WO2001085134A1 - Compositions pharmaceutiques solides et procede de production de comprimes se dissolvant dans la bouche - Google Patents

Compositions pharmaceutiques solides et procede de production de comprimes se dissolvant dans la bouche Download PDF

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Publication number
WO2001085134A1
WO2001085134A1 PCT/IN2000/000055 IN0000055W WO0185134A1 WO 2001085134 A1 WO2001085134 A1 WO 2001085134A1 IN 0000055 W IN0000055 W IN 0000055W WO 0185134 A1 WO0185134 A1 WO 0185134A1
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WO
WIPO (PCT)
Prior art keywords
composition
tablet
tablets
pharmaceutically acceptable
mixture
Prior art date
Application number
PCT/IN2000/000055
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English (en)
Inventor
Satish Mehta
Mahesh Shah
Manjusha Joshi
Dhanashri Kale
Original Assignee
Emcure Pharmaceuticals Ltd
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 Emcure Pharmaceuticals Ltd filed Critical Emcure Pharmaceuticals Ltd
Priority to PCT/IN2000/000055 priority Critical patent/WO2001085134A1/fr
Publication of WO2001085134A1 publication Critical patent/WO2001085134A1/fr

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Classifications

    • 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

Definitions

  • This invention relates to pharmaceutical compositions and a process for manufacturing rapid disintegrating tablets. More particularly it relates to the said composition containing a Non-steroid Anti Inflammatory Drugs (NSAIDs) such as Nimesulide and a process for manufacturirrg the tablets characterized by high disintegrating property in the buccal cavity, using the said pharmaceutical compositions.
  • NSAIDs Non-steroid Anti Inflammatory Drugs
  • the tablets are administered along with water to pass through the buccal cavity or required to be chewed to disintegrate to release the active ingredient, which is absorbed in the body.
  • the time in which the active ingredient of the tablet is available depends upon the type of the tablets and its disintegrating time.
  • US patent no. 5,958,453 describes a solid pharmaceutical preparation with improved buccal disintegrating and dissolving properties.
  • a solid pharmaceutical preparation comprising a pharmaceutically active ingredient, erythritol, crystalline cellulose and a disintegrant, exhibiting fast buccal disintegrating/dissolving property has been provided.
  • this patent mentions use of mannitol as one of the components of the pharmaceutical composition it is optional or in addition to erythritol.
  • US Patent no. 5,955,107 describes pharmaceutical suspension tablet composition comprising of a therapeutic amount of pharmaceutically active ingredient, croscaarmellose sodium, micro-crystalline cellulose and co- processed additives of consisting essentially of micro-crystalline cellulose and calcium, sodium alginate complex. However it does not disclose the composition and the preparation of tablets which have rapid disintegrating properties in the buccal cavity.
  • the PCT application no. 99/59544 describes orally disintegrating tablets, however they are coated with an enteric coating layer.
  • the average particle diameter also is limited to 400.
  • Still another PCT application No. WO 99/47124 describes tablets quickly disintegrating in the oral cavity containing drug, saccharides and amorphous saccharides.
  • the crystalline drug and the saccharides are converted into amorphous ones in pharmaceutically acceptable solvent.
  • the amorphous saccharides are irreversibly converted into crystalline ones after the step of drying under moistening.
  • the WO 99/32092 describes a method for the manufacture of tablets, which disperse easily and quickly in the oral cavity, however they necessarily need a bite for disintegration. These tablets also contain waxy material and phospholipid or an intense sweetener derived from fruit flavonoids.
  • Still another PCT application no. WO 99/04758 published on February 4, 1999 teaches a process for the preparation of a granulate suitable to the preparation of rapidly disintegrating mouth soluble tablets.
  • the process comprises granulating in a fluidized bed a polyalcohol and optionally other solid components selected for active principles, lubricants, sweetening agents, flavours with an aqueous solution or aqueous dispersion of a water soluble or water dispersible polymer.
  • compositions mentioned above have various limitations. They contain insoluble inorganic matters, which interfere with the disintegrated active ingredient in the buccal cavity. Others need presence of an aqueous solution or an aqueous dispersion of water-soluble polymer. Some of the formulations need to be prepared in pharmaceutically acceptable solvents. Still others need presence of swellable fillers with crystalline cellulose or waxy materials. It is therefore desirable to develop a formulation for the preparation of the tablets, which rapidly dissolve in the buccal cavity even without water. It is also desirable that such tablets should have pleasant, palatable and refreshing taste and aroma.
  • the tablets are prepared by either dry or wet mixing of the solid or liquid ingredients such as pharmaceutically active component, additives, preservatives, flavours in a granulator, mixing thoroughly using conventional kneading process, drying the granules and compressing into tablets of desired shape, size and configuration.
  • the solid or liquid ingredients such as pharmaceutically active component, additives, preservatives, flavours in a granulator, mixing thoroughly using conventional kneading process, drying the granules and compressing into tablets of desired shape, size and configuration.
  • the inventors of the present invention have observed that the processing a pharmaceutical composition comprising the active ingredient, a polyalcohol like mannitol, sweetening agents like sugars, artificial flavours and stabilizing agents for the production of tablets as per process described hereunder yield tablets having very fast disintegrating property in the buccal cavity. These tablets do not have other insoluble matters in the tablets in such quantities, which interfere with the disintegration of the tablets in the buccal cavity.
  • the main object of the present invention therefore is to provide an improved pharmaceutical composition useful for manufacture of solid preparations, particularly tablets, which rapidly disintegrate into the buccal cavity. Another object is to provide compositions, which have negligible quantities of the insoluble ingredients thereby considerably reducing their interference with the disintegrated active ingredient.
  • Still another object is to provide compositions, which are independent of any water-soluble or water dispersible polymers, waxy materials or microcrystalline cellulose.
  • Yet another object is to provide an improved process for the manufacture of solid preparations, useful for preparation of rapid mouth disintegrating tablets using the pharmaceutical solid compositions described in the present invention. Disclosure of the invention
  • the present invention provides pharmaceutical solid compositions useful for preparing rapid mouth disintegrating tablets, having a general formula
  • A is a pharmaceutically active ingredient
  • C is mixture of pharmaceutically acceptable colour, sweetener, buffering agent, disintegrating agent, and lubricant and pharmaceutically acceptable flavour.
  • the pharmaceutically active ingredient may be such as Non steroidal Analgesic or anti- inflammatory drug exemplified by Nimesulide, Piroxicam preferably Nimesulide.
  • the polyalcohol used may be mannitol, sorbitol or mixtures thereof, preferably mannitol.
  • polysaccharide used may be maltose, glucose, sucrose, preferably maltose.
  • pharmaceutically acceptable colouring agent may be Quinoline Yellow, sunset yellow, erythrosine, brilliant blue, preferably Quinoline yellow.
  • the sweetener may be selected from pharmaceutically acceptable Aspartame, sodium saccharin, glycerizha powder or mixtures thereof, preferably Aspartame.
  • the buffering agent may be pharmaceutically acceptable Citric Acid, tartaric acid, or mixture thereof, preferably Citric Acid.
  • the disintegrating agent may be selected from pharmaceutically acceptable Crospovidone, sodium starch glycolate, croscarmeUose, preferably Crospovidone.
  • the lubricant may be selected from pharmaceutically acceptable Stearate of magnesium, calcium or talc, preferably Magnesium Stearate.
  • pharmaceutically accepted flavour may be selected from Trusil Lemon flavour, Trusil orange, Trusil mix fruit, Trusil pineapple, Trusil mint, or mixtures thereof, preferably Trusil Lemon flavours.
  • the concentration of the active ingredient may be 50 to 400 mg. /tablet
  • the combined concentration of the polyalcohol and the polysaccharide may be in the range of 0.1 to 20% w/w of the tablet.
  • the concentration of the colouring agent may be 0.011 to 1.0% w/w of the tablet.
  • the concentration of the sweetener may be 0.1 to 5.0% w/w of the tablet.
  • the concentration of buffering agent may be 1 to 6 % w/w of the tablet.
  • the concentration of disintegrating agent may be 0.1 to 6,0 % w/w of the tablet.
  • the concentration of the lubricant may be 0.1 to 6,0% w/w of the tablet. In still another embodiment the concentration of the flavour may be 0.1 to 5.0% w/w of the tablet.
  • the present invention provides a process for the manufacture of rapid mouth disintegrating tablets using the abovementioned composition, which comprises preparing a granulating solution of a saccharide in pharmaceutically acceptable purified water, separately preparing a dry mix of polyalcohol, active ingredient and the pharmaceutically acceptable colouring agent, loading the said drymix in a fluidized bed granulator/ processor, allowing the drymix to fluidize at a temperature ranging between 40 to 70°C, granulating the drymix by spraying the granulating solution on the dry mix, at the constant temperature in the range of 40 to 70 °C, drying the granulated mixture till the loss on drying of the said mixture is less than 1 to 2%, adding a mixture of buffering agent, disintegrating agent, lubricating agent and the desired pharmaceutically acceptable flavour to obtain the granulated mixture and preparing the tablets of desired shape using this granulated mixture by conventional compressing methods.
  • the granulation and the drying is carried out simultaneously in the fluidized bed machines provided by Sapphire or Glatt.
  • compositions of the present invention in details and the process for the preparation of tablets, which are illustrative only and should not be construed to limit the scope of the present invention in any manner whatsoever.
  • Nimesulide 100 mg. tablets were prepared using following composition. Batch size: 1,00,000 tablets
  • Nimesulide 10.00 kg. of Nimesulide was pulverized through multimill. Mannitol 18.7 kg. was separately sifted through 40-mesh sieve. The dry mixture of prepared by mixing the Nimesulide, mannitol and Quinoline yellow 30.0 gm. The mixture was mixed thoroughly in a planetary mixer for 30 minutes. A granulating solution was prepared by dissolving 18.70 kg. of Mannitol in 2.0 It. of boiled and cooled water. The granulating mixture was loaded in a fluidized bed dryer equipped with spraying mechanism and was allowed to fluidize at 40°C. The granulating solution was sprayed on the dry mix keeping the temperature constant till the entire granulating solution was exhausted.
  • the granulated mixture so obtained was allowed to dry till the loss on drying was below 1%.
  • a mixture of Crospovidone 1.245 kg., Aspartame 0.510 kg., Citric acid 1.050 kg., and Trusil lemon flavour 0.510 kg was sifted through 80 mesh. The above mixture was mixed with dried granulated mixture in a drum mixer for ten minutes and the tablets were prepared from the granulated mixture so obtained by compression method.
  • the disintegration time of the tablet as determined by disintegration method was 40 seconds.
  • the buccal cavity disintegration time as determined on adult sample was 35 seconds.
  • Piroxicam 10 mg. tablets were prepared using following composition. Batch size: 5000 tablets.
  • a mixture of Crospovidone 62.50 g., Aspartame 28.5 g., Citric acid 52.50 g, Magnesium stearate 25.0 g and Trusil Mango flavour 25.0 g were sifted through 80 mesh.
  • the above mixture was mixed with dried granulated mixture in a tub for 5 minutes and the tablets were prepared from the granulated mixture so obtained by compression method.
  • the disintegration time of the tablet as determined by using disintegration test apparatus was 40 seconds.
  • the buccal cavity disintegration time as determined on adult sample was 45 seconds.
  • Nimesulide 50 mg. tablets were prepared using following composition. Batch Size: 10,000 tablets.
  • the granulated mixture so obtained was allowed to dry till the loss on drying was below 1%.
  • a mixture of Crospovidone 88.30 g., Aspartame 25.0 g., Citric acid 65.00 g, Magnesium stearate 30.0 g and Trusil Lemon flavour 30.0 g were sifted through 80 mesh. The above mixture was mixed with dried granulated mixture in a tub for 5 minutes and the tablets were prepared from the granulated mixture so obtained by compression method.
  • the disintegration time of the tablet as determined by using disintegration test apparatus was 50 seconds.
  • the buccal cavity disintegration time as determined on adult sample was 35 seconds.
  • Nimesulide 50 mg. tablets were prepared using following composition. Batch Size : 10,000 tablets.
  • Nimesulide , Mannitol 1150 gm & Quinoline yellow colour 1.750 gm. were separately sifted through 40-mesh sieve.
  • the dry mixture prepared by mixing the Nimesulide, mannitol & Quinoline yellow. The mixture was mixed thoroughly in a tub for 5 minutes.
  • a granulating solution was prepared by dissolving 110.00 g. of Maltose in 500 ml. of boiled and cooled water. The granulating mixture was loaded in a fluidized bed dryer equipped with spraying mechanism and was allowed to fluidize at 40°C. The granulating solution was sprayed on the dry mix keeping the temperature constant till the entire granulating solution was exhausted.
  • the granulated mixture so obtained was allowed to dry till the loss on drying was below 1%.
  • a mixture of Sodium Starch Glycolate IP [Primojel] 108.30 g., Aspartame 25.0 g., Citric acid 65.00 g, Magnesium stearate 30.0 g and Trusil Lemon flavour 30.0 g were sifted through 80 mesh.
  • the above mixture was mixed with dried granulated mixture in a tub for 5 minutes and the tablets were prepared from the granulated mixture so obtained by compression method.
  • the disintegration time of the tablet as determined by using disintegration test apparatus was 35 seconds.
  • the buccal cavity disintegration time as determined on adult sample was 30 seconds.
  • Nimesulide 50 mg. tablets were prepared using following composition. Batch Size: 10,000 tablets
  • Nimesulide, Mannitol 1150 gm & Quinoline yellow colour 1.750 gm. were separately sifted through 40-mesh sieve.
  • the dry mixture prepared by mixing the Nimesulide, mannitol & Quinoline yellow. The mixture was mixed thoroughly in a tub for 5 minutes.
  • a granulating solution was prepared by dissolving 110.00 g. of Maltose in 500 ml. of boiled and cooled water. The granulating mixture was loaded in a fluidized bed dryer equipped with spraying mechanism and was allowed to fluidize at 45°C. The granulating solution was sprayed on the dry mix keeping the temperature constant till the entire granulating solution was exhausted.
  • the granulated mixture so obtained was allowed to dry till the loss on drying was below 1%.
  • a mixture of Sodium Starch Glycolate IP [Primojel] 108.30 g., Aspartame 25.0 g., Tartaric acid 80.00 g, Magnesium stearate 30.0 g and Trusil Lemon flavour 30.0 g were sifted through 80 mesh.
  • the above mixture was mixed with dried granulated mixture in ⁇ tub for 5 minutes and the tablets were prepared from the granulated mixture so obtained by compression method.
  • the disintegration time of the tablet as determined by using disintegration test apparatus was 40 seconds.
  • the buccal cavity disintegration time as determined on adult sample was 35 seconds.
  • the main advantages of the present invention are as follows: l.
  • the composition provided by the present invention for preparation of the tablets contains almost negligible quantities of inorganic insoluble material thereby giving pleasant feeling in the buccal cavity during disintegration of the tablets.
  • the tablets do not require any chewing or water or any other drink for administration of the tablets. This is useful for administrating the drug to the aged or infants and un-cooperating patients.
  • composition does not contain any polymers, wax or any other substances.
  • the process provided by the present invention ensures uniform granulation as the granulation and drying is done simultaneously by spraying the granulating material on the dry mix.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques solides contenant différents ingrédients qui permettent de produire des comprimés se dissolvant dans la bouche (MDT). L'invention concerne également un procédé utilisant lesdites compositions, qui lorsqu'elles sont traitées selon le procédé décrit, produisent des comprimés contenant des ingrédients pharmaceutiquement actifs, de préférence des analgésiques non stéroïdes. Ces compositions sont préparées par vaporisation d'une solution de granulation sur un mélange sec constitué d'un polyalcool et d'un ingrédient actif placé dans un séchoir à lit fluidisé contenant une installation de vaporisation. Les comprimés préparés au moyen desdites compositions à l'aide du procédé précité possèdent une rapidité de désintégration dans la cavité buccale remarquable sans action de mastication, même en l'absence de support tel que l'eau ou des boissons chaudes/froides. Du fait de leur désintégration rapide, ces comprimés peuvent facilement être administrés à des personnes âgées, des enfants, ou des patients non coopérants.
PCT/IN2000/000055 2000-05-12 2000-05-12 Compositions pharmaceutiques solides et procede de production de comprimes se dissolvant dans la bouche WO2001085134A1 (fr)

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PCT/IN2000/000055 WO2001085134A1 (fr) 2000-05-12 2000-05-12 Compositions pharmaceutiques solides et procede de production de comprimes se dissolvant dans la bouche

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PCT/IN2000/000055 WO2001085134A1 (fr) 2000-05-12 2000-05-12 Compositions pharmaceutiques solides et procede de production de comprimes se dissolvant dans la bouche

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067894A2 (fr) * 2001-02-27 2002-09-06 Ranbaxy Laboratories Limited Comprimes a dissolution rapide d'inhibiteurs de l'enzyme cyclooxygenase-2
WO2004108110A1 (fr) * 2003-06-10 2004-12-16 Silvestrini, Bruno Administration sublinguale de substances pharmacologiques anti-inflammatoires non steroidiennes
WO2010029037A1 (fr) * 2008-09-09 2010-03-18 Europharmaceuticals Composition de nimesulide orodispersible
WO2016029496A1 (fr) * 2014-08-29 2016-03-03 武汉光谷人福生物医药有限公司 Comprimé de methosulide et procédé pour le préparer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052541A1 (fr) * 1997-05-20 1998-11-26 Warner-Lambert Company Comprimes a dissolution rapide et procede de fabrication par compression directe
WO1999004758A1 (fr) * 1997-07-25 1999-02-04 Elan Corporation Plc Procede de preparation de granules servant a produire des comprimes solubles dans la bouche a desintegration rapide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052541A1 (fr) * 1997-05-20 1998-11-26 Warner-Lambert Company Comprimes a dissolution rapide et procede de fabrication par compression directe
WO1999004758A1 (fr) * 1997-07-25 1999-02-04 Elan Corporation Plc Procede de preparation de granules servant a produire des comprimes solubles dans la bouche a desintegration rapide

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067894A2 (fr) * 2001-02-27 2002-09-06 Ranbaxy Laboratories Limited Comprimes a dissolution rapide d'inhibiteurs de l'enzyme cyclooxygenase-2
WO2002067894A3 (fr) * 2001-02-27 2002-12-19 Ranbaxy Lab Ltd Comprimes a dissolution rapide d'inhibiteurs de l'enzyme cyclooxygenase-2
WO2004108110A1 (fr) * 2003-06-10 2004-12-16 Silvestrini, Bruno Administration sublinguale de substances pharmacologiques anti-inflammatoires non steroidiennes
WO2010029037A1 (fr) * 2008-09-09 2010-03-18 Europharmaceuticals Composition de nimesulide orodispersible
BE1018279A3 (fr) * 2008-09-09 2010-08-03 Squarepoint Pointcarre Sprl Composition de nimesulide orodispersible.
WO2016029496A1 (fr) * 2014-08-29 2016-03-03 武汉光谷人福生物医药有限公司 Comprimé de methosulide et procédé pour le préparer

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