WO2018109693A1 - Composition améliorée de lansoprazol et de siméticone et procédé de préparation de cette dernière - Google Patents

Composition améliorée de lansoprazol et de siméticone et procédé de préparation de cette dernière Download PDF

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Publication number
WO2018109693A1
WO2018109693A1 PCT/IB2017/057904 IB2017057904W WO2018109693A1 WO 2018109693 A1 WO2018109693 A1 WO 2018109693A1 IB 2017057904 W IB2017057904 W IB 2017057904W WO 2018109693 A1 WO2018109693 A1 WO 2018109693A1
Authority
WO
WIPO (PCT)
Prior art keywords
microgranules
simethicone
lansoprazole
high concentration
pharmaceutical composition
Prior art date
Application number
PCT/IB2017/057904
Other languages
English (en)
Spanish (es)
Inventor
Esteban Alejandro Fiore
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 PE2019001165A priority Critical patent/PE20191654A1/es
Priority to BR112019011966-3A priority patent/BR112019011966A2/pt
Priority to CR20190290A priority patent/CR20190290A/es
Publication of WO2018109693A1 publication Critical patent/WO2018109693A1/fr
Priority to CONC2019/0006693A priority patent/CO2019006693A2/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
    • A61K31/33—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a pharmaceutical composition for oral administration, comprising the fixed-dose combination of Simethicone in high concentration microgranules and Lansoprazole or its enantiomer (Dexlansoprazole) in enteric release microgranules and the process for obtaining high concentration microgranules. of Simethicone.
  • This compound belonging to the family of substituted benzimidazoles, is a proton pump inhibitor, since it suppresses gastric acid secretion by specific inhibition of the enzymatic system H + , K + - ATPase (proton pump) on the secretory surface of gastric parietal cells.
  • the H + , K + - ATPase of the apical membrane of the parietal cell is the final mediator of acid secretion, that is to say that Lansoprazole blocks the last step in acid production.
  • Lansoprazole is a weak, chemically stable, fat-soluble base, devoid of inhibitory activity, and is destroyed in gastric acid.
  • Lansoprazole is a racemic mixture of the Dexlansoprazole and Levolansoprazole isomers (also called R-Lansoprazole and S-Lansoprazole, respectively).
  • the enantiomer that has demonstrated better clinical results is Dexlansoprazole, whose IUPAC formula is represented by formula (II):
  • Simethicone is a chemically inert compound that is not absorbed in the gastrointestinal tract. It is excreted as ingested, in the feces and without evidence of entire hepatic circulation. Simethicone alters the surface tension of gas bubbles that form in the gastrointestinal tract, either in the digestive process itself or by lactose intolerance. Its action allows 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 antifoam property demonstrated in vitro. This compound is indicated in the treatment of functional gastrointestinal conditions in which gas retention can be a problem.
  • European patent EP 1,108,425 Bl whose owner is Laboratorio Medinfar-Productos Farmaicos S.A. and the priority date is 16-12-1999 (PT), it claims stable pellets containing benzimidazole derivatives, on an inert core, with a polymeric coating and finally an enteric coating. Does not include Simethicone as active ingredient.
  • the object of the present invention relates to a pharmaceutical composition in a unit dose containing a combination of Simethicone in the form of high concentration microgranules and Lansoprazole or its enantiomer (Dexlansoprazole) in the form of enteric release microgranules. , in therapeutically effective amounts, contained in capsules or sachets.
  • the composition is designed for the treatment of functional gastrointestinal disorders, especially dyspepsia with a pharmaceutical form that is easy to ingest.
  • the granulate obtained is very fragile and this is detrimental to its dosage in the chosen pharmaceutical form, since it does not have good fluidity generating variations in the dosage and caking of the granulate at the time of dosing the product either in capsules or in sachets.
  • Lansoprazole and its enantiomer degrade in gastric medium (acid) and are stable in neutral to alkaline medium.
  • the parietal cells, where they are, are absorbed through the bloodstream into the site of action. hydrolyzed into active metabolites that combine with H +, KH-ATPase (proton pump), inhibiting it in that way.
  • Lansoprazole and its enantiomer must be formulated gastro-resistant (enteric release). It was decided that the most suitable formulation for Lansoprazole or its enantiomer is to use enteric microgranules.
  • the technical solution found was to obtain high concentration microgranules of the desired dose of Simethicone and encapsulate or envelop them together with enteric microgranules of Lansoprazole or its enantiomer.
  • Simethicone in the form of microgranules of high concentration allows its administration together with Lansoprazole or its enantiomer, in a single pharmaceutical form, of small volume and easy to ingest, and on the other hand it allows them to be dosed in capsules or in sachets with ease and using conventional equipment.
  • the encapsulation of the microgranules of both active ingredients can be obtained using a conventional encapsulator equipped with two microgranule dispensers, working in the operating conditions characteristic of the solids encapsulation.
  • the invention relates to a pharmaceutical composition for oral administration, comprising the fixed dose combination of Simethicone and Lansoprazole or its enantiomer, in therapeutically effective doses and pharmaceutical excipients.
  • Simethicone is in the form of high concentration microgranules
  • Lansoprazole or its enantiomer is in the form of enteric release microgranules, both of which are contained in hard capsules or sachets.
  • the therapeutically effective doses of Simethicone are in the range of 20 to 1000 mg, according to Martindale: The complete drug reference, Simethicone, Volume A, Edition 38, 2014, 1886: 1887.
  • the therapeutically effective doses of Lansoprazole or its enantiomer are in the range of 10 mg to 180 mg per day, according to the well-known book Goodman & Gilman, H + Inhibitors, K + ATPase, The Pharmacological Bases of Therapeutics, 1996, 971-973.
  • the invention relates to the process for obtaining high concentration microgranules of Simethicone.
  • Said microgranules are obtained by applying Simethicone on rolling sugar spheres in a solid-walled bed or in tangential rotor fluid bed equipment at regular intervals. Cycles of humidification of the microgranules are alternated with Simethicone and drying cycles consisting of sprinkling a defined amount of a mixture of colloidal silicon dioxide and magnesium carbonate, this drying stage being very important in order to fix the Simethicone in the microgranules. a high concentration of Simethicone.
  • the obtained microgranules are allowed to roll until they are completely dry and optionally coated with a protective membrane.
  • the protective membrane is formed by a soluble polymer, preferably Polyvinylpyrrolidone.
  • the process for preparing a pharmaceutical formulation for oral administration comprising the fixed dose combination of high-concentration microgranules of 120 mg of Simethicone and enteric-release microgranules of 15 mg of Lansoprazole, both being contained in a hard capsule.
  • Enteric release Lansoprazole microgranules 1 Prepare a syrup by dissolving the sugar in 3.6 kg of purified water, heating at 40 ° - 45 ° C with stirring until homogenized.
  • step 2) Sift through 100 mesh: Lansoprazole, Magnesium carbonate, Mannitol, calcium carboxymethyl ilcellulose and hydrogenated disodium phosphate and mix in a medium speed dump mixer for 15 minutes. 3) Sprinkle the mixture obtained in step 2) on the sugar spheres in a stainless steel pail at 36 rpm, using the sugar syrup obtained in step 1) as an adhesive, until reaching microgranules of size between 0.4 and 0.9 mm diameter.
  • step c) Dry the microgranules obtained in step c) at 45 ° C for 8 hours or until no more than 1% moisture is obtained.
  • capsules containing 120 mg of Simethicone and 30 mg of Lansoprazole are prepared.
  • Both microgranules are filled in gelatin capsules number 0 elongated using a double station encapsulator placing:
  • Simethicone 200.0 microgranules containing 120 mg of Simethicone
  • Lansoprazole microgranules 166.8 (containing 15 mg of Lansoprazole)
  • the excipients for the suspension are prepared as follows: a) Mix Corn starch, Red iron oxide, Sucralose powder, Citric acid anhydrous, Essence of banana powder, Essence of strawberry powder and Sugar and Mannitol, for 10 minutes to 12 rpm
  • step b) Grind the mixture obtained in point a) by Fitzpatrick mill, at 4800 rpm. with 40 mesh, hammers forward.
  • step c) Mix the grinding obtained in step b) with the Granular Mannitol and Ionized RD Xantana Gum and previously ground by Fitzpatrick mill with 1.7 mm mesh at 400 rpm, hammers forward for 20 minutes at 12 rpm.
  • the process for preparing a pharmaceutical formulation for oral administration comprising the fixed dose combination of 200 mg high concentration microgranules of Simethicone and 60 mg enteric release microgranules of Dexlansoprazole, both of which are contained in a hard capsule.
  • Theoretical content of Simethicone in the microgranules 500 mg / g of microgranules.
  • Theoretical content of Dexlansoprazole in the microgranules 200.0 mg / g of microgranules.
  • Simethicone high concentration microgranules 500 mg / g made in a fluid bed with a tangential rotor
  • Gastro-resistant coating Dissolve Eudragit L100-55, Eudragit S100 and triethylcitrate in ethyl alcohol. Scatter the talc in the solution. Apply the coating solution on the dried microgranules obtained in step d).
  • Screening Pass the dried microgranules through a mesh of 1.4 mm in pore size.
  • Example 4 Using the microgranules of Example 4, the capsule entry of different doses was manually verified.
  • Pharmaco-technical determinations and in vitro tests were performed to evaluate the physical characteristics of the microgranules of examples 1 and 4, and the dissolution of the formulations of examples 1, 2, 3 and 4.
  • Pharmaco-technical determinations methodology and equipment.
  • Density VANDERKAMP equipment or equivalent is used to obtain density. In a 50 ml graduated cylinder with a cap, approximately 30 g of sample are weighed exactly, it is adjusted on the base of the equipment and 15 seconds of movement are applied. The surface is matched and the final volume is read.
  • the compacted density obtained should be between: 0.6 - 1.0 g / ml.
  • Average diameter of the microgranules it is measured by means of a particle size analyzer Malvern model Mastersizer 2000, Equipped with a Laser transmitter and a detector.
  • Example 4 1,040 mm 1,145 mm Evaluation of Lansoprazole and enantiomer: by HPLC (High Performance Liquid Chromatography) according to the Lansoprazole Monographs of the United States Pharmacopoeia 32 Capsules (USP).
  • Gastroristance test according to USP 32 (United States Pharmacopoeia 32), General Tests and Tests ⁇ 711>.
  • Antifoam activity according to USP 32 (United States Pharmacopoeia 32). Test performed on bulk microgranules.
  • Dissolution test Lansoprazole or enantiomer according to USP 32 (United States Pharmacopoeia 32) General Tests and Tests ⁇ 711>.
  • the SOTAX Type AT7 device or its equivalent was used.
  • Antifoam Complies Complies Complies Complies required time
  • the foam should not be greater than 45

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique à administration par voie orale qui comprend la combinaison d'une dose fixe de Siméticone sous forme de microgranules à haute concentration et de Lansoprazol ou son énantiomère (Dexlansoprazol) sous forme de microgranules à libération entérique et le procédé d'obtention des microgranules à haute concentration de Siméticone.
PCT/IB2017/057904 2016-12-14 2017-12-13 Composition améliorée de lansoprazol et de siméticone et procédé de préparation de cette dernière WO2018109693A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PE2019001165A PE20191654A1 (es) 2016-12-14 2017-12-13 Composicion mejorada de lansoprazol y simeticona y proceso para prepararla
BR112019011966-3A BR112019011966A2 (pt) 2016-12-14 2017-12-13 composição aprimorada de lansoprazol e simeticona e processo para preparação
CR20190290A CR20190290A (es) 2016-12-14 2017-12-13 Composición mejorada de lansoprazol y simeticona y proceso para prepararla
CONC2019/0006693A CO2019006693A2 (es) 2016-12-14 2019-06-21 Composición mejorada de lansoprazol y simeticona y proceso para prepararla

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXMX/A/2016/016587 2016-12-14
MX2016016587A MX2016016587A (es) 2016-12-14 2016-12-14 Composicion mejorada de lansoprazol y simeticona y procesos para prepararla.

Publications (1)

Publication Number Publication Date
WO2018109693A1 true WO2018109693A1 (fr) 2018-06-21

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PCT/IB2017/057904 WO2018109693A1 (fr) 2016-12-14 2017-12-13 Composition améliorée de lansoprazol et de siméticone et procédé de préparation de cette dernière

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Country Link
AR (1) AR110183A1 (fr)
BR (1) BR112019011966A2 (fr)
CL (1) CL2019001462A1 (fr)
CO (1) CO2019006693A2 (fr)
CR (1) CR20190290A (fr)
DO (1) DOP2019000145A (fr)
MX (1) MX2016016587A (fr)
PE (1) PE20191654A1 (fr)
WO (1) WO2018109693A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5073384A (en) * 1989-10-19 1991-12-17 Valentine Enterprises, Inc. Maltodextrin/defoaming composition combinate
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
EP1297825A1 (fr) * 2001-09-28 2003-04-02 McNEIL-PPC, INC. Forme orale solide de siméthicone
US20050181052A1 (en) * 2004-02-17 2005-08-18 Patel Satishkumar A. Lansoprazole microtablets
WO2008056200A1 (fr) * 2006-11-10 2008-05-15 Ranbaxy Laboratories Limited Compositions pharmaceutiques orales de siméthicone
US20150119422A1 (en) * 2011-12-14 2015-04-30 Disphar International B.V. Simethicone formulation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5073384A (en) * 1989-10-19 1991-12-17 Valentine Enterprises, Inc. Maltodextrin/defoaming composition combinate
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
EP1297825A1 (fr) * 2001-09-28 2003-04-02 McNEIL-PPC, INC. Forme orale solide de siméthicone
US20050181052A1 (en) * 2004-02-17 2005-08-18 Patel Satishkumar A. Lansoprazole microtablets
WO2008056200A1 (fr) * 2006-11-10 2008-05-15 Ranbaxy Laboratories Limited Compositions pharmaceutiques orales de siméthicone
US20150119422A1 (en) * 2011-12-14 2015-04-30 Disphar International B.V. Simethicone formulation

Also Published As

Publication number Publication date
AR110183A1 (es) 2019-03-06
BR112019011966A2 (pt) 2019-11-05
MX2016016587A (es) 2018-06-13
DOP2019000145A (es) 2019-08-15
CO2019006693A2 (es) 2019-07-10
PE20191654A1 (es) 2019-11-07
CR20190290A (es) 2019-11-18
CL2019001462A1 (es) 2019-08-23

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