WO2018146575A1 - Rapid-release composition of cinitapride and simeticone and method for preparing same - Google Patents

Rapid-release composition of cinitapride and simeticone and method for preparing same Download PDF

Info

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
Spanish (es)
French (fr)
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/en
Priority to CR20190402A priority patent/CR20190402A/en
Priority to PE2019001412A priority patent/PE20191491A1/en
Publication of WO2018146575A1 publication Critical patent/WO2018146575A1/en
Priority to CONC2019/0008347A priority patent/CO2019008347A2/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166Amides, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/695Silicon compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations 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)

Abstract

The present invention relates to an orally-administered pharmaceutical composition, in the form of capsules with liquid content, which comprises a fixed-dose combination of cinitapride tartrate and simeticone together with at least one surfactant and, optionally, one or more pharmaceutically acceptable excipients, and to the method for obtaining said composition.

Description

COMPOSICION DE LIBERACION RAPIDA DE CINITAPRIDA Y SIMETICONA COMPOSITION OF QUICK RELEASE OF CINITAPRIDA AND SIMETICONA
Y PROCESO PARA PREPARARLA. AND PROCESS TO PREPARE IT.
CAMPO TÉCNICO DE LA INVENCIÓN TECHNICAL FIELD OF THE INVENTION
La presente invención se refiere a una composición farmacéutica de administración oral, bajo la forma de cápsulas con contenido liquido, de liberación rápida, que comprende una combinación a dosis fija de Cinitaprida tartrato y Simeticona junto con al menos un agente surfactante y opcionalmente uno o más excipientes farmacéuticamente aceptables, y el proceso para obtener dicha compos ición . 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.
ANTECEDENTES DE LA INVENCIÓN El compuesto Cinitaprida, fue revelado como principio activo en la solicitud de patente Alemana DE 2,751,139 y sus equivalentes, el solicitante fue ANPHAR S.A. y reclamó como prioridad la solicitud inglesa con número de serie No. 47739 del 16 de noviembre de 1976. De acuerdo con la nomenclatura IUPAC el compuesto Cinitaprida es conocido bajo el nombre 4- amino-N- [ 1- ( 3-ciclohexen-l-ilmet il ) -4-piperidinil ] -2-etoxi-5- nitrobenzamida, y está representado por la siguiente Fórmula (I) : BACKGROUND OF THE INVENTION The compound 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):
Figure imgf000003_0001
Figure imgf000003_0001
Fórmula (I) Este compuesto es una ortopramida con actividad procinética a nivel del tracto gastrointestinal que posee una marcada acción procolinérgica . Mediante el bloqueo de los receptores presinápticos para la serotonina, aumenta la liberación de la misma, resultando en una mayor actividad serotoninérgica . Su discreta actividad antidopaminérgica contribuye al efecto terapéutico. En ensayos clínicos efectuados en pacientes y en voluntarios sanos, la Cinitaprida ha demostrado que antagoniza la gastroparesia y los vómitos inducidos por L-dopa. 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. In clinical trials in patients and healthy volunteers, Cinitapride has been shown to antagonize gastroparesis and vomiting induced by L-dopa.
En un estudio comparativo con placebo, la Cinitaprida aceleró de forma significativa el tiempo de evacuación gástrica en pacientes con retraso patológico del vaciamiento gástrico. La Cinitaprida mejora la sintomatología clínica de los pacientes con dispepsia asociada a enlentecimiento del vaciamiento gástrico y retraso del tránsito gastrointestinal. La absorción de Cinitaprida, luego de la administración por vía oral, es rápida y alcanza la concentración plasmática máxima a las 2 horas. Se metaboliza a nivel hepático (>90%) con un importante metabolismo de primer paso hepático. No se ha observado acumulación tras la administración repetida de Cinitaprida. Este compuesto está indicado en el tratamiento de las dispepsias de tipo dismotilidad leve a moderada en una dosis de hasta 3 mg por día. In a comparative study with placebo, 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.
El compuesto Simeticona, es una mezcla de Dimeticona con Dióxido de silicio. Su nomenclatura IUPAC es a- (trimetilsilil) - ω - metilpoli [oxi (dimetilsilileno) ] , mezclado con dióxido de silicio, y está representado por la Fórmula (II)  The compound Simethicone, is a mixture of Dimethicone with silicon dioxide. Its IUPAC nomenclature is a- (trimethylsilyl) - ω-methylpoly [oxy (dimethylsilylene)], mixed with silicon dioxide, and is represented by Formula (II)
Figure imgf000004_0001
Figure imgf000004_0001
20 < n <400  20 <n <400
Fórmula (II) Formula (II)
El método de preparación de polímeros de metil siloxano fue descrito en la patente Estadounidense No. 2,441,098, la cual reclamó como prioridad la solicitud Estadounidense No. 695, 803 de fecha 09 de septiembre de 1946, y su titular fue CORNING GLASS WORKS. The method of preparing polymers of methyl siloxane was described in U.S. Patent No. 2,441,098, which claimed as a priority US Application No. 695, 803 dated September 9, 1946, and its owner was CORNING GLASS WORKS.
En el Journal of Clinical Pharmacology, publicado el 12 de noviembre de 1974, fue incluido un artículo sobre la evaluación clínica del uso de Simeticona en el tracto gastrointestinal superior, de los autores Joel E. Bernstein y Anthony M. Kasich. In the Journal of Clinical Pharmacology, published on November 12, 1974, an article was included on the clinical evaluation of the use of Simethicone in the tract Gastrointestinal superior, by the authors Joel E. Bernstein and Anthony M. Kasich.
La Simeticona es un compuesto químicamente inerte que no se absorbe en el tracto gastrointestinal. Se excreta tal como fue ingerido, en las heces y sin evidencia de circulación entero hepática. La Simeticona altera la tensión superficial de las burbujas de gases que se forman en el tracto gastrointestinal, ya sea en el proceso digestivo mismo o por intolerancia a la lactosa. Su acción permite que las burbujas de gases se rompan y se formen otras mucho más pequeñas que son fácilmente eliminadas tanto por vía oral como por vía rectal. El uso clínico de la Simeticona está basado en su propiedad antiespuma demostrada in vitro. Este compuesto es indicado en el tratamiento de condiciones gastrointestinales funcionales en la cual la retención de gases puede ser un problema .  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.
La patente Estadounidense No. 4,582,709, cuyo titular fue Warner Lambert, con fecha de prioridad Estadounidense del 08 de febrero de 1985, reivindicó un suplemento mineral masticable y proceso para obtener el mismo. Dicho producto comprende de aproximadamente 3 a aproximadamente 40% en peso de compuesto mineral, y de aproximadamente 1.5 a aproximadamente 6% en peso de un polialcohol comestible mezclado con una base dulce de caramelo,  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,
La patente europea con número de publicación EP 596 049 The European patent with publication number EP 596 049
Bl , cuyo titular es Advanced Technology Pharmaceuticals Corp, y con fecha de prioridad Estadounidense del 12 de diciembre de 1991, reivindica una composición granular seca, antiespumante comprendiendo un aglomerado soluble en agua, a base de carbohidratos y un líquido no acuoso seleccionado entre aceites hidrocarbonados y aceites de silicona. Los carbohidratos fueron seleccionados de maltodext riña, dextrosa, sacarosa, fructuosa, manitol y aglomerados de sorbit ol . 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.
La solicitud de patente Estadounidense con número de publicación US 2004/0092511 Al, continuación de la solicitud No. 09/722, 784 de fecha 27 de noviembre de 2000 y cuya prioridad es la solicitud provisional No. 60/266,333 de fecha 10 de diciembre de 1999, reivindica combinaciones de agonistas del receptor 5-HT4, o antagonistas de 5- HT3, con un co-agente, para tratar desórdenes gastrointestinales y vi scero-abdominales . The US patent application with publication number US 2004/0092511 Al, continuation of application No. 09/722, 784 dated November 27, 2000 and whose priority is provisional application No. 60 / 266,333 dated December 10 of 1999, claims combinations of 5-HT 4 receptor agonists, or 5-HT 3 antagonists, with a co-agent, to treat gastrointestinal and abdominal-abdominal disorders.
La patente europea con número de publicación EP 1 297 825 Bl, cuyo titular es McNeil-PPC, INC y con prioridad estadounidense No. 09/966,441 de fecha 28 de septiembre del 2001, reivindica una composición para producir una forma de dosificación sólida comprimida comprendiendo Simeticona, una mezcla de Celulosa microcristalina silicificada y Aluminometasilicato de magnesio como adsorbente, y un agente activo opcional.  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.
La solicitud de patente internacional con número de publicación WO 2008/056200, cuyo solicitante es Ranbaxy Laboratories Limited, reivindica una composición farmacéutica oral conteniendo Simeticona, un material inerte, una Sal de silicato y opcionalmente excipientes. La Simeticona se encuentra adsorbida en un material inerte que puede ser, Celulosa microcristalina, Fosfato de calcio, Almidón de maíz pregelatinizado, Silica coloidal, Hidroxipropilcelulosa, Oxido de magnesio e Hidróxido de magnesio, bajo la forma de comprimido masticable. Incluye combinaciones con uno o más antiácidos, ant idiarreicos , ant iespasmódicos , laxantes, antieméticos y ant icolinérgicos . DESCRIPCIÓN DETALLADA DE LA INVENCIÓN The international patent application with publication number WO 2008/056200, whose applicant is Ranbaxy Laboratories Limited, claims an oral pharmaceutical composition containing Simethicone, an inert material, a Silicate Salt and optionally excipients. 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. DETAILED DESCRIPTION OF THE INVENTION
El objeto de la presente invención se refiere a una composición farmacéutica de administración oral, bajo la forma de cápsulas con contenido liquido, que comprende una combinación a dosis fija de Cinitaprida tartrato y Simeticona junto con al menos un agente surfactante y opcionalmente uno o más excipientes farmacéuticamente aceptables. La composición está diseñada para que la Cinitaprida y la Simeticona se liberen rápidamente luego de la desintegración de la cápsula en el tracto gastrointestinal. 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.
Esta composición fue diseñada para tratar los desórdenes gastrointestinales en especial la dispepsia. Los pacientes a los que se les indica esta clase de composición, no solo adolecen de dispepsia, sino que además suelen cursar con otros síntomas tales como reflujo gastroesofágico, gastritis, acidez gástrica elevada generando irritación de la mucosa esofágica, pudiendo esta afección llevar a una disfagia (dificultad en la deglución) y/o dinofagia (dolor durante la deglución) . Con base en lo anteriormente descrito es que se desarrolló una formulación de fácil pasaje a nivel deglutorio, de tamaño reducido y con buen deslizamiento en el tracto faríngeo, sin adhesiones a las paredes del esófago, al momento de la deglución, y de rápida liberación de la Cinitaprida y la Simeticona en estado líquido.  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). Based on what has been described above, an easy-to-swallow formulation was developed, reduced in size and with good slippage in the pharyngeal tract, without adhesions to the walls of the esophagus, at the time of swallowing, and rapid release of Cinitapride and Simethicone in liquid state.
Para obtener una composición farmacéutica de tamaño reducido y de rápida liberación, se diseñó una formulación conteniendo los dos principios activos, Cinitaprida y Simeticona en dosis terapéuticamente efectivas, en donde la Cinitaprida se incorporó micronizada a la Simeticona, hallando inmediatamente el inconveniente de la falta de homogeneidad de la composición ya que Cinitaprida tiende a aglomerarse luego de incorporada en la Simeticona, quedando una fracción de Cinitaprida flotando en la superficie de la Simeticona, sin integrarse a la formulación. Para resolver este inconveniente se seleccionaron una serie de excipientes (vehículos líquidos) en los cuales se incorporó la Cinitaprida micronizada, antes de suspenderla en la Simeticona, con la finalidad de disminuir su tensión superficial y poder integrarla a la Simeticona. Este compuesto en forma pura es un líquido muy viscoso, absolutamente hidrofóbico. Estas características dificultan su combinación con otro principio activo y más aún si el compuesto es hidrofílico como es el caso de la Cinitaprida tartrato . To obtain a pharmaceutical composition of reduced size and rapid release, 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. To solve this problem, a series of excipients (liquid vehicles) were selected, in which the micronized Cinitapride was incorporated, before suspending it in the Simethicone, in order to reduce its surface tension and integrate it into Simethicone. This compound in pure form is a very viscous, absolutely hydrophobic liquid. These characteristics make it difficult to combine them with another active principle and even more so if the compound is hydrophilic, as is the case of Cinitapride tartrate.
Para salvar este inconveniente se seleccionaron una serie de vehículos líquidos miscibles con Simeticona, para dispersar la Cinitaprida. Los excipientes probados fueron:  To overcome this problem, a series of liquid vehicles miscible with Simethicone were selected to disperse Cinitapride. The tested excipients were:
• Polietilenglicol 400 USP-NF (Polyglykol 400) • Polyethylene glycol 400 USP-NF (Polyglykol 400)
• Ácido Oleico USP-NF • Oleic Acid USP-NF
• Caprilocaproil polioxil-8 glicérido USP-NF (Labrasol) • Caprilocaproil polioxil-8 glyceride USP-NF (Labrasol)
• Glicerina USP-NF • Glycerin USP-NF
• Polisorbato 80 USP-NF (Tween 80) • 80 USP-NF Polysorbate (Tween 80)
• Sorbitan monooleato USP-NF (Span 80) • Sorbitan monooleate USP-NF (Span 80)
• Sorbitol 70% USP-NF • Sorbitol 70% USP-NF
• Triglicéridos de cadena media USP-NF (Miglyol 812) Propilenglicol dicapri locaprato USP-NF (Miglyol 840) • Medium Chain Triglycerides USP-NF (Miglyol 812) Propylene glycol dicapri locaprate USP-NF (Miglyol 840)
• Propilenglicol dilaurato USP-NF (Capmul PG2L) • Propylene glycol dilaurate USP-NF (Capmul PG2L)
• Propilenglicol monocaprilato tipo II USP-NF (Capryol 90) • Propylene glycol monocaprylate type II USP-NF (Capryol 90)
• Propilenglicol monolaurato tipo II USP-NF (Lauroglycol 90) • Propylene glycol monolaurate type II USP-NF (Lauroglycol 90)
Por otro lado se probaron diferentes granulometrias para determinar cuál era la de mejor integración en la formulación y rápida liberación. Se comprobó que cuando la Cinitaprida tiene una granulometria d(90) de aproximadamente 100 micrones no se forma una buena dispersión, por lo tanto, debe estar molida. Se encontró que el valor óptimo es de 50 micrones o menos . On the other hand, different granulometries were tested to determine which was the best integration in the formulation and rapid release. It was found that when 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.
La solución técnica hallada consistió en moler la Cinitaprida hasta obtener un d (90) de 50 micrones o menor e incorporarla al surfactante liquido e incorporar finalmente esta suspensión a la Simeticona, para luego llenar capsulas, pudiendo ser capsulas de gelatina blanda o capsulas duras. The technical solution found was to grind Cinitapride until obtaining a d (90) of 50 microns or less and incorporate it into the liquid surfactant and finally incorporate this suspension into the Simethicone, to then fill capsules, which could be soft gelatin capsules or hard capsules.
El hecho de utilizar Cinitaprida suspendida en Simeticona liquida permite su administración simultánea en una capsula de pequeño volumen y fácil deglución.  The fact of using Cinitapride suspended in Simeticona liquida allows its simultaneous administration in a capsule of small volume and easy swallowing.
Los ensayos de liberación in vitro de la forma farmacéutica obtenida conteniendo la combinación de los dos principios activos, cumplieron las especificaciones requeridas, liberándose la Cinitaprida rápidamente del medio que lo contiene.  The in vitro release assays of the pharmaceutical form obtained containing the combination of the two active ingredients fulfilled the required specifications, releasing Cinitapride rapidly from the medium containing it.
Los aspectos mencionados previamente hacen que esta composición se diferencie de otras composiciones que contienen los mismos principios activos y es por consiguiente, el objeto principal de la presente invención. The previously mentioned aspects make this composition different from other compositions that they contain the same active principles and is therefore the main object of the present invention.
Por lo tanto, en un aspecto la invención, se refiere a una composición farmacéutica de administración oral, de liberación rápida, que comprende una combinación a dosis fija de Cinitaprida tartrato y Simeticona, estando la Cinitaprida molida y suspendida en la Simeticona junto con al menos un agente surfactante, y encapsuladas en cápsulas duras con contenido liquido o en cápsulas blandas. Esta composición está diseñada para el tratamiento de los desórdenes gastrointestinales funcionales, en especial la dispepsia .  Therefore, in one aspect 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.
Las dosis terapéuticamente efectivas de la Cinitaprida están comprendidas en el rango de 1 a 3 mg, según Martindale, Cinitapride, The complete drug reference, Volumen 1, edición 36, 2009, 1720.  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.
Por su parte, las dosis terapéuticamente efectivas de Simeticona, están comprendidas en el rango de 20 a 1000 mg, según Martindale, Simeticona, The complete drug reference, Volumen A, edición 38, 2014, 1886:1887.  On the other hand, 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.
En otro aspecto la invención, se refiere al proceso para obtener la composición, el cual incluye moler la Cinitaprida a un tamaño de d(90) de 50 micrones o menor, incorporarla en el vehículo (agente surfactante liquido) , mezclar con la Simeticona y finalmente encapsular.  In another aspect 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.
A continuación, en los siguientes ejemplos de realización se describen los diferentes ensayos realizados utilizando los diferentes vehículos, para finalmente elegir el vehículo más adecuado. También se evaluó la granulometría de la Cinitaprida y la compatibilidad de la composición con las cápsulas duras y capsulas blandas. Se realizaron ensayos con ambas cápsulas. Next, in the following examples of embodiment, the different tests carried out using the different vehicles are described, in order to finally choose the most suitable vehicle. The granulometry of Cinitapride and the compatibility of the composition with the hard capsules and soft capsules. Tests were carried out with both capsules.
EJEMPLOS DE REALIZACIÓN EXAMPLES OF REALIZATION
EJEMPLO 1. Cápsulas de 1 mg Cinitaprida (como tartrato ácido) + 200 mg de Simeticona 120 mg y Miglyol 812 (Triglicéridos de cadena media) como vehículo EXAMPLE 1. Capsules of 1 mg Cinitapride (as acid tartrate) + 200 mg of Simethicone 120 mg and Miglyol 812 (Medium Chain Triglycerides) as vehicle
Se describe el proceso para preparar una composición que comprende una combinación de Cinitaprida, suspendida en Simeticona mediante la utilización de Triglicéridos de cadena media como vehículo líquido. El lote ensayo es de 100 g. 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.
Figure imgf000011_0001
Figure imgf000011_0001
^Equivale a 1 mg de Cinitaprida ^ Equivalent to 1 mg of Cinitapride
Contenido Neto por cápsula: 250 mg Net content per capsule: 250 mg
MÉTODO DE ELABORACIÓN METHOD OF PREPARATION
1. Dispersar la Cinitaprida tartrato ácido en el vehículo líquido, agitando durante 10 minutos a temperatura ambiente. Verificar que se forme una dispersión homogénea o una solución. 1. Disperse the acid tartrate Cinitapride in the liquid vehicle, stirring for 10 minutes at room temperature ambient. Verify that a homogeneous dispersion or solution is formed.
2. Agregar la Simeticona a la dispersión del paso 1 y calentar a una temperatura de aproximadamente 352 C mientras se mantiene en agitación constante. 2. Add Simethicone to the dispersion from step 1 and heat to a temperature of approximately 35 2 C while maintaining constant agitation.
3. Dejar enfriar a temperatura ambiente durante 30 minutos . 3. Allow to cool to room temperature for 30 minutes.
Resultado: No se logró una buena dispersión de la Cinitaprida en el Miglyol 812. Se forman grumos que se mantienen al mezclar con la Simeticona. Result: A good dispersion of Cinitapride was not achieved in Miglyol 812. Lumps are formed that are maintained when mixed with Simethicone.
Se decide repetir el ensayo pero previamente moliendo laIt is decided to repeat the test but previously grinding the
Cinitaprida utilizando un molido pulverizador. Una vez molido el principio activo se registra un tamaño de partículas (d90) de 47 micrones. Cinitapride using a ground pulverizer. Once the active ingredient is ground, a particle size (d90) of 47 microns is recorded.
Resultado: Al utilizar Cinitaprida molida se logró una buena dispersión en el Miglyol 812. Al mezclar con la Simeticona se forma una suspensión homogénea, apta para encapsular . Result: When using ground Cinitaprida, a good dispersion was achieved in the Miglyol 812. When mixed with the Simethicone a homogeneous suspension is formed, apt to encapsulate.
EJEMPLO II. Cápsulas de 1 mg Cinitaprida (como tartrato ácido) + 200 mg de Simeticona. Prueba de vehículos. EXAMPLE II. Capsules of 1 mg Cinitapride (as acid tartrate) + 200 mg of Simethicone. Test of vehicles.
Utilizando Cinitaprida tartrato molida con d(90) menor a 50 micrones y el método de elaboración empleado en el Ejemplo 1, se probaron los siguientes vehículos: Polietilenglicol 400 USP-NF (Polyglykol 400), Ácido Oleico USP-NF, Caprilocaproil polioxil-8 glicérido USP-NF (Labrasol) , Glicerina USP-NF, Polisorbato 80 USP-NF (Tween 80) , Sorbitan monooleato USP-NF (Span 80), Sorbitol 70% USP-NF y Triglicéridos de cadena media USP-NF (Miglyol 812), Propilenglicol dicaprilocaprato USP-NF (Miglyol 840) , Propilenglicol dilaurato USP-NF (Capmul PG2L) , Propilenglicol monocaprilato tipo II USP-NF (Capryol 90) y Propilenglicol monolaurato tipo II USP-NF (Lauroglycol 90) . Using Cinitapride tartrate ground with d (90) less than 50 microns and the processing method used in Example 1, the following vehicles were tested: Polyethylene glycol 400 USP-NF (Polyglykol 400), Oleic acid USP-NF, Caprilocaproil polyoxyl-8 glyceride USP-NF (Labrasol), Glycerin USP-NF, Polysorbate 80 USP-NF (Tween 80), Sorbitan monooleate USP-NF (Span 80), Sorbitol 70% USP-NF and Chain triglycerides medium USP-NF (Miglyol 812), propylene glycol dicaprilocaprate USP-NF (Miglyol 840), propylene glycol dilaurate USP-NF (Capmul PG2L), Propylene glycol monocaprylate type II USP-NF (Capryol 90) and Propylene glycol monolaurate type II USP-NF (Lauroglycol 90).
Figure imgf000013_0001
Figure imgf000013_0001
A partir de los resultados obtenidos, se seleccionaron las mezclas que contienen Miglyol 812, Miglyol 840, Capmul PG-2L, Capryol 90 y Lauroglycol 90 como vehículos para continuar ensayando. Se preparon capsulas duras de gelatina (coni-snap, Capsugel) tamaño Nr . 3 con las siguientes formulas : From the results obtained, mixtures containing Miglyol 812, Miglyol 840, Capmul PG-2L, Capryol 90 and Lauroglycol 90 were selected as vehicles to continue testing. Hard gelatine capsules were prepared (coni-snap, Capsugel) size Nr. 3 with the following formulas:
Figure imgf000014_0001
Figure imgf000014_0001
EJEMPLO III. DETERMINACIONES FARMACOTECNICAS Y PRUEBASEXAMPLE III. PHARMACOTECHNICAL DETERMINATIONS AND EVIDENCE
IN VITRO IN VITRO
-Valoración Cinitaprida: Por HPLC - Cromatógrafo liquido marca HEWLETT PACKARD, o equivalente, equipado con detector de arreglo de diodos en circuito integrado. - Valorization Cinitaprida: By HPLC - Liquid chromatograph brand HEWLETT PACKARD, or equivalent, equipped with diode array detector in integrated circuit.
-Valoración Simeticona: por Espect rofotometria -Simeticone assessment: by Espect rofotometry
Infrarroja, Infrared,
-Ensayo de disolución Cinitaprida: según la Farmacopea de los Estados Unidos (USP) Ensayos generales y Ensayos <711>, - Cinitapride solution test: according to the United States Pharmacopeia (USP) General Tests and Tests <711>,
EQUIPO: SOTAX Type AT7 o equivalente equipado con paletas .  EQUIPMENT: SOTAX Type AT7 or equivalent equipped with pallets.
Medio de Disolución: Solución 0.01 N de ácido clorhídrico .  Dissolution medium: 0.01 N solution of hydrochloric acid.
Temperatura: 36.52 C - 37.52 C. Volumen: 500 mi Temperature: 36.5 2 C - 37.5 2 C. Volume: 500 mi
Velocidad: 75 r.p.m.  Speed: 75 r.p.m.
Tiempo de Ensayo: 30 minutos.  Test Time: 30 minutes.
Se realizaron determinaciones farmacotécnicas y pruebas in vitro para evaluar las características físicas y químicas de las composiciones Fl a F5.  Pharmacotechnical determinations and in vitro tests were carried out to evaluate the physical and chemical characteristics of the compositions Fl a F5.
Figure imgf000015_0001
Figure imgf000015_0001
Conclusión: Las fórmulas a base de Fl y F2 (a base de Miglyol 812 y Miglyol 840, respectivamente) no tienen una rápida liberación de Cinitaprida. Las fórmulas que contienen Capryol 90, Lauroglycol 90 o Capmul PG-2L cumplen con el criterio de rápida disolución de la Cinitaprida. Conclusion: The formulas based on Fl and F2 (based on Miglyol 812 and Miglyol 840, respectively) do not have a rapid release of Cinitapride. The formulas that contain Capryol 90, Lauroglycol 90 or Capmul PG-2L meet the criteria for rapid dissolution of Cinitapride.
Los excipientes Capryol 90, Lauroglycol 90 y Capmul PG- 2L son ásteres de propilenglicol con ácidos grasos de cadena media y tienen acción surfactante. The excipients Capryol 90, Lauroglycol 90 and Capmul PG-2L are propylene glycol esters with medium chain fatty acids and have a surfactant action.
Figure imgf000016_0001
Figure imgf000016_0001
EJEMPLO IV. Cápsulas de gelatina blanda conteniendo 1 mg Cinitaprida (como tartrato ácido) + 200 mg de Simeticona . EXAMPLE IV. Soft gelatin capsules containing 1 mg Cinitapride (as acid tartrate) + 200 mg Simeticone.
Utilizando el método de elaboración empleado en el Ejemplo 1, se elaboró la siguiente suspensión: Using the processing method employed in Example 1, the following suspension was made:
Figure imgf000016_0002
Figure imgf000016_0002
^Equivale a 1 mg de Cinitaprida Se obtuvieron 4.96 kg de suspensión. Utilizando equipos convencionales, la suspensión fue llenada en cápsulas de gelatina blanda con un peso de contenido de 300 mg por cápsula. ^ Equivalent to 1 mg of Cinitapride 4.96 kg of suspension were obtained. Using conventional equipment, the suspension was filled into soft gelatine capsules with a content weight of 300 mg per capsule.
Resultados analíticos : Analytical results:
Valoración de Cinitaprida: 1.03 mg por cápsula.  Cinitapride titration: 1.03 mg per capsule.
Valoración Simeticona: 208 mg por cápsula.  Simethicone rating: 208 mg per capsule.
Disolución de Cinitaprida: 94.9% (cumple)  Cinitapride solution: 94.9% (compliant)

Claims

REIVINDICACIONES
1. Una composición farmacéutica de administración oral en la forma de cápsulas con contenido liquido que comprende1. A pharmaceutical composition for oral administration in the form of capsules with liquid content comprising
Cinitaprida tartrato ácido, Simeticona, al menos un vehículo líquido y opcionalmente otros excipientes farmacéuticos, en donde el vehículo líquido es un agente surfactante seleccionado de ésteres de propilenglicol con ácidos grasos de cadena media. Cinitapride acid tartrate, Simethicone, at least one liquid carrier and optionally other pharmaceutical excipients, wherein the liquid carrier is a surfactant agent selected from propylene glycol esters with medium chain fatty acids.
2. La composición de conformidad con la reivindicación 1, en donde el vehículo liquido es Propilenglicol monocaprilato . 2. The composition according to claim 1, wherein the liquid carrier is Propylene glycol monocaprylate.
3. La composición de conformidad con la reivindicación 1, en donde el vehículo liquido es Propilenglicol monolaurato . 3. The composition according to claim 1, wherein the liquid carrier is Propylene glycol monolaurate.
4. La composición de conformidad con la reivindicación 1, en donde el vehículo liquido es Propilenglicol dilaurato. 4. The composition according to claim 1, wherein the liquid carrier is Propylene glycol dilaurate.
5. La composición de conformidad con las reivindicaciones 1 a 4, en donde la Cinitaprida se encuentra molida con un tamaño de partículas menor o igual a 50 micrones . 5. The composition according to claims 1 to 4, wherein the Cinitapride is milled with a particle size less than or equal to 50 microns.
6. La composición de conformidad con la reivindicación 5 en donde el contenido por unidad de dosis de la Cinitaprida es 1 mg o su equivalente como Cinitaprida tartrato ácido y el contenido por unidad de dosis de la Simeticona es 200 mg . 6. The composition according to claim 5 wherein the content per unit dose of Cinitapride is 1 mg or its equivalent as Cinitapride tartrate acid and the content per unit dose of Simethicone is 200 mg.
7. La composición de conformidad con la reivindicación 6 en donde la unidad de dosis es una cápsula dura de gelatina. The composition according to claim 6 wherein the dosage unit is a hard gelatin capsule.
8. La composición de conformidad con la reivindicación 6 en donde la unidad de dosis es una cápsula de gelatina blanda . 8. The composition according to claim 6 wherein the dosage unit is a soft gelatin capsule.
9. Un proceso para obtener la composición de la reivindicación 1, que comprende las etapas de dispersar9. A process for obtaining the composition of claim 1, comprising the steps of dispersing
Cinitaprida tartrato ácido en Propilenglicol monocaprilato, Propilenglicol monolaurato o Propilenglicol dilaurato, mezclar la suspensión obtenida con Simeticona y agitar manteniendo la mezcla a 352 C hasta obtener una dispersión homogénea. Cinitapride tartrate acid Propylene glycol monocaprylate, Propylene glycol monolaurate or dilaurate Propylene glycol, mixing the obtained suspension with stirring Simethicone and maintaining the mixture at 35 2 C to obtain a homogeneous dispersion.
PCT/IB2018/050528 2017-02-07 2018-01-29 Rapid-release composition of cinitapride and simeticone and method for preparing same WO2018146575A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
BR112019015989-4A BR112019015989A2 (en) 2017-02-07 2018-01-29 COMPOSITION OF QUICK RELEASE OF CINITAPRIDE AND SIMETICONE AND PROCESS TO PREPARE THE SAME
CR20190402A CR20190402A (en) 2017-02-07 2018-01-29 Rapid-release composition of cinitapride and simeticone and method for preparing same
PE2019001412A PE20191491A1 (en) 2017-02-07 2018-01-29 QUICK RELEASE COMPOSITION OF CINITAPRIDE AND SYMETICONE AND PROCESS TO PREPARE IT
CONC2019/0008347A CO2019008347A2 (en) 2017-02-07 2019-07-30 Quick release composition of cinitapride and simethicone and process to prepare it

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2017001714A MX2017001714A (en) 2017-02-07 2017-02-07 Rapid-release composition of cinitapride and simeticone and method for preparing same.
MXMX/A/2017/001714 2017-02-07

Publications (1)

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

Family

ID=63108046

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/050528 WO2018146575A1 (en) 2017-02-07 2018-01-29 Rapid-release composition of cinitapride and simeticone and method for preparing same

Country Status (10)

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

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 (en) * 2003-02-11 2004-08-26 Torrent Pharmaceuticals Limited Once a day orally administered pharmaceutical compositions
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 (en) * 2007-11-19 2009-05-28 Cadila Pharmaceuticals Ltd. Stable solutions of sparingly soluble actives

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 (en) * 2003-02-11 2004-08-26 Torrent Pharmaceuticals Limited Once a day orally administered pharmaceutical compositions
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 (en) * 2007-11-19 2009-05-28 Cadila Pharmaceuticals Ltd. Stable solutions of sparingly soluble actives

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

Similar Documents

Publication Publication Date Title
ES2863500T3 (en) Abiraterone Acetate Lipid Formulations
ES2892029T3 (en) Enzalutamide formulations
ES2627531T5 (en) Pharmaceutical composition with improved bioavailability for a high-melting hydrophobic compound
ES2341510T3 (en) MICROEMULSIONS AS SOLID PHARMACEUTICAL FORMS FOR ORAL ADMINISTRATION.
TWI490216B (en) Pharmaceutical composition for a hepatitis c viral protease inhibitor
ES2563735T3 (en) Pharmaceutical dosage form comprising 6&#39;-fluor- (N-methyl- or N, N-dimethyl-) -4-phenyl-4 &#39;, 9&#39;-dihydro-3&#39;H-spiro [cyclohexane-1,1&#39;- pyrano [3,4, b] indole] -4-amine
CN103153282B (en) The pharmaceutical dosage form of &#39;, 9 &#39;-dihydro-3 &#39; H-spiral shell [cyclohexane extraction-1,1 &#39;-pyrans is [3,4, B] indole also]-4-amine containing 6 &#39;-fluoro-(N-methyl-or N, N-dimethyl-)-4-phenyl-4
ES2451540T3 (en) Oral dosage forms of bendamustine
ES2668203T3 (en) Fexofenadine microcapsules and compositions containing them
ES2717282T3 (en) Formulations and methods for manufacturing formulations for use in colonic evacuation
Singh et al. Fast dissolving drug delivery systems: formulation, preparation techniques and evaluation
ES2253354T3 (en) NEW SUPPLY SYSTEM OF A SELF-EMULSIONING MEDICINAL PRODUCT.
ES2690257T3 (en) Oral dosage forms of bendamustine
ES2301455T3 (en) Antacid pharmaceutical composition in powder form, pharmaceutical preparation containing it and process for its preparation
US20150342882A1 (en) Methods of treatment using cadotril compositions
JP2013028603A (en) Liquid dosage form of proton pump inhibitor
US20120213855A1 (en) Dosage forms for weakly ionizable compounds
JP2020526512A (en) New Secnidazole soft gelatin capsule formulation and its use
WO2018146575A1 (en) Rapid-release composition of cinitapride and simeticone and method for preparing same
Karthika et al. Formulation development and in vitro evaluation of curcumin-loaded solid selfnanoemulsifying drug delivery system for colon carcinoma
WO2010030667A2 (en) Dosage forms for weakly ionizable compounds
ES2733113T3 (en) Stable pharmaceutical composition of a water soluble vinorelbine salt
ES2763945T3 (en) Pharmaceutical compositions incorporating drugs in low doses
CN103179953A (en) Pharmaceutical dosage form comprising 6&#39;-fluoro-(n-methyl- or n,n-dimethyl-)-4-phenyl-4,9&#39;-dihydro-3&#39;h-spiro[cylohexane-1,1&#39;-pyrano[3,4,b]indol]-4-amine
Patel Design, Development, Evaluation and Optimization of Antiulcer Delayed Release Tablets

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18751654

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112019015989

Country of ref document: BR

122 Ep: pct application non-entry in european phase

Ref document number: 18751654

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 112019015989

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20190801