WO2018146575A1 - Composition à libération rapide de cinitapride et de siméticone, et procédé de préparation correspondante - Google Patents

Composition à libération rapide de cinitapride et de siméticone, et procédé de préparation correspondante Download PDF

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Publication number
WO2018146575A1
WO2018146575A1 PCT/IB2018/050528 IB2018050528W WO2018146575A1 WO 2018146575 A1 WO2018146575 A1 WO 2018146575A1 IB 2018050528 W IB2018050528 W IB 2018050528W WO 2018146575 A1 WO2018146575 A1 WO 2018146575A1
Authority
WO
WIPO (PCT)
Prior art keywords
cinitapride
propylene glycol
simethicone
composition according
composition
Prior art date
Application number
PCT/IB2018/050528
Other languages
English (en)
Spanish (es)
Inventor
José Luis LAURIA
Original Assignee
Siegfried Rhein, S.A. De C.V.
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 Siegfried Rhein, S.A. De C.V. filed Critical Siegfried Rhein, S.A. De C.V.
Priority to BR112019015989-4A priority Critical patent/BR112019015989A2/pt
Priority to CR20190402A priority patent/CR20190402A/es
Priority to PE2019001412A priority patent/PE20191491A1/es
Publication of WO2018146575A1 publication Critical patent/WO2018146575A1/fr
Priority to CONC2019/0008347A priority patent/CO2019008347A2/es

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/695—Silicon compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a pharmaceutical composition for oral administration, in the form of capsules with liquid content, of rapid release, comprising a fixed-dose combination of Cinitapride tartrate and Simethicone together with at least one surfactant and optionally one or more pharmaceutically acceptable excipients, and the process for obtaining said composition.
  • Cinitapride was revealed as active ingredient in the German patent application DE 2,751,139 and its equivalents, the applicant was ANPHAR SA and claimed as a priority the English application with serial number No. 47739 of November 16, 1976 According to the IUPAC nomenclature the compound Cinitapride is known under the name 4-amino-N- [1- (3-cyclohexen-1-ylmethyl) -4-piperidinyl] -2-ethoxy-5-nitrobenzamide, and is represented by the following Formula (I):
  • This compound is an orthopramide with prokinetic activity at the level of the gastrointestinal tract that possesses a marked pro-cholinergic action.
  • By blocking the presynaptic receptors for serotonin the release of serotonin increases, resulting in increased serotonergic activity. Its discrete antidopaminergic activity contributes to the therapeutic effect.
  • Cinitapride has been shown to antagonize gastroparesis and vomiting induced by L-dopa.
  • Cinitapride significantly accelerated the gastric evacuation time in patients with pathological delay of gastric emptying. Cinitapride improves the clinical symptomatology of patients with dyspepsia associated with slowing of gastric emptying and delay of gastrointestinal transit.
  • the absorption of Cinitapride, after oral administration, is rapid and reaches the maximum plasma concentration at 2 hours. It is metabolized at the hepatic level (> 90%) with an important hepatic first pass metabolism. No accumulation has been observed after repeated administration of Cinitapride. This compound is indicated in the treatment of dyspepsia of mild to moderate dysmotility in a dose of up to 3 mg per day.
  • the compound Simethicone is a mixture of Dimethicone with silicon dioxide. Its IUPAC nomenclature is a- (trimethylsilyl) - ⁇ -methylpoly [oxy (dimethylsilylene)], mixed with silicon dioxide, and is represented by Formula (II)
  • Simethicone is a chemically inert compound that is not absorbed in the gastrointestinal tract. It is excreted as it was ingested, in the stool and without evidence of hepatic whole circulation. Simethicone alters the surface tension of gas bubbles that form in the gastrointestinal tract, either in the digestive process itself or due to lactose intolerance. Its action allows the gas bubbles to break and form much smaller ones that are easily eliminated both orally and rectally. The clinical use of Simethicone is based on its anti-foam property demonstrated in vitro. This compound is indicated in the treatment of functional gastrointestinal conditions in which gas retention can be a problem.
  • U.S. Patent No. 4,582,709 whose headline was Warner Lambert, with a US priority date of February 8, 1985, claimed a chewable mineral supplement and process to obtain it.
  • Said product comprises from about 3 to about 40% by weight of mineral compound, and from about 1.5 to about 6% by weight of an edible polyalcohol mixed with a sweet caramel base,
  • Bl whose title is Advanced Technology Pharmaceuticals Corp, and with a US priority date of December 12, 1991, claims a dry, antifoam granular composition comprising a water-soluble agglomerate, based on carbohydrates and a non-aqueous liquid selected from hydrocarbon oils. and silicone oils.
  • the Carbohydrates were selected from maltodext quarrel, dextrose, sucrose, fructose, mannitol and agglomerates of sorbitol.
  • European patent with publication number EP 1 297 825 Bl whose title is McNeil-PPC, INC and with US priority No. 09 / 966,441 dated September 28, 2001, claims a composition for producing a compressed solid dosage form comprising Simethicone, a mixture of silicified microcrystalline cellulose and magnesium aluminometasilicate as an adsorbent, and an optional active agent.
  • Simethicone is adsorbed in an inert material that can be, microcrystalline cellulose, calcium phosphate, pregelatinized corn starch, colloidal silica, hydroxypropylcellulose, magnesium oxide and magnesium hydroxide, in the form of a chewable tablet. It includes combinations with one or more antacids, antidiarrheals, antispasmodics, laxatives, antiemetics and anticholinergics.
  • the subject of the present invention relates to a pharmaceutical composition for oral administration, in the form of liquid-containing capsules, comprising a fixed-dose combination of Cinitapride tartrate and Simethicone together with at least one surfactant and optionally one or more excipients pharmaceutically acceptable.
  • the composition is designed so that Cinitapride and Simethicone are released quickly after the disintegration of the capsule in the gastrointestinal tract.
  • This composition was designed to treat gastrointestinal disorders, especially dyspepsia.
  • the patients to whom this kind of composition is indicated not only suffer from dyspepsia, but also tend to have other symptoms such as gastroesophageal reflux, gastritis, high gastric acidity generating irritation of the esophageal mucosa, this condition can lead to a dysphagia (difficulty in swallowing) and / or dinophagia (pain during swallowing).
  • a formulation containing the two active ingredients, Cinitapride and Simethicone was designed in therapeutically effective doses, where Cinitapride was incorporated micronized to Simethicone, immediately finding the drawback of the lack of homogeneity of the composition since Cinitaprida tends to agglomerate after being incorporated in the Simethicone, leaving a fraction of Cinitaprida floating on the surface of Simethicone, without being integrated into the formulation.
  • Cinitapride has a granulometry d (90) of approximately 100 microns a good dispersion is not formed, therefore, it must be ground. It was found that the optimal value is 50 microns or less.
  • Cinitapride suspended in Simeticona liquida allows its simultaneous administration in a capsule of small volume and easy swallowing.
  • the invention relates to a pharmaceutical composition for oral administration, of rapid release, comprising a fixed-dose combination of Cinitapride tartrate and Simethicone, with Cinitapride ground and suspended in Simethicone together with at least a surfactant agent, and encapsulated in hard capsules with liquid content or in soft capsules.
  • This composition is designed for the treatment of functional gastrointestinal disorders, especially dyspepsia.
  • Cinitapride Therapeutically effective doses of Cinitapride are in the range of 1 to 3 mg, according to Martindale, Cinitapride, The Complete Drug Reference, Volume 1, Edition 36, 2009, 1720.
  • the therapeutically effective doses of Simethicone are comprised in the range of 20 to 1000 mg, according to Martindale, Simeticona, The complete drug reference, Volume A, edition 38, 2014, 1886: 1887.
  • the invention relates to the process for obtaining the composition, which includes milling the Cinitapride to a size of d (90) of 50 microns or less, incorporating it into the vehicle (liquid surfactant agent), mixing with the Simethicone and finally encapsulate.
  • the process for preparing a composition comprising a combination of Cinitapride, suspended in Simethicone by the use of medium chain Triglycerides as liquid carrier is described.
  • the test batch is 100 g.
  • step 2 Add Simethicone to the dispersion from step 1 and heat to a temperature of approximately 35 2 C while maintaining constant agitation.
  • Cinitapride using a ground pulverizer Once the active ingredient is ground, a particle size (d90) of 47 microns is recorded.
  • Dissolution medium 0.01 N solution of hydrochloric acid.
  • the excipients Capryol 90, Lauroglycol 90 and Capmul PG-2L are propylene glycol esters with medium chain fatty acids and have a surfactant action.
  • Cinitapride titration 1.03 mg per capsule.
  • Simethicone rating 208 mg per capsule.
  • Cinitapride solution 94.9% (compliant)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique d'administration orale, sous forme de capsules à teneur en liquide, qui comprend une combinaison d'une dose fixe de cinitapride tartrate et de siméticone avec au moins un agent tensio-actif et éventuellement un ou plusieurs excipients pharmaceutiquement acceptables, et le procédé d'obtention de cette composition.
PCT/IB2018/050528 2017-02-07 2018-01-29 Composition à libération rapide de cinitapride et de siméticone, et procédé de préparation correspondante WO2018146575A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
BR112019015989-4A BR112019015989A2 (pt) 2017-02-07 2018-01-29 Composição de liberação rápida de cinitaprida e simeticona e processo para preparar a mesma
CR20190402A CR20190402A (es) 2017-02-07 2018-01-29 Composición de liberación rápida de cinitaprida y simeticona y proceso para prepararla
PE2019001412A PE20191491A1 (es) 2017-02-07 2018-01-29 Composicion de liberacion rapida de cinitaprida y simeticona y proceso para prepararla
CONC2019/0008347A CO2019008347A2 (es) 2017-02-07 2019-07-30 Composición de liberación rápida de cinitaprida y simeticona y proceso para prepararla

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2017001714A MX2017001714A (es) 2017-02-07 2017-02-07 Composicion de liberacion rapida de cinitaprida y simeticona y proceso para prepararla.
MXMX/A/2017/001714 2017-02-07

Publications (1)

Publication Number Publication Date
WO2018146575A1 true WO2018146575A1 (fr) 2018-08-16

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/050528 WO2018146575A1 (fr) 2017-02-07 2018-01-29 Composition à libération rapide de cinitapride et de siméticone, et procédé de préparation correspondante

Country Status (10)

Country Link
AR (1) AR110797A1 (fr)
BR (1) BR112019015989A2 (fr)
CL (1) CL2019001944A1 (fr)
CO (1) CO2019008347A2 (fr)
CR (1) CR20190402A (fr)
DO (1) DOP2019000190A (fr)
EC (1) ECSP19051198A (fr)
MX (1) MX2017001714A (fr)
PE (1) PE20191491A1 (fr)
WO (1) WO2018146575A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6676933B2 (en) * 2001-05-23 2004-01-13 Osmotica Corp. Pharmaceutical composition containing mosapride and pancreatin
WO2004071374A2 (fr) * 2003-02-11 2004-08-26 Torrent Pharmaceuticals Limited Compositions pharmaceutiques d'administration orale une fois par jour
US20070298099A1 (en) * 2004-11-24 2007-12-27 Peresypkin Andrey V Liquid and Semi-Solid Pharmaceutical Formulations for Oral Administration of a Substituted Amide
WO2009066146A2 (fr) * 2007-11-19 2009-05-28 Cadila Pharmaceuticals Ltd. Solutions stables d'actifs solubles de façon restreinte

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6676933B2 (en) * 2001-05-23 2004-01-13 Osmotica Corp. Pharmaceutical composition containing mosapride and pancreatin
WO2004071374A2 (fr) * 2003-02-11 2004-08-26 Torrent Pharmaceuticals Limited Compositions pharmaceutiques d'administration orale une fois par jour
US20070298099A1 (en) * 2004-11-24 2007-12-27 Peresypkin Andrey V Liquid and Semi-Solid Pharmaceutical Formulations for Oral Administration of a Substituted Amide
WO2009066146A2 (fr) * 2007-11-19 2009-05-28 Cadila Pharmaceuticals Ltd. Solutions stables d'actifs solubles de façon restreinte

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ROGASTRIL PLUS MASTICABLE, 29 June 2015 (2015-06-29), Retrieved from the Internet <URL:https://web.archive.org/web/20150629172859/bttps://www.roemmers.com.ar/es/productos/rogastril-plus> [retrieved on 20180411] *
ROGASTRIL PLUS, 29 June 2015 (2015-06-29), Retrieved from the Internet <URL:hEtps://web.archive.org/web/20150629172859/btEps://wvsw.n)eaimers.coin.ar/es/productos/roeastrll-plus> [retrieved on 20180411] *

Also Published As

Publication number Publication date
BR112019015989A2 (pt) 2020-03-31
DOP2019000190A (es) 2019-10-15
ECSP19051198A (es) 2019-07-31
MX2017001714A (es) 2018-08-06
CO2019008347A2 (es) 2019-08-30
PE20191491A1 (es) 2019-10-21
AR110797A1 (es) 2019-05-02
CL2019001944A1 (es) 2019-12-06
CR20190402A (es) 2019-09-20

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