WO2014081338A1 - Médicament sous forme de comprimé orodispersible et procédé de production de ce médicament - Google Patents

Médicament sous forme de comprimé orodispersible et procédé de production de ce médicament Download PDF

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Publication number
WO2014081338A1
WO2014081338A1 PCT/RU2013/000929 RU2013000929W WO2014081338A1 WO 2014081338 A1 WO2014081338 A1 WO 2014081338A1 RU 2013000929 W RU2013000929 W RU 2013000929W WO 2014081338 A1 WO2014081338 A1 WO 2014081338A1
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WO
WIPO (PCT)
Prior art keywords
diclofenac
potassium
crospovidone
aspartame
polyvinylpyrrolidone
Prior art date
Application number
PCT/RU2013/000929
Other languages
English (en)
Russian (ru)
Inventor
Максим Эдуардович ЗАПОЛЬСКИЙ
Аллан Герович БЕНИАШВИЛИ
Маргарита Алексеевна МОРОЗОВА
Original Assignee
Zapolsky Maxim Eduardovich
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zapolsky Maxim Eduardovich filed Critical Zapolsky Maxim Eduardovich
Publication of WO2014081338A1 publication Critical patent/WO2014081338A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the field of pharmaceuticals and medicine, in particular to agents used in various spastic conditions of the gastrointestinal tract and pancreaticobiliary system, especially with irritable bowel syndrome (IBS) and methods for their preparation.
  • IBS irritable bowel syndrome
  • IBS Irritable bowel syndrome
  • IBS central nervous system
  • IBS Infrared bowel syndrome, both the small and large intestines exhibit increased reactivity in the form of intestinal cramping, slowing down or accelerating the motility of various irritants, including drugs and even food. Patients are prone to depression, anxiety, carcinophobia, they often respond more actively to stress. Borderline neuropsychiatric disorders are found in 75% of patients with IBS. Thus, the leading factors in the pathogenesis of IBS are given to the following factors: psychological, impaired motility and visceral sensitivity, changes in the chemical composition of intestinal contents.
  • Hyoscine butyl bromide was created in Germany in 1951. It is highly selective for Ml and MH subtypes of receptors, which are most found in the upper gastrointestinal tract, gall bladder, and biliary ducts, which determines its frequent use in this pathology.
  • RF patent 2424793 relates to a pharmaceutical composition in the form of a food film for oral administration, where the food film includes diclofenac in the form of free acid or diclofenac resinate in an amount of from 10 to 50 wt.% And a film-forming polymer in an amount of from 10 to 80 wt.% In the calculation on the dry weight of the resulting food film.
  • the composition contains from 10 to 50 mg of diclofenac in a dissolved or uniformly dispersed state, while the food film has a thickness of 20-250 microns.
  • the invention provides for the rapid decomposition of food film in the patient's oral cavity in less than 20 seconds.
  • Patent RU 2242968 C2 is known, which relates to a fast-dispersing solid dosage form which dissolves in the oral cavity within sixty (60), more preferably thirty (30), most preferably ten (10) seconds.
  • a matrix modified starch is used, and hyoscine butyl bromide may be selected as the active substance.
  • the orodispersible tablet disintegrates into easily swallowed small particles within a few tens of seconds after ingestion.
  • oral dispersion provides faster absorption by the body compared with swallowed forms due to the increase in the area of exchange with physiological fluids.
  • the patent of the Russian Federation 2317812 is known, which discloses an orodisperse solid dosage form containing homogeneous granules of lactose and starch obtained by drying by co-spraying.
  • a variety of pharmacologically active substances can be included as an active principle.
  • these excipients may have a negative effect when used with irritable bowel syndrome.
  • Levsin sublingual tablets containing as of the active principle, belladonna alkaloids, and as auxiliary substances, lactose, magnesium stearate, stearic acid, mannitol, starch and dye, which can be used in various spastic conditions, including irritable bowel syndrome. and method for their preparation
  • the objective of the present invention is to develop a composition and method of an effective dosage form that can be used in various spastic conditions of the gastrointestinal tract and pancreatic-biliary system, especially with irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • a new drug in the form of an orodispersed tablet containing a combination of hyoscine butyl bromide and diclofenac or its sodium salt in combination with an ion-exchange resin (1: 2), as well as a method for producing this drug, characterized in that mannitol and silicon dioxide are mixed anhydrous, 20% solution of polyvinylpyrrolidone K 30, granulate the mixture by spraying in a fluidized bed, separately mix previously the resulting complex of Diclofenac or diclofenac sodium with potassium polacryllin, hyoscine butyl bromide, Crospovidone, aspartame and flavoring, combine the resulting mixtures and mix until a homogeneous state is obtained, followed by tablet compression method, including preliminary compression with a force of 2-3 kN and final compression with force 8-10 kN.
  • the proposed tool has the following composition, wt.%:
  • Flavoring additive 2.83-3.57
  • Orodispersed tablets are white, round, uncovered, flat tablets with a beveled edge.
  • Preferred dosages of the active principle are per tablet: Hyoscine butyl bromide 1-50.0 mg
  • Potassium Polacrillin (PP) is a monofunctional minimally cross-linked carboxylic acid exchange resin obtained by co-polymerization of methacrylic acid with divinylbenzene and subsequently neutralized with potassium hydroxide:
  • PP is an effective disintegrating agent in a low concentration in various formulations in the form of tablets, including many hydrophobic formulations, where standard disintegrating agents are not very effective.
  • the claimed composition it is used to obtain a complex with diclofenac or its diclofenac sodium salt resinate.
  • Mannitol has an additional stabilizing effect on the composition.
  • Aspartame sugar substitute is used in this form as a digestible low-calorie sweetener, providing, in combination with other components, acceptable palatability.
  • the optimal combination of two types of polyvinylpyrrolidone - Crospovidone and Polyvinylpyrrolidone K 30 was also selected. This combination provides the required compressibility, stability, and also affects the taste of the tablets.
  • flavoring additive you can enter food acceptable additives, such as lemon, tangerine, blueberry, peppermint, etc., preferably dry mint.
  • Anhydrous colloidal silicon dioxide was introduced into the composition as an antifriction and dispersing component, for example, Aerosil 200 brand dioxide can be used.
  • a method of producing tablets is as follows: Mannitol, silicon dioxide, colloidal anhydrous, 20% solution of polyvinylpyrrolidone K 30 are mixed, the mixture is granulated by spraying in a fluidized bed. Separately mix the pre-obtained complex of Diclofenac or diclofenac sodium with potassium polacrilin (Diclofenac resinate or diclofenac resinate) taken at a ratio of 1: 2, with hyoscine butyl bromide, crospovidone, aspartame and flavoring.
  • the mixture is tabletted by the compression method in two stages: preliminary compression with a force of 2-3 kN and final compression with a force of 8-10 kN.
  • the hardness of the tablets is 25-44 N.
  • Stage A Granulation Weighing and sieving fillers for the granulation process:
  • All suspended material is sieved through a 40 mesh strainer.
  • the fluidized bed granulator is preheated before filling the mixture and before spraying the solution of the sprayed material to begin to flow the mixture of Mannitol and Aerosil 200 for at least 3 minutes.
  • the moisture content in the granulate is between 1.0 and 3.0%.
  • Stage B obtaining the Complex Diclofenac Sodium Resinate
  • the Diclofenac Sodium - Resin complex will be stabilized, and a pop-up liquid will be present on the upper layer of the paste. Drain pop-up liquid.
  • the paste is dried at a temperature of 60 ° C for 30 minutes or until the loss upon drying is NMT 3.0%.
  • Crospovidone (6.08 kg)
  • the method used to produce tablets is compression using a SMART Kilian 250 rotary tablet press. Compression is carried out in two stages: pre-compression and final compression. Conditions: the main compression force is 8-10 kN, the preliminary compression force is 2-3 kN. The hardness of the tablets is 40 N.
  • IBS irritable bowel syndrome
  • 21 patients were diagnosed with IBS with a predominance of pain and flatulence, 16 - with IBS with a predominance of constipation and 6 - with IBS with a predominance of diarrhea.
  • a colonoscopy was performed; a special study was a balloon dilatation test to determine visceral hypersensitivity.
  • the intensity of the pain syndrome was evaluated by a known method using a visual analogue scale of abdominal pain and a point score.
  • the tool in example 2 was prescribed a tablet 3 times a day before meals for 2 weeks.
  • the intensity of pain abdominal syndrome decreased in 100% of patients with IBS.
  • the pain syndrome was completely stopped in 80% of patients with IBS with a predominance of constipation and in 50% of patients with a predominance of diarrhea.
  • the severity of constipation decreased by an average of 11%.
  • Tablets disintegrate in 20-30 seconds.
  • the maximum plasma concentration is reached on average after 1 hour and is approximately 4.8 ng / ml for butyl bromide hyoscine and 1.5 ⁇ g / ml for diclofenac.
  • the proposed new tool is an effective drug for the treatment of irritable bowel syndrome. Because the drug showed improved bioavailability, it It can also be successfully used for other disorders of the gastrointestinal tract and pancreaticobiliary system, in which the use of butyl bromide and diclofenac hyoscine is indicated.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne le domaine de la pharmaceutique et de la médecine et notamment des produits utilisés dans différents états spasmodiques du canal alimentaire ou du système pancréatique et biliaire, notamment en cas de syndrome du côlon irritable (SII), et leurs procédés de production. Le médicament se présente comme un comprimé orodispersible caractérisé en ce qu'il contient une combinaison de butylscopolamine et de diclofénac ou de son sel sodique formant un complexe avec le polyacrylate de potassium, avec un rapport de diclofénac ou de son sel sodique avec le polyacrylate de potassium de 1:2 et des additifs pharmaceutiquement acceptables, y compris Mannitol, Aspartame et Crospovidone. Polyvinylpyrrolidone K 30, agent aromatisant et dioxyde de silicium colloïde non aqueux. Les comprimés possèdent une biodisponibilité améliorée du prinicipe actif.
PCT/RU2013/000929 2012-11-20 2013-10-21 Médicament sous forme de comprimé orodispersible et procédé de production de ce médicament WO2014081338A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2012149397 2012-11-20
RU2012149397/15A RU2503447C1 (ru) 2012-11-20 2012-11-20 Лекарственное средство в форме ородисперсной таблетки и способ получения лекарственного средства

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WO2014081338A1 true WO2014081338A1 (fr) 2014-05-30

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PCT/RU2013/000929 WO2014081338A1 (fr) 2012-11-20 2013-10-21 Médicament sous forme de comprimé orodispersible et procédé de production de ce médicament

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RU (1) RU2503447C1 (fr)
WO (1) WO2014081338A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016129140A1 (fr) * 2015-02-10 2016-08-18 富士フイルム株式会社 Comprimé à désintégration intrabuccale rapide et son procédé de fabrication

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2242968C2 (ru) * 1999-01-27 2004-12-27 Ар.Пи.Шерер Корпорейшн Быстродиспергирующаяся лекарственная форма, не содержащая желатин
RU2317812C2 (ru) * 2002-01-18 2008-02-27 Рокетт Фрер Диспергируемая во рту твердая лекарственная форма

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2592882T3 (es) * 2008-10-14 2016-12-02 Mcneil Ab Forma de dosificación intra-oral de múltiples porciones y uso de la misma

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2242968C2 (ru) * 1999-01-27 2004-12-27 Ар.Пи.Шерер Корпорейшн Быстродиспергирующаяся лекарственная форма, не содержащая желатин
RU2317812C2 (ru) * 2002-01-18 2008-02-27 Рокетт Фрер Диспергируемая во рту твердая лекарственная форма

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Levsin /SLtablets (hyoscyamine sulfate tablets USP)", February 2008 (2008-02-01), Retrieved from the Internet <URL:http://mediapharma.us/products/pi/LevsinSLTablets_Pl.pdf> [retrieved on 20140220] *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016129140A1 (fr) * 2015-02-10 2016-08-18 富士フイルム株式会社 Comprimé à désintégration intrabuccale rapide et son procédé de fabrication
JPWO2016129140A1 (ja) * 2015-02-10 2017-06-29 富士フイルム株式会社 口腔内崩壊錠及びその製造方法
JP2018150384A (ja) * 2015-02-10 2018-09-27 富士フイルム株式会社 口腔内崩壊錠及びその製造方法

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