WO2019164192A1 - Composition pharmaceutique filmogène contenant un principe actif analgésique de type anti-inflammatoire non stéroïdien - Google Patents

Composition pharmaceutique filmogène contenant un principe actif analgésique de type anti-inflammatoire non stéroïdien Download PDF

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WO2019164192A1
WO2019164192A1 PCT/KR2019/001891 KR2019001891W WO2019164192A1 WO 2019164192 A1 WO2019164192 A1 WO 2019164192A1 KR 2019001891 W KR2019001891 W KR 2019001891W WO 2019164192 A1 WO2019164192 A1 WO 2019164192A1
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alcohol
pharmaceutical composition
active ingredient
composition
group
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PCT/KR2019/001891
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Korean (ko)
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전준호
한상덕
강민형
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동아제약 주식회사
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention is a non-steroidal anti-inflammatory analgesic active ingredient that is directly applied to the affected area that requires analgesic, anti-inflammatory action to form a film is convenient to use and drug absorption into the skin is significantly increased to maximize the efficacy and significantly improved skin irritation It relates to a film-forming pharmaceutical composition comprising, and a method for producing the same.
  • Pain refers to uncomfortable sensations caused by stimulation of specific nerves with pain receptors, and is classified into headache, chest pain, abdominal pain, low back pain, and so on depending on the mechanism. Somatic pain, visceral pain And neurogenic pain.
  • Pain can be treated in a variety of ways depending on its cause. In particular, if the cause of pain is identified and it is determined that the onset of pain will be temporary or not significant, the symptomatic treatment that improves the quality of life by treating drugs that can alleviate pain (an analgesic) is implemented. It is desirable to.
  • Analgesic can be divided into narcotic or nonnarcotic analgesics. Narcotic analgesics are very effective, but they are not used for serious pain because of side effects such as hallucinations, addiction and constipation.
  • Non-narcotic analgesics can be divided into steroidal anti-inflammatory agents such as dexamethasone, prednisolone and methylprednisolone, and nonsteroidal anti-inflammatory agents such as acetaminophen, aspirin, indomethacin, diclofenac, pullulbiprofen, ketoprofen, ibuprofen and naproxen.
  • steroidal anti-inflammatory agents such as dexamethasone, prednisolone and methylprednisolone
  • nonsteroidal anti-inflammatory agents such as acetaminophen, aspirin, indomethacin, diclofenac, pullulbiprofen, ketoprofen, ibuprofen and naproxen.
  • COX cyclooxygenase
  • COX-1 is mainly involved in inflammation, pain and fever
  • COX-1 is involved in the secretion of gastrointestinal defense factors in the gastrointestinal tract. 2 Inhibition of analgesic, anti-inflammatory and antipyretic effects, but inhibition of defense factor production by COX-1 inhibition can cause gastrointestinal side effects such as bleeding, ulcers.
  • Nonsteroidal analgesics are administered by oral or topical administration, and when the pain is extensive and accompanied by fever, or when the pain is deep and the topical medication is not effective enough, oral administration Preferred, however, may cause gastrointestinal side effects as described above, the administration of which is preferably for a short time.
  • the localized location of the pain, the deeply affected area can be expected to have sufficient effect by drug delivery to the skin, and the patients who need long-term administration or have gastrointestinal underlying diseases such as gastric ulcer can be administered topically. desirable.
  • Formulations such as plaster or cataplasma are advantageous for long-term application, since the drug is mixed with a pressure sensitive adhesive and the like and can be attached directly to the affected area with a certain area.
  • a pressure sensitive adhesive and the like there is a problem in that it is inconvenient to apply to a lot of movement such as elbow, knee and finger joints.
  • the color of the formulation is much different from the skin color, so there is a disadvantage that aesthetically sensitive consumers cannot easily apply.
  • the skin irritation may occur due to the skin seal of the pressure-sensitive adhesive when applying the formulation, there is a disadvantage that the skin or hair attached to the adhesive when the formulation is applied and may suffer.
  • various permeation accelerators and pressure-sensitive adhesives have the disadvantage that often cause skin irritation in a closed environment.
  • Gel, ointment, and liquid formulations are applied to the surface of the skin to absorb the drug into the affected area to express the medicinal benefits. It has the advantage of being easy to be applied to areas of high movement such as elbows, knees and finger joints. In addition, there is an advantage that it is easy to apply to aesthetically sensitive areas because it is transparent. However, after applying the product, it is not completely dry and sticky, and the formulation is easily lost by physical contact such as contacting the cloth, and thus the drug efficacy is not sustained.
  • Topical anti-inflammatory drugs are known to have several orders of magnitude lower concentrations in tissues than oral administration. The causes are very small compared to the area of the gastrointestinal tract, and drug penetration through the skin is very low. Because.
  • Korean Patent Registration No. 10-0288190 discloses a composition having increased absorption containing pyoxycam and containing lower alcohol, HPMC, Carbopol, dimethyl glycol monoethylether, oleic acid, and alkanolamine. have.
  • Japanese Patent Publication No. 2002-503914 discloses a composition containing diclofenac and containing C2 to C4 alkyl alcohol, short chain N-alkyl pyrrolidone, and long chain alkyl pyrrolidone.
  • Korean Unexamined Patent Publication No. 2011-012678 discloses a composition containing a nonsteroidal anti-inflammatory analgesic active ingredient and including a polyhydric alcohol, a polyoxyalkylene alkyl ether, and a polyoxyalkylene alkenyl ether, and having an improved analgesic effect.
  • Korean Patent Laid-Open Publication No. 1999-0082208 discloses a transparent aqueous solution of diclofenac sodium consisting of diclofenac sodium, dialkyrroleamide and water.
  • Korean Patent Laid-Open Publication No. 2015-0074009 discloses an O / W emulsion composition having improved stability and absorption including oxybenzone as a ketoprofen and light stability improving material.
  • Japanese Patent Publication No. 2014-208623 discloses a composition having increased absorption including diclofenac, monoterpene, lactic acid and polar oils.
  • Japanese Patent Publication No. 2015-189759 discloses a composition comprising diclofenac, tocopherol or a derivative thereof, lactic acid and menthol.
  • Korean Patent Publication No. 2010-0083799 discloses a composition exhibiting high skin permeability and low systemic absorption of diclofenac diethylammonium salt including carbomer, stearyl alcohol and the like.
  • Korean Patent No. 10-0190450 discloses a composition
  • a composition comprising a polyurethane film on the back layer and containing chitosan, a solvent, a dissolution aid, and an alkali metal salt of C16-C17 saturated or unsaturated fatty acid as an adhesive aid component.
  • the composition is inconvenient to apply to a variety of sites, such as a patch-shaped curved patch that is already defined in shape before applying to the affected area.
  • Korean Patent Laid-Open Publication No. 1998-076273 discloses a film forming polymer as polyethylene oxide; Sorbitol, mannitol, hyaluronic acid and allatoin as humectants; Ethanol and 2-propanol as water vaporization accelerators; Triethyl citrate as softener; Disclosed is a composition which minimizes the increase in foot edema, which contains polysorbate 80, oleic acid, and the like as a drug absorption accelerator, and contains various physiologically active ingredients such as ketoprofen and amikacin.
  • the composition has a severe skin irritation, so when applied to the human skin abnormalities such as skin redness occurs, it is necessary to improve it.
  • topical anti-inflammatory analgesics have been tried and developed without rapid skin irritation, with rapid drying of the formulation, film formation in the affected area, keeping the formulation strong from physical friction, and long lasting effects.
  • the present inventors quickly dry the film when applied to the affected area, and thus, there is no stickiness, and no drug is lost even when it touches physical friction or cloth, Formulations that can be attached have been studied for a long time, and as a result, the present invention has been completed.
  • composition of the present invention not only has such ease of use, but also surprisingly, the drug permeability is remarkably superior compared to the existing commercial formulations and the skin irritation is remarkably improved compared to the inventions disclosed in the prior literature.
  • the present invention not only increases the ease of use as described above by immediately forming a film when applied to the affected area, but also significantly increases skin delivery of the drug and at the same time hardly causes skin irritation, the film-forming pharmaceutical composition, and a method of preparing the same. To provide that purpose.
  • the present invention provides a pharmaceutical composition to form a film immediately when applied to the affected area, improve the skin absorption and skin irritation of the drug, to maximize the ease of use and effect, and a method for preparing the same. .
  • composition according to the invention comprises a) at least one nonsteroidal anti-inflammatory analgesic active ingredient or a pharmaceutically acceptable salt thereof, b) a film former, c) a C8 to C24 fatty alcohol, d) a C2 to C4 alcohol and e) an interface. It contains a activator and forms a film when applied to the affected area or skin.
  • the composition according to the invention comprises at least one nonsteroidal anti-inflammatory analgesic active ingredient.
  • the nonsteroidal anti-inflammatory analgesic active ingredient is a generic name for a substance that inhibits COX without having a steroid structure, and includes, but is not limited to, the following active ingredients. It may be a free acid or a salt thereof, as the active ingredient itself, or a free acid or salt thereof, of an isomer thereof.
  • Salicylates aspirin, dipulunisal, salicylic acid or derivatives thereof, salsalates, etc.
  • Propionic acid derivatives ibuprofen, phenopropene, flubiprofen, dexibuprofen, ketoprofen, oxaprozin, naproxen, dexketoprofen, loxopropene
  • Acetic acid derivatives indomethacin, sulindac, ketorolac, aceclofenac, tolmetin, etodolak, diclofenac, nabumentone
  • Oxycam derivatives pyroxicam, tenoxycam, lornoxicam, phenylbutazone, meloxycam, doxycamp, isoxiccam
  • -Ansranilic acid derivatives mephenamic acid, mecrofenamic acid, pullulatemic acid, tolpenamic acid
  • composition of the present invention may comprise one or more nonsteroidal anti-inflammatory analgesic active ingredients, and it is preferable that the active ingredient is acidic when in the base form.
  • the content of the active substance is in a concentration range in which the safety and effectiveness are found, and a range of 0.1 to 10 times the concentration in which each component is marketed is preferable.
  • the composition according to the invention comprises at least one film forming material.
  • the film forming material volatilizes the solvent when applied to the skin to produce a film containing the active ingredient in the affected part.
  • the film forming material prevents moisture evaporation of the skin and makes it wet, so that the connective tissue can be softened and increase the skin absorption of the active ingredient. It also forms a non-stick film to minimize the loss of formulation by physical contact.
  • the film forming material according to the present invention is hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, polyethylene oxide, polyvinylpyrrolidone; Methyl vinyl ether maleic acid copolymer or a salt thereof, or methyl, ethyl, isopropyl, butyl ester; Vinylpyrrolidone / vinylacetate copolymer, octylacrylamide copolymer, aminoalkyl methacrylate copolymer, amoniomethacrylate copolymer, ethylacrylate / methylmethacrylate copolymer, hydroxypropylmethylcellulose phthale Latex, or acetate succinate, polyvinyl alcohol, polyvinylacetate, polyoxyethylene glycol / polyvinylacetate graft copolymer, chitosan, polyvinylacetal diethylamino acetate.
  • the film forming material is chitosan, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetal diethylamino acetate polyoxyethylene glycol / polyvinylacetate graft copolymer or poly Vinyl alcohol.
  • the film forming material should contain a sufficient amount to form a film on the affected part, it is preferable to include 2 to 20% by weight based on the total weight of the composition.
  • the composition according to the present invention comprises at least one C8-C24 fatty acid alcohol, in order to maximize skin absorption of the nonsteroidal anti-inflammatory analgesic active ingredient.
  • the C8-C24 fatty acid alcohol dissolves the nonsteroidal anti-inflammatory analgesic active ingredient, and after the volatile substances in the composition is volatilized, present the active ingredient which is insoluble in water in a dissolved state, whereby the formulation is dried to form a film. It can increase skin absorption of NSAIDs.
  • the C8 ⁇ C24 fatty alcohols are undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, Arachidyl alcohol, behenyl alcohol, elusyl alcohol, and the like, but are not limited thereto.
  • C8 to C24 fatty acid alcohol of the present invention may be included in one or a combination, it is preferable to include 0.1 to 10% by weight based on the total weight of the composition.
  • composition according to the invention After the composition according to the invention is applied to the skin and the volatile solvent has evaporated, it comprises a surfactant which makes the active ingredient and C8 to C24 fatty alcohols present as fine particles.
  • the surfactant may be a material generally known below.
  • Polysorbate 20 polysorbate 40, polysorbate 60, polysorbate 80, polyethylene hydroxystearate (Solutol HS15), polyethoxylated castor oil (Cremophor EL, Cremophor RH40, Cremophor RH60), ethylene oxide / Propylene oxide copolymers (poloxamer 124, poloxamer 188, poloxamer 407), Gelucire 50/13, Gelicire 44/14, Labrfil, Capryol, Lauroglycol 90, Plurol Oleique, Labrafac, Maisine 35-1, Peceol, Transcutol, Nonionic Surfactants, such as Labrasol
  • -Ionic surfactants such as sodium lauryl sulfate, sodium docusate, benzalkonium chloride, benzetonium chloride
  • the surfactant of the present invention may be a nonionic surfactant, specifically, hydroxystearate (Solutol HS15), polyethoxylated castor oil (Cremophor EL, Cremophor RH40, Cremophor RH60), ethylene oxide / propylene oxide Copolymers (poloxamer 124, poloxamer 188, poloxamer 407).
  • the surfactant may be included in an amount of 0.005 to 10 parts by weight, and preferably 0.01 to 5 parts by weight, based on 1 part by weight of the active ingredient.
  • the composition according to the invention comprises a C2 to C4 alcohol.
  • C2 ⁇ C4 alcohol dissolves the active ingredient to exist in a constant concentration, maximizes skin absorption of nonsteroidal anti-inflammatory analgesic active ingredients, and minimizes stickiness by rapidly evaporating and drying the composition when it is applied to the affected area It increases the ease of use.
  • the C2 to C4 alcohol may be ethanol, 1-propanol, 2-propanol, butanol, ethylene glycol, propene glycol, glycerol, allyl alcohol, and the like, but is not limited thereto.
  • the boiling point may be ethanol, 1-propanol or 2-propanol having a boiling point of 100 ° C. or less.
  • the C2 ⁇ C4 alcohol may be included in 10 to 90% by weight, preferably 30 to 90% by weight relative to the total weight of the composition.
  • composition according to the invention may comprise further additives in addition to the above materials.
  • pH adjusters may be included.
  • the pH adjusting agent may be used for the purpose of helping to dissolve the nonsteroidal anti-inflammatory analgesic active ingredient, to dissolve the cationic film-forming substance or thickener, or to maintain the preservation of the preparation from the microorganism.
  • PH adjusters that may additionally be included in the compositions of the present invention may include materials and amounts typically used in the art.
  • composition according to the present invention may include an additional solvent, in addition to the C2 ⁇ C4 alcohol.
  • Additional solvents may be added in consideration of skin moisturizing, active ingredient solubility, film forming agent or thickener solubility, the type and amount may be included to the extent generally known in the art.
  • compositions according to the invention may further comprise plasticizers, surfactants, co-solvents, preservatives, flavoring agents and the like.
  • compositions of the present invention are specifically illustrated and listed in Handbook of Pharmaceutical Excipients 7 th edition by Raymond C. Rowe.
  • the present invention provides the following effects.
  • the composition according to the present invention when directly applied to the affected area, quickly forms a film, not as sticky as the conventional external preparation, easy to use because it does not adhere to cloth and the like.
  • composition according to the present invention is free in terms of shape compared to plaster or cataplasmase, and can be easily applied to a lot of flexion and movement such as fingers, knees and elbows.
  • Figure 1 shows the skin permeability of Example 1 (100mg and 14.2mg) and Comparative Example 1.
  • Figure 2 shows the skin permeability of Examples 1, 7, 8, 11, 12, 14 and 19 and Comparative Examples 2 to 4.
  • Figure 3 shows the change in edema size in the arthritis animal model of the untreated group, Example 1, Comparative Examples 1 and 3.
  • Figure 4 shows the skin irritation of Examples 1 and 16, and Comparative Example 4.
  • composition comprising various nonsteroidal anti-inflammatory analgesic active ingredients
  • compositions containing various nonsteroidal anti-inflammatory analgesic active ingredients were prepared.
  • Ethanol, monoethanolamine, benzyl alcohol, oleyl alcohol, polyethoxylated castor oil (Koliphor EL), and hydroxypropylmethylcellulose were added to the nonsteroidal active ingredient, and the mixture was stirred by a paddle mixer. After hydroxypropyl cellulose was added to purified water and dispersed for 5 minutes with a Homomixer, the ethanol solution containing the active ingredient was added, followed by Homomixing and degassing under reduced pressure.
  • Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Ketoprofen 3 - - - - - - Diclofenac Sodium - One - - - - Pullulbiprofen - - 5 - - - Lysopropene sodium - - - One - - Piroxycam - - - - - 5 - Ibuprofen - - - - - 5 Hydroxypropylmethylcellulose 3 2 15 3 One 5 Hydroxypropyl cellulose 5 4 3 3 5 One Propylene glycol 4 4 4 4 4 4 Oleyl alcohol One One 3 One 3 3 3 Benzyl alcohol 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Monoethanolamine One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One Koli
  • compositions comprising various film forming polymers were prepared.
  • Ethanol or isopropyl alcohol, Koliphor EL, oleyl alcohol, benzyl alcohol, propylene glycol, and lactic acid or monoethanolamine were added to the nonsteroidal active ingredient and stirred by mixing with a paddle mixer.
  • Example 7 the chitosan was added to purified water, followed by Homomixing, the mixture was mixed with the mixed solution, followed by Homomixing, and purified water was added to make 100 g of the composition of Example 7.
  • each of the indicated film-forming materials of the mixed solution was added to form a gel by Homomixing, and purified water was added to 100 g to prepare the compositions of Examples 8 to 13.
  • Example 7 Example 8 Example 9 Example 10
  • Example 11 Example 12
  • Example 13 Ketoprofen 3 3 3 3 3 3 3 3 Chitosan 3 - - - - - - Hydroxyethyl cellulose - 3 - - - - Hydroxypropyl cellulose - - 12 - One One Hydroxypropyl Methyl Cellulose - - 5 4 - - - Polyvinyl acetal diethylamino acetate - - - - 5 - - Polyvinylacetate Graft Copolymer - - - - - 5 - Polyvinyl alcohol - - - - - 5 Propylene glycol 2 3 4 5 3 4 2 Oleyl alcohol 0.5 One 2 2 2 2 2 2 Benzyl alcohol 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Lactic acid One - - - - - - Monoethanolamine - One One One One One One One Koli
  • hydroxypropyl methyl cellulose was added and homomixed, followed by dispersion mixing for 30 minutes.
  • the ethanol solution prepared above was mixed and homomixed for 1 hour to prepare the pharmaceutical compositions of Examples 14-19.
  • compositions of Examples 14 to 19 were applied to the skin, they dried after a few minutes to form a thin film and there was no stickiness on the surface.
  • Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Ketoprofen 3 3 3 3 3 3 3 Lauryl Alcohol 2 - - - - - Myristyl Alcohol - 2 - - - - Cetyl alcohol - - One - - - Stearyl alcohol - - - One - - Oleyl alcohol - - - - One - Behenyl Alcohol - - - - - - One Hydroxypropylmethylcellulose 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Monoethanolamine One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One One
  • Ketotopplasta (Handok), Kenofengel (Ildong Pharmaceutical Co., Ltd.), and Ketotopgel (Handok), which are commercially available products, were prepared as Comparative Examples 1 to 3.
  • composition of the Republic of Korea Patent Application Publication No. 10-1998-0076273 was prepared as in Table 4 to the Comparative Example 4, and changed to the oleic alcohol in Example 1 to Comparative Example 5.
  • the skin of the hairless rat was taken, cut into a certain area, mounted in a Franz diffusion cell, and filled with pH 7.4 PBS in the receptor portion.
  • Comparative Example 1 The formulation of Comparative Example 1 was cut to a certain size and attached to the skin of a donor cell.
  • 100 mg or 14.2 mg of the same drug as a ketotop patch was injected and spread evenly in a donor cell.
  • the liquid was collected from the receptor at regular intervals for 12 hours and HPLC analysis was performed to evaluate the degree of penetration of the drug per hour and skin area per skin (Flux, ⁇ g / cm 2 / h).
  • composition of the present invention can be seen to significantly increase the permeability of the nonsteroidal anti-inflammatory analgesic active ingredient, compared to the patch of Comparative Example 1.
  • composition of the present invention was confirmed to significantly increase the permeability of the nonsteroidal anti-inflammatory analgesic active ingredient compared to Comparative Example 4 of the composition of the existing patent invention.
  • Example 1 and Comparative Examples 1 and 2 were treated for 3 days to measure the difference in the thickness of the knee between the edema-induced leg and non-induced leg to confirm the extent to which the drug reduces edema is shown in Figure 3 It was.
  • composition of the present invention shows a rapid effect on the first day of treatment, it was confirmed that the effect is superior to the untreated group.
  • the composition of this invention shows that the patch agent of the comparative example 1 which is a commercial product, and the comparative example 3 show the outstanding edema reduction effect also compared with a gel product.
  • Comparative Example 1 was less effective in reducing the edema on day 2 than the treatment day 1, Comparative Example 3 was found to take a long time to express the effect because the difference in the edema reduction effect between the treatment 1 and 2 days.

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Abstract

La présente invention concerne : une composition pharmaceutique contenant un principe actif analgésique de type anti-inflammatoire non stéroïdien (AINS), pratique à utiliser en raison de la formation d'un film lors de son application sur une zone affectée, permettant que l'absorption soit optimisée, et provoquant peu d'irritation de la peau ; et un procédé de préparation de ladite composition. La composition pharmaceutique selon la présente invention permet qu'un film soit rapidement formé lors de son application sur une zone affectée, ce qui lui permet de ne pas être collante et de ne pas se déposer sur les vêtements, et analogues, contrairement à une préparation classique destinée à une utilisation externe, et est de ce fait pratique à utiliser. De plus, la composition peut être facilement appliquée à des endroits, tels que les articulations des doigts, les genoux et les coudes, où il est difficile de fixer des adhésifs tels que des pansements. De plus, l'efficacité thérapeutique peut être optimisée par augmentation notable de l'absorption de médicament depuis la formulation par la partie affectée, et la composition provoque peu d'irritation de la peau, ce qui permet de réduire au minimum les symptômes anormaux au niveau de la peau tels que la rubéfaction même en cas d'application sur la peau pendant longtemps. Par conséquent, la composition pharmaceutique selon la présente invention est efficace et pratique à utiliser par des patients qui attendent des effets analgésiques et analgésiques anti-inflammatoires contre les symptômes de l'arthrose, de la périarthrite de l'épaule, de la douleur musculaire et de la péritendinite.
PCT/KR2019/001891 2018-02-22 2019-02-15 Composition pharmaceutique filmogène contenant un principe actif analgésique de type anti-inflammatoire non stéroïdien WO2019164192A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2018-0021128 2018-02-22
KR1020180021128A KR20190101140A (ko) 2018-02-22 2018-02-22 비스테로이드성 소염진통 활성성분을 함유하는 필름 형성 약제학적 조성물

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KR102481006B1 (ko) * 2020-11-25 2022-12-23 충북대학교 산학협력단 멜록시캄 또는 이의 약학적으로 허용가능한 염을 포함하는 필름형성 겔 및 상기 필름형성 겔의 제조방법

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KR20140041504A (ko) * 2011-05-03 2014-04-04 아포니아 라보라토리즈, 인크. 이부프로펜의 경피 조성물들 및 이의 이용 방법들
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KR20010031828A (ko) * 1997-11-05 2001-04-16 비비안 뤼 Ｎｓａｉ 약물 전달을 위한 국소 투여용 조성물
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