 표준오차로 표시하고, SPSS(version 20, IBM SPSS Statistics, USA)를 사용하여 검정하였다. 또한, 모든 자료들에 대해 분산의 동질성을 비교하기 위한 Levene's Test를 실시하였으며, 분산이 동질성을 갖는 경우 일원 분류 분산분석(one-way Analysis of Variance: ANOVA)을 실시하여 유의성이 관찰되면, 대조군과의 유의차가 있는 시험군을 알아내기 위하여 Dunnett's T-test를 실시하였다. 각 그룹별 개체수는 8 수였고, 통계학적 유의성 판정을 하여 별표(* 또는 **)로 표기하였다. (유의수준 *: 양측 5%, **: 1%)All test results obtained in the test were expressed as mean ± standard error and tested using SPSS (version 20, IBM SPSS Statistics, USA). In addition, Levene's Test was conducted to compare the homogeneity of variances for all data.If variances were homogeneous, one-way analysis of variance (ANOVA) was performed, and significance was observed. Dunnett's T-test was conducted to identify the test groups with significant differences. The number of individuals in each group was 8, and statistical significance was determined by an asterisk (* or **). (Significance level *: 5% on both sides, **: 1%)
적출한 서혜부 지방을 측정한 결과, 비만 유발 대조군(또는 비만 대조군)의 서혜부 지방 상대 중량은 정상 대조군과 비교 시, 유의한 수준으로 높게 나타나 비만 유발에 의한 서혜부 지방이 크게 형성된 것을 관찰할 수 있었다.As a result of measuring the extracted inguinal fat, the relative weight of the inguinal fat of the obesity-induced control group (or obese control group) was significantly higher than that of the normal control group.
도 3에 도시된 바와 같이, 비만 동물에 본 발명의 실시예에 따른 주사제와 비교예 1 ~ 비교예 6의 주사제를 4주간 주 1회 피하 주사한 결과, 비교예 2, 비교예 3, 비교예 6과 본 발명의 실시예에 따른 주사제는 좌측 서혜부 지방과 현저한 차이가 나타났다.As shown in FIG. 3, a subcutaneous injection of an injection agent according to an embodiment of the present invention and an injection agent of Comparative Examples 1 to 6 once a week for 4 weeks was performed in an obese animal. Comparative Example 2, Comparative Example 3, and Comparative Example 6 and the injection according to the embodiment of the present invention was significantly different from the left inguinal fat.
또한, 상기 도 3에 도시된 바와 같이, 비교예 2, 비교예 6과 본 발명의 실시예에 따른 주사제는 비만 유발 대조군의 우측 서혜부 지방 상대중량과의 대비에서도 유의하게 낮은 상대 중량이 나타났다.In addition, as shown in Figure 3, 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.
특히, 다음의 [표 5]에 나타낸 바와 같이, 본 발명의 실시예에 따른 주사제를 투여한 그룹의 우측 서혜부 지방의 상대 중량은 0.0120 ± 0.0019로 비만 유발 대조군의 우측 서혜부 지방 상대 중량 0.0167 ± 0.0026에 비해 약 28.1% 감소하여 가장 낮은 상대 중량을 보였다.In particular, as shown in the following Table 5, 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.
주사제조성Injection Preparation 그룹group 좌측 서혜부 지방 상대중량(좌측 서혜부 지방무게/체중)Left Inguinal Fat Relative Weight (Left Inguinal Fat Weight / Weight) 우측 서혜부 지방 상대중량(우측 서혜부 지방무게/체중)Right inguinal fat relative weight (right inguinal fat weight / weight) 비만유발대조군대비 지방 감소율Fat Reduction in Obesity-Induced Control
비교예1Comparative Example 1 정상 대조군Normal control 0.0057 ± 0.00080.0057 ± 0.0008 0.0055 ± 0.0010**0.0055 ± 0.0010 ** --
비교예1Comparative Example 1 비만유발 대조군Obesity-induced Control 0.0169 ± 0.00300.0169 ± 0.0030 0.0167 ± 0.00260.0167 ± 0.0026 --
비교예2Comparative Example 2 실험군 1Experiment group 1 0.0168 ± 0.00310.0168 ± 0.0031 0.0128 ± 0.00200.0128 ± 0.0020 23.3%23.3%
비교예3Comparative Example 3 실험군 2Experiment group 2 0.0170 ± 0.00260.0170 ± 0.0026 0.0139 ± 0.00280.0139 ± 0.0028 16.7%16.7%
비교예4Comparative Example 4 실험군 3Experiment group 3 0.0167 ± 0.00440.0167 ± 0.0044 0.0157 ± 0.00350.0157 ± 0.0035 5.9%5.9%
비교예5Comparative Example 5 실험군 4Experimental Group 4 0.0165 ± 0.00250.0165 ± 0.0025 0.0162 ± 0.00250.0162 ± 0.0025 2.9%2.9%
비교예6Comparative Example 6 실험군 5Experimental group 5 0.0168 ± 0.00380.0168 ± 0.0038 0.0130 ± 0.0038*0.0130 ± 0.0038 * 22.1%22.1%
실시예Example 실험군 6Experimental Group 6 0.0172 ± 0.00230.0172 ± 0.0023 0.0120 ± 0.0019**0.0120 ± 0.0019 ** 28.1%28.1%
이와 같이, 생리식염수에 고용량의 데옥시콜린산 또는 히알루로니다아제를 단독으로 사용하거나, 생리식염수에 데옥시콜린산과 히알루로니다아제를 사용하는 경우에 비해서, 본 발명의 실시예에 따른 저장성 용액에 데옥시콜린산과 히알루로니다아제를 사용하는 경우, 국부 지방 분해 효과가 더 우수한 것을 확인할 수 있다.As described above, 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. When deoxycholic acid and hyaluronidase are used, it can be seen that local lipolytic effect is better.
본 발명의 실시예에서는, 상기 저장성 지방 분해 조성물의 지방 분해 효과를 극대화하고, 운동 신경의 영구 손상에 따른 부작용을 줄이기 위해서, 사용자의 이중턱 부위에 상기 저장성 지방 분해 조성물을 직접 주입하는 것을 설명하고 있으나, 이에 한정되는 것은 아니며, 안면부(예를 들어 광대, 볼, 안와지방 등 포함), 신체부(예를 들어 복부, 등, 옆구리, 상완, 허벅지, 종아리 등 포함) 등에 대해서도, 상기 저장성 지방 분해 조성물에 포함되는 데옥시콜린산과 히알루로니다아제의 조성비에 따른 안정성 시험 등을 통해, 상기 안면부, 신체부 등에도 상기 저장성 지방 분해 조성물을 주입할 수도 있다.In the embodiment of the present invention, 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 However, 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.) Through the stability test according to the composition ratio of the deoxycholic acid and hyaluronidase contained in, etc., the hypotonic lipolytic composition may also be injected into the face, body and the like.
본 발명의 실시예는 앞서 설명된 바와 같이, 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제 등이 포함된 저장성 지방 분해 조성물을 제조하여, 고농도(예를 들어 조성물 총 중량의 10 중량% ~ 95 중량%)의 데옥시콜린산 단독 사용에 따른 주입 부위 경결(consolidation) 현상 발생을 줄이고, 데옥시콜린산 단독 사용에 비해 지방 세포 외 다른 지방 성분을 함유하는 세포들(예를 들어 신경 세포, 근육 세포, 골 세포 등 포함)에 대한 영향을 줄여 신경마비, 근육위축, 골위축 등의 부작용 발생을 줄이며, 부종(edema, swelling), 홍반(erythema), 통증(pain) 등의 부작용(adverse effect)을 줄이며, 저장성 용액을 바탕으로 히알루로니다아제를 복합 사용함에 따라 지방 세포 파괴의 효율을 증가시키고, 피하 내 투여로써 국소부위 축적된 지방감소용 약제로 사용할 수 있다.As described above, 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. To reduce the 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.
또한, 본 발명의 실시예는 앞서 설명된 바와 같이, 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제, 완충제, 첨가제 등이 포함된 저장성 지방 분해 조성물을 제조하여, 저장성 지방 분해 조성물이 주입된 조직(tissue)에서 데옥시콜린산이 지방 세포에 효과적으로 전달되어, 저농도(예를 들어 저장성 지방 분해 조성물 총 중량의 0.01 중량% ~ 9.9 중량%)의 데옥시콜린산으로도 효율적인 지방분해의 효과를 얻을 수 있으며, 고농도의 데옥시콜린산 주입으로 인한 주입부 부종, 홍반, 통증, 피부경결 등의 현상을 줄일 수 있다.In addition, an embodiment of the present invention, as described above, 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.
전술된 내용은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자라면 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 수정 및 변형이 가능할 것이다. 따라서, 본 발명에 개시된 실시예들은 본 발명의 기술 사상을 한정하기 위한 것이 아니라 설명하기 위한 것이고, 이러한 실시예에 의하여 본 발명의 기술 사상의 범위가 한정되는 것은 아니다. 본 발명의 보호 범위는 아래의 청구범위에 의하여 해석되어야 하며, 그와 동등한 범위 내에 있는 모든 기술 사상은 본 발명의 권리범위에 포함되는 것으로 해석되어야 할 것이다.The above description may be modified and modified by those skilled in the art without departing from the essential characteristics of the present invention. Therefore, the embodiments disclosed in the present invention are not intended to limit the technical idea of the present invention but to describe the present invention, and the scope of the technical idea of the present invention is not limited by these embodiments. The protection scope of the present invention should be interpreted by the following claims, and all technical ideas within the equivalent scope should be interpreted as being included in the scope of the present invention.
본 발명은 증류수와 염화나트륨으로 구성된 저장성 용액에, 데옥시콜린산, 히알루로니다아제 등이 포함된 저장성 지방 분해 조성물을 제조함으로써, 데옥시콜린산 단독 사용에 따른 주입 부위 경결(consolidation) 현상 발생을 줄이고, 데옥시콜린산 단독 사용에 비해 지방 세포 외 다른 지방 성분을 함유하는 세포들(예를 들어 신경 세포, 근육 세포, 골 세포 등 포함)에 대한 영향을 줄여 신경마비, 근육위축, 골위축 등의 부작용 발생을 줄이며, 부종(edema, swelling), 홍반(erythema), 통증(pain) 등의 부작용(adverse effect)을 줄이며, 저장성 용액을 바탕으로 히알루로니다아제를 복합 사용함에 따라 지방 세포 파괴의 효율을 증가시키고, 피하 내 투여로써 국소부위 축적된 지방감소용 약제로 사용할 수 있는 것으로, 피부 미용 분야, 의료 산업 분야 등에서 광범위하게 이용될 수 있다.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. It can be used as a medicinal agent for reducing fat accumulated in the local area by increasing the efficiency and subcutaneously, and is widely used in the field of skin beauty and medical industry. Can be used.

Claims (9)

  1. 저장성 지방 분해 조성물에 있어서,In a hypotonic lipolytic composition,
    히알루로니다아제(hyaluronidase) 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 저장성 지방 분해 조성물 총중량 대비 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산(sodium deoxycholate)을 0.01 중량% ~ 9.9 중량% 및 나머지는 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 저장성 용액으로 구성하는 저장성 지방 분해 조성물.Hyaluronidase (hyaluronidase) comprises 50 IU / ml ~ 3,000 IU / ml, to reduce the fat volume by selectively destroying fat cells during subcutaneous fat layer injection of the hypotonic lipolytic composition relative to the total weight of the hypotonic lipolytic composition A hypotonic lipolytic composition comprising 0.01% to 9.9% by weight of oxycholine acid and a remaining solution that induces physical fat cell degradation by osmotic pressure difference.
  2. 저장성 지방 분해 조성물에 있어서,In a hypotonic lipolytic composition,
    히알루로니다아제 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 저장성 지방 분해 조성물 총중량 대비 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산을 0.01 중량% ~ 9.9 중량%, 상기 저장성 지방 분해 조성물의 산도(pH)를 조절하기 위한 완충제 0.01 중량% ~ 50 중량%, 상기 저장성 지방 분해 조성물의 약효 기간을 유지하기 위한 첨가제 0.01 중량% ~ 50 중량% 및 나머지는 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 저장성 용액으로 구성하는 저장성 지방 분해 조성물.Deoxycholic acid comprising hyaluronidase 50 IU / ml ~ 3,000 IU / ml, selectively destroying fat cells upon subcutaneous fat layer injection of the hypotonic lipolytic composition relative to the total weight of the hypotonic lipolytic composition to reduce fat volume 0.01 wt% to 9.9 wt%, 0.01 wt% to 50 wt% of a buffer for adjusting the acidity (pH) of the hypotonic lipolytic composition, and 0.01 wt% to 50 wt% of an additive for maintaining the shelf life of the hypotonic lipolytic composition A hypotonic lipolysis composition comprising the percent by weight and the remainder of a hypotonic solution that induces physical adipose cell degradation by osmotic pressure difference.
  3. 제 1 항 또는 제 2항에 있어서,The method according to claim 1 or 2,
    상기 저장성 용액은,The storage solution is,
    증류수 1000ml에 염화나트륨(sodium chloride) 0.1g ~ 8.9g을 투입하고 교반하여 준비하는 것을 특징으로 하는 저장성 지방 분해 조성물.A hypotonic lipolysis composition, characterized in that 0.1g to 8.9g of sodium chloride is added to 1000ml of distilled water and prepared by stirring.
  4. 제 2 항에 있어서,The method of claim 2,
    상기 완충제는,The buffer,
    유당 수화물(lactose hydrate), 석시네이트(succinate), 아세테이트(acetate), 포스페이트(phosphate), 시트레이트(citrate), 아코니테이트(aconitate), 말레이트(malate) 및 카보네이트(carbonate) 중 적어도 하나를 포함하는 것을 특징으로 하는 저장성 지방 분해 조성물.At least one of lactose hydrate, succinate, acetate, phosphate, citrate, aconitate, malate and carbonate A hypotonic lipolytic composition comprising a.
  5. 제 2 항에 있어서,The method of claim 2,
    상기 첨가제는,The additive,
    희석제, 아쥬반트(adjuvant), 부형제(excipient) 및 비히클(vehicle) 중 적어도 하나를 포함하는 것을 특징으로 하는 저장성 지방 분해 조성물.A hypotonic lipolytic composition comprising at least one of a diluent, an adjuvant, an excipient, and a vehicle.
  6. 저장성 지방 분해 조성물의 제조 방법에 있어서,In the method for producing a hypotonic lipolytic composition,
    증류수에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 염화나트륨을 투입하고 교반하여 저장성 용액을 제조하는 단계;Preparing a storage solution by injecting and stirring sodium chloride which induces physical fat cell decomposition due to an osmotic pressure difference when the subcutaneous fat layer is injected into the distilled water;
    상기 제조된 저장성 용액에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산을 투입하고 교반하여 A 혼합액을 제조하는 단계; 및Preparing 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
    상기 제조된 A 혼합액에 피하 결합 조직의 약물 침투력을 증가시켜 상기 데옥시콜린산이 지방 세포에 확산(dispersion), 전달(delivery) 및 작용(effect)하도록 히알루로니다아제를 투입하고 교반하여 상기 저장성 지방 분해 조성물을 제조하는 단계를 포함하는 저장성 지방 분해 조성물의 제조 방법.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. A method of making a hypotonic lipolysis composition comprising the step of preparing a degradation composition.
  7. 제 6 항에 있어서,The method of claim 6,
    상기 저장성 지방 분해 조성물은,The hypotonic lipolytic composition,
    히알루로니다아제 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 데옥시콜린산을 0.01 중량% ~ 9.9 중량% 및 나머지는 상기 저장성 용액으로 구성하는 것을 특징으로 하는 저장성 지방 분해 조성물의 제조 방법.Hyaluronidase 50 IU / ml ~ 3,000 IU / ml, wherein the deoxycholic acid 0.01% to 9.9% by weight and the rest of the storage solution is a process for producing a lipolytic composition, characterized in that .
  8. 저장성 지방 분해 조성물의 제조 방법에 있어서,In the method for producing a hypotonic lipolytic composition,
    증류수에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 염화나트륨을 투입하고 교반하여 저장성 용액을 제조하는 단계;Preparing a storage solution by injecting and stirring sodium chloride which induces physical fat cell decomposition due to an osmotic pressure difference when the subcutaneous fat layer is injected into the distilled water;
    상기 제조된 저장성 용액에 상기 저장성 지방 분해 조성물의 피하 지방층 주입 시 지방 세포를 선택적으로 파괴하여 지방 부피를 감소시키는 데옥시콜린산을 투입하고 교반하여 A 혼합액을 제조하는 단계;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;
    상기 제조된 A 혼합액에 피하 결합 조직의 약물 침투력을 증가시켜 상기 데옥시콜린산이 지방 세포에 확산(dispersion), 전달(delivery) 및 작용(effect)하도록 히알루로니다아제를 투입하고 교반하여 B 혼합액을 제조하는 단계; 및Hyaluronidase 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
    상기 제조된 B 혼합액에 상기 저장성 지방 분해 조성물의 산도(pH)를 조절하기 위한 완충제 및 상기 저장성 지방 분해 조성물의 약효 기간을 유지하기 위한 첨가제를 투입하고 교반하여 상기 저장성 지방 분해 조성물을 제조하는 단계를 포함하는 저장성 지방 분해 조성물의 제조 방법.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 A method for producing a hypotonic lipolytic composition comprising.
  9. 제 8 항에 있어서,The method of claim 8,
    상기 저장성 지방 분해 조성물은,The hypotonic lipolytic composition,
    히알루로니다아제 50 I.U/ml ~ 3,000 I.U/ml를 포함하고, 상기 데옥시콜린산을 0.01 중량% ~ 9.9 중량%, 상기 완충제 0.01 중량% ~ 50 중량%, 상기 첨가제 0.01 중량% ~ 50 중량% 및 나머지는 삼투압 차이에 의한 물리적인 지방 세포 분해를 유도하는 저장성 용액으로 구성하는 저장성 지방 분해 조성물의 제조 방법.Hyaluronidase 50 IU / ml to 3,000 IU / ml, 0.01% to 9.9% by weight of the deoxycholic acid, 0.01% to 50% by weight of the buffer, 0.01% to 50% by weight of the additive And the rest of the method for producing a hypotonic lipolysis composition comprising a hypotonic solution that induces the physical fat cell degradation by the osmotic pressure difference.
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