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WO2016118040A1 - Gels comprenant la nifédipine et le chlorure d'hydrogène de lidocaïne et son application et procédé de sa préparation à l'aide de nanotechnologies - Google Patents

Gels comprenant la nifédipine et le chlorure d'hydrogène de lidocaïne et son application et procédé de sa préparation à l'aide de nanotechnologies Download PDF

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Publication number
WO2016118040A1
WO2016118040A1 PCT/RU2015/000034 RU2015000034W WO2016118040A1 WO 2016118040 A1 WO2016118040 A1 WO 2016118040A1 RU 2015000034 W RU2015000034 W RU 2015000034W WO 2016118040 A1 WO2016118040 A1 WO 2016118040A1
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WIPO (PCT)
Prior art keywords
nifedipine
poloxamer
gel
lidocaine hydrochloride
purified water
Prior art date
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Ceased
Application number
PCT/RU2015/000034
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English (en)
Russian (ru)
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WO2016118040A8 (fr
Inventor
Михаил Александрович ГЕТЬМАН
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Novamedical LLC
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Novamedical LLC
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Priority to PCT/RU2015/000034 priority Critical patent/WO2016118040A1/fr
Publication of WO2016118040A1 publication Critical patent/WO2016118040A1/fr
Publication of WO2016118040A8 publication Critical patent/WO2016118040A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245Amino benzoic acid types, e.g. procaine, novocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/60Salicylic acid; Derivatives thereof

Definitions

  • the invention relates to pharmaceuticals, including pharmaceutical compositions that form the basis of gels and to methods for producing gels intended mainly for use in the treatment of hemorrhoids and anal fissures, namely, the invention relates to compositions and methods for preparing gels, including nifedipine and lidocaine hydrochloride, the preparation of gels is carried out using nanotechnology.
  • Known drugs presented in the form of ointments or emulsions for external use using a fat base including those containing nifedipine [1-3].
  • Nifedipine being a calcium antagonist
  • Nifedipine being a calcium antagonist
  • nifedipine taking into account the mechanism of action of nifedipine, it can be successfully used for various other diseases requiring a vasodilating effect, for example, in proctology.
  • Nifedipine being a calcium channel blocker, prevents the transport of calcium ions into the cells and thereby reduces the tone of the anal sphincter. Reducing the spasticity of the anal sphincter is the main way to reduce pain in patients with hemorrhoids and anal fissure [6].
  • the pharmacological activity of nifedipine also causes a decrease in the intensity of the inflammatory reaction [7], has a modulating effect on microcirculation [8].
  • Nifedipine eliminating its hypertonicity, improves blood supply to the ischemic mucosa and restores its functional state.
  • nifedipine affects the main pathogenetic mechanisms underlying hemorrhoids, as well as the symptoms associated with the development of an anal fissure.
  • the advantage of the gel dosage form is the prolonged action, the presence of a moisturizing effect and ease of use.
  • gels are close to ointments and creams, but have a number of differences, for example, when it gets on your skin or clothes, the gel, unlike an ointment, is easily washed off with water, leaving no residue, which is an obvious advantage that enhances the patient’s compliance with the prescribed treatment [ 10].
  • the invention relates to medicine and pharmacology and is a medicinal composition for the treatment of anal fissures, comprising a base, a drug that reduces spasms of smooth muscle muscles, lidocaine, contains tizol gel as a base, and as a drug that reduces smooth spasms muscle muscles - nifedipine or nitroglycerin, and the components in the composition are contained in a certain ratio in grams.
  • the invention provides effective treatment for reducing the concentration of active substances, reducing side effects, reducing the duration of treatment [1 1].
  • nitroglycerin ointment 0.2% which is currently considered to be one of the most important components of the conservative treatment of anal fissure, since nitroglycerin relaxes the muscles of the anal sphincter, removing its spasm, which is one of the pathogenetic factors of the development of the fissure, since it leads to ischemia, that is, to n impaired blood flow.
  • nitroglycerin ointment it is necessary to apply a small amount, since in large doses it can be absorbed into the systemic circulation and cause headaches, dizziness [12].
  • calcium channel blockers including, for example, nifedepine or diltiazem and other drugs that are used in the treatment of heart diseases, but have recently found their application in the treatment of anal fissures, the principle of which is the same as that of nitroglycerin ointments - they relieve spasm of the anal sphincter [12].
  • nifedipine and other similar agents as a calcium channel blocker
  • the technical result, to which the data of the invention are directed, is to obtain such a gel composition, including nifedipine and lidocaine hydrochloride, each variant of which provides stability of gel-like properties, transparency, preservation of stability of properties for up to 2 years, the use of which allows to reduce the clinical symptoms of hemorrhoids, up to their complete exclusion, healing of the anal fissure and relief of pain, including after hemorrhoidectomy.
  • the technical result to which the present invention is directed is the creation of such a method of preparing a gel comprising nifedipine and lidocaine hydrochloride, using nanotechnology, which would ensure the stability of the gel-like properties, transparency, maintaining stability for a period of at least two years.
  • a gel comprising nifedipine, lidocaine hydrochloride, additionally comprising poloxamer 188, macrogol 400, nipagin, nipazole, poloxamer 407, Cekol 2000 T or Karbopol Ultrez 10, purified water, which prevents and / or treats anal fissures, hemorrhoids, reduces pain after hemorrhoidectomy and related diseases with a ratio of ingredients, wt.%:
  • a gel comprising nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reducing pain after hemorrhoidectomy as a means to prevent and / or treating anal fissures, hemorrhoids and related diseases, reducing pain after hemorrhoidectomy in the ratio of ingredients, wt.% :
  • a gel that includes a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400 , nipagin, nipazole, Cekol 2000 T or an aqueous solution of arbopol Ultrez 10, purified water, with a ratio of ingredients, wt.%:
  • a calcium channel blocker including nifedipine, a local anesthetic, including lidocaine hydrochloride
  • auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400 , nipagin, nipazole, Cekol 2000 T or an aqueous solution of arbopol Ultrez 10, purified water, with a ratio of ingredients, wt.%:
  • nifedipine 0, 01-0,4 local anesthetic including:
  • lidocaine hydrochloride 0, 02-2.0 auxiliary substances that provide the required stability and rheological properties, including:
  • poloxamer 407 1.0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0, 01-0.07 nipazole 0, 01-0.03
  • a gel including a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400 , nipagin, nipazole, Cekol 2000 T or an aqueous solution of Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy, with the ratio of ingredients, wt.%:
  • nifedipine 0, 01-0,4 local anesthetic including:
  • lidocaine hydrochloride 0, 02-2.0 auxiliary substances that provide the required stability and rheological properties, including:
  • poloxamer 407 1.0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0, 01-0.07 nipazole 0, 01-0.03
  • a method for preparing a gel comprising nifedipine and lidocaine hydrochloride using nanotechnology, in which about 1, 0 - 19.0 g of poloxamer 407 and about 0.01 - 10.0 g of poloxamer 188 are placed in a measuring cup, protected from light, with a capacity of the order of 0 - 150 ml, add about 18
  • the proposed invention is as follows:
  • a gel comprising nifedipine and lidocaine hydrochloride using nanotechnology
  • about 1.0-19.0 g of poloxamer 407 for example 1.0 g or 10.0 g, or 19.0 g and about 0.01-10
  • 0 g of poloxamer 188 for example, 0.01 g or 5.0 g, or 10.0 g is placed in a measuring cup, protected from light, with a capacity of the order of up to 150 ml, for example, 50 ml or 100 ml, or 150 ml
  • lidocaine drochloride for example, 0.01 g or 0.5 g, or 2 g
  • a measuring cup with a capacity of up to 50 ml about 10 ml of purified water is added and mixed until dissolved to obtain a solution of 2.
  • nifedipine of the order of 0.01 to 0.4 g of nifedipine for example, 0.01 g or 0.1 g, or 0.04 g is placed in a measuring glass, protected from light, with a capacity of about 50 ml, about 0.01 - 34 g are added macrogol 400, for example, 0.01 g or 15 g, or 34 g, or of the order of 0.01 - 34 g of purified water, for example, 0.01 g or 15 g, or 34 g and mixed.
  • solution 2 is added to solution 1
  • a suspension of nifedipine is added to the resulting solution
  • the pH of the resulting solution is adjusted to 2.5-9.5, for example, to 2.5 or to 7.5, or to 9.5, by any known method, including a one-molar solution of sodium hydroxide or a one-molar solution of hydrochloric acid, add purified water to a total amount of the order of 93 - 95 g, for example, up to 93 g or 94 g, or 95 g, and mix for 1-9 hours, for example, 1 hour or 4 hours, or 9 hours, including, for example, on a magnetic stirrer at a temperature of the order of 20-37 ° C, for example, at 20 ° C or at 30 ° C, or at 37 ° C, constantly monitoring the pH, including using a pH meter, then the resulting solution is left to stand for at least 15 minutes, filtered, including through filter paper, into a measuring cup protected from light, and measure the pH, which, in the
  • nipagin for example 0.01 g or 0.03 g, or 0.07 g, and about 0.01-0.03 g of nipazole, for example 0, are added to the resulting aqueous solution.
  • a Cekol 2000 T carboxymethyl cellulose derivative for example, 0.01 g or 1
  • 0.01 g or 1 are added in portions of the order of 0.01 to 5 g g, or 5 g, or of the order of 0.01 to 1.5 g of an aqueous solution of the acrylic acid derivative of Carbopol Ultrez 10, for example, 0.01 g or 1 g, or 1, 5 g, which is obtained by mixing 0.01 - 1, 5 g Carbopol Ultrez 10, for example ep, 0.01 g or 1 g, or 1.5 g, with 0.01 - 5.5 g of purified water, for example, with 0.01 g or 1 g, or 1, 5 g, followed by stirring until a gel forms, the resulting gel is packed in containers intended for this ..
  • the proposed gel which includes nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, is used as a means to prevent and / or treat anal fissures, hemorrhoids, reduce pain after hemorrhoidectomy and related diseases with a ratio of the following ingredients, wt.%:
  • a gel is used, including nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy with a ratio of ingredients, wt.%:
  • nifedipine 0.01 - 0.4 lidocaine hydrochloride 0.01 - 2.0 poloxamer 407 1.0 - 19.0 poloxamer 188 0.01 - 10.0 macrogol 400 0.01 - 34 nipagin 0.01 - 0.07 nipazole 0.01 - 0.03
  • a variant of the proposed gel which includes a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, prepared as follows: to an aqueous solution including nifedipine, lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties including poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole in a dark place add Cekol 2000 T 0-34 g, or an aqueous solution of Carbopol Ultrez 10 purified water, with wearing ingredients, wt.%:
  • nifedipine 0, 01-0,4 local anesthetic including:
  • lidocaine hydrochloride 0, 02-2.0 auxiliary substances that provide the required stability and rheological properties, including:
  • poloxamer 407 1.0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0,01-0,07 nipazole 0,01-0,03 Cekol 2000 T 0,01-5, 0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest The resulting gel is mixed and packaged,
  • a gel including a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, excipients providing the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, gelling agent, including Cekol 2000 T or aqueous Carbo solution ol Ultrez 10, purified water at a ratio of ingredients, wt.%:
  • nifedipine 0, 01-0,4 local anesthetic including:
  • lidocaine hydrochloride 0, 02-2.0 auxiliary substances that provide the required stability and rheological properties, including:
  • poloxamer 407 1.0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0, 01-0.07 nipazole 0, 01-0.03
  • the proposed gel in all the presented options provides high efficiency in eliminating the symptoms of chronic anal fissure, external hemorrhoids, reducing pain after hemorrhoidectomy.
  • Examples of gels are presented in the Table.
  • the gel was applied perianally, twice a day for fourteen days, to rats with a model of anal fissure.
  • the use of the gel made it possible to completely eliminate the morphological changes characteristic of the anal fissure, that is, to achieve complete healing in 95% of the tested rats, namely in 38 out of 40 animals.
  • the proportion of animals with resolution of symptoms of anal fissure was 15%, namely, six out of forty animals.
  • the gel was applied perianally and rectally, twice a day for fourteen days to rats with a model of acute hemorrhoids.
  • the use of the gel completely eliminated the manifestations of hemorrhoids in 92.5% of the animals, thirty-seven out of forty animals), while in the control group receiving treatment with a gel base, complete resolution of the manifestations of hemorrhoids was achieved in 45% of the animals, namely, 18 out of forty animals.
  • the effectiveness of the gel in reducing pain after hemorrhoidectomy was evaluated in rats indirectly. It is known that the main cause of pain after surgery to remove hemorrhoids is a spasm of the anal sphincter. Therefore, the resolution of pain in rats with a hemorrhoid model was assessed as a stable restoration of anorectal manometry to the initial level.
  • the gel was applied perianally and rectally, twice a day for fourteen days. The use of the gel made it possible to return the anorectal manometry index to the initial level in all 40 animals, while in the control group receiving gel base treatment, a complete restoration of the indicator was observed only in 17.5% of the animals, namely, 7 out of forty animals.
  • composition of the gel including nifedipine and lidocaine hydrochloride, each version of which provides stability of the gel-like properties, transparency, preservation of stability of properties for up to 2 years, the use of which allows to reduce the clinical symptoms of hemorrhoids, up to their complete elimination, healing of the anal cracks and relief of pain, including after hemorrhoidectomy.
  • the proposed pharmaceutical compositions that form the basis of gels, a method for the production of gels are mainly intended to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy.
  • the invention relates to compositions and methods of preparation, as well as to the use of gels, including nifedipine and lidocaine hydrochloride.
  • the preparation of gels is carried out using nanotechnology.
  • the proposed gel in all the presented variants, obtained by the proposed method, provides, when applied, high efficiency in eliminating the symptoms of chronic anal fissure, external hemorrhoids, reducing pain, up to their elimination.
  • L-type calcium channel blockers modulate the microvascular hyperpermeability induced by plateletactivating factor in vivo. J Vase Surg, 1995; 22: 723-39.
  • nifedipine 0.01 or 0.1 or 0.4 from the range of values: 0.01 - 0.4
  • lidocaine hydrochloride 0.02 or 0.5 or 2
  • Poloxamer 188 0.01 or 5.0, or 10.0

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne la pharmaceutique y compris les compositions pharmaceutiques formant la base de gels et des procédés de fabrication de gels destinés principalement à prévenir et/ou à traiter des fissures anales, des hémorroïdes et des maladies qui y sont liées, et à réduire les sensations douloureuses suit à une hémorroïdectomie. L'invention concerne aussi des compositions et des procédés de préparation ainsi que l'application de gels comprenant la nifédipine et le chlorure d'hydrogène de lidocaïne. La préparation de gels se fait à l'aide de nanotechnologies. Le résultat technique est obtenu grâce à l'obtention d'une composition de gel qui comprend la nifédipine et le chlorure d'hydrogène de lidocaïne dont chaque variante assure la stabilité de propriétés gélifiantes, la transparence, une stabilité inaltérable pendant une période jusqu'à 2 ans dont l'utilisation permet d'atténuer le symptômes cliniques des hémorroïdes, jusqu'à leur élimination total, la cicatrisation de la fissure anale et la cessation des douleurs, y compris après l'hémorroïdectomie. En outre, le résultat technique est obtenu grâce à la mise au point d'un procédé de préparation de gel qui comprend la nifédipine et le chlorure d'hydrogène de lidocaïne utilisant différentes nanotechnologies qui assurent la stabilité de particularités de gels, la transparence et une stabilité inaltérable pendant une période jusqu'à 2 ans. Toutes les inventions proposées peuvent avoir une application industrielle, et les tests de laboratoire ont montré que les objets présentés sont réalisables dans la pratique et peuvent trouver un large usage en industrie pharmaceutique.
PCT/RU2015/000034 2015-01-21 2015-01-21 Gels comprenant la nifédipine et le chlorure d'hydrogène de lidocaïne et son application et procédé de sa préparation à l'aide de nanotechnologies Ceased WO2016118040A1 (fr)

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PCT/RU2015/000034 WO2016118040A1 (fr) 2015-01-21 2015-01-21 Gels comprenant la nifédipine et le chlorure d'hydrogène de lidocaïne et son application et procédé de sa préparation à l'aide de nanotechnologies

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IT201800002413A1 (it) * 2018-02-05 2019-08-05 Carmine Antropoli "composizione a base di nifedipina per uso nel trattamento delle ragadi anali e proctalgie"
WO2019207059A1 (fr) * 2018-04-25 2019-10-31 Ferring B.V. Composition pharmaceutique topique pour le traitement de fissures anales et d'hémorroïdes
EA036752B1 (ru) * 2019-02-25 2020-12-16 ОБЩЕСТВО С ОГРАНИЧЕННОЙ ОТВЕТСТВЕННОСТЬЮ "НоваМедика" Способ получения геля для ректального и наружного применения, включающего нифедипин и лидокаина гидрохлорид (варианты)
CN113679663A (zh) * 2021-10-09 2021-11-23 海南回元堂药业有限公司 一种斑蝥素乳膏及其制备方法
US20220362247A1 (en) * 2019-12-13 2022-11-17 Alexander Evgenevich BARANNIKOV Pharmacological composition for treating proctological diseases (variants)
US11766428B2 (en) 2018-06-01 2023-09-26 Tavanta Therapeutics Hungary Incorporated Topical amlodipine salts for the treatment of anorectal diseases
EP4312984A4 (fr) * 2021-04-01 2025-02-19 Steel Therapeutics, Inc. Lingette topique contenant de la nifédipine et de la lidocaïne

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2684326C1 (ru) * 2017-11-15 2019-04-08 федеральное государственное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет) Способ получения геля нифедипина
IT201800002413A1 (it) * 2018-02-05 2019-08-05 Carmine Antropoli "composizione a base di nifedipina per uso nel trattamento delle ragadi anali e proctalgie"
EP3520791A1 (fr) * 2018-02-05 2019-08-07 Carmine Antropoli Composition à base de nifédipine pour le traitement de fissures anales et de proctalgya, et son procédé d'administration
US11865207B2 (en) 2018-04-25 2024-01-09 Ferring B.V. Topical pharmaceutical composition for treatment of anal fissures and hemorrhoids
WO2019207059A1 (fr) * 2018-04-25 2019-10-31 Ferring B.V. Composition pharmaceutique topique pour le traitement de fissures anales et d'hémorroïdes
EP4403176A3 (fr) * 2018-04-25 2024-11-06 Ferring B.V. Composition pharmaceutique topique pour le traitement de fissures anales et d'hémorroïdes
US11766428B2 (en) 2018-06-01 2023-09-26 Tavanta Therapeutics Hungary Incorporated Topical amlodipine salts for the treatment of anorectal diseases
EA036752B1 (ru) * 2019-02-25 2020-12-16 ОБЩЕСТВО С ОГРАНИЧЕННОЙ ОТВЕТСТВЕННОСТЬЮ "НоваМедика" Способ получения геля для ректального и наружного применения, включающего нифедипин и лидокаина гидрохлорид (варианты)
US20220362247A1 (en) * 2019-12-13 2022-11-17 Alexander Evgenevich BARANNIKOV Pharmacological composition for treating proctological diseases (variants)
EP4074305A4 (fr) * 2019-12-13 2024-01-03 Alexander Evgenevich Barannikov Composition pharmaceutique pour traiter des maladies proctologiques (variantes)
EP4312984A4 (fr) * 2021-04-01 2025-02-19 Steel Therapeutics, Inc. Lingette topique contenant de la nifédipine et de la lidocaïne
CN113679663B (zh) * 2021-10-09 2023-09-29 海南回元堂药业有限公司 一种斑蝥素乳膏及其制备方法
CN113679663A (zh) * 2021-10-09 2021-11-23 海南回元堂药业有限公司 一种斑蝥素乳膏及其制备方法

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