WO2004103340A1 - Water dispersible tablets of lamotrigine - Google Patents

Water dispersible tablets of lamotrigine Download PDF

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Publication number
WO2004103340A1
WO2004103340A1 PCT/IB2004/001640 IB2004001640W WO2004103340A1 WO 2004103340 A1 WO2004103340 A1 WO 2004103340A1 IB 2004001640 W IB2004001640 W IB 2004001640W WO 2004103340 A1 WO2004103340 A1 WO 2004103340A1
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WO
WIPO (PCT)
Prior art keywords
water
starch
sodium
cellulose
cross
Prior art date
Application number
PCT/IB2004/001640
Other languages
French (fr)
Inventor
Suhani Sinha
Kamal Mehta
Rajeev Shanker Mathur
Sanjeev Sethi
Rajiv Malik
Original Assignee
Ranbaxy Laboratories Limited
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Publication date
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Publication of WO2004103340A1 publication Critical patent/WO2004103340A1/en

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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to water-dispersible tablets of lamotrigine and pharmaceutically acceptable acid addition salts thereof.
  • the invention also relates to processes for the preparation of such tablets.
  • Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine. Lamotrigine is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.
  • European Patent EP 685231 discloses a water-dispersible tablet that includes granules of 2% to 90% w/w lamotrigine and 0.25% to 40% w/w of a pharmaceutically acceptable swellable clay, such as smectite or attapulgite.
  • a pharmaceutically acceptable swellable clay such as smectite or attapulgite.
  • the patent teaches ⁇ e use of swellable clays as a disintegrant.
  • the use of swellable clays in the manufacture of tablets is avoided due to their off-white appearance, which causes discoloration in tablets, and because clays are prone to microbial contamination due to their origin from natural sources.
  • the viscosity also may vary due to their origin. Further, when the suspension produced by these tablets is consumed, it may give a feeling of chalkiness in the mouth. These factors may affect patient compliance.
  • dispersible tablets of lamotrigine can be prepared without using intragranular swellable clays and nonetheless the tablet is capable of dispersing in water within a period of 3 minutes to provide a suspension which passes through a sieve screen with a mesh aperture of 710 ⁇ m in accordance with the test-for dispersible tablets defined in the British Pharmacopoeia, 1988, volume II, page 895. Summary of the Invention
  • a water-dispersible tablet that includes granules or compacts, the granules or compacts including lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants.
  • the one or more disintegrants are not swellable clay disintegrants.
  • the tablet is capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 ⁇ m in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895.
  • Embodiments of the tablet may include one or more of the following features.
  • the tablet may be between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
  • the disintegrant may be one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymefhyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.
  • the disintegrant may be cross-linked polyvinylpyrrolidone and the tablet may include between about 3% w/w and about 10% w/w cross-linked polyvinylpyrrolidone.
  • the disintegrant may be sodium starch glycolate and the tablet may include up to about 10% w/w sodium starch glycolate.
  • the disintegrant may be between about 3% w/w and about 10% w/w cross-linked polyvinylpyrrolidone and sodium starch glycolate.
  • the disintegrant in particular may be cross-linked sodium carboxymethyl cellulose.
  • the tablet may further include one or more extragranular disintegrants, fillers, binders, flavours, lubricants and glidants.
  • the extragranular disintegrant may be one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof.
  • the filler may be one or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof.
  • the binder may be one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanfh, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, and combinations thereof.
  • the binder may be polyvinylpyrrolidone and/or hydroxypropylmethylcellulose.
  • the lubricant may be one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate and polyethylene glycol.
  • the lubricant may be magnesium stearate.
  • the glidant may be colloidal silicon dioxide.
  • a process for the preparation of a water- dispersible tablet of lamotrigine or a pharmaceutically acceptable salt thereof includes preparing a mixture of lamotrigine or a pharmaceutically acceptable salt thereof with one or more disintegrants and optionally one or more phannaceutically acceptable excipients, the disintegrants not being a swellable clay disintegrant; granulating the mixture with a binder solution or solvent to form granules or compacting the mixture to form compacts; blending the granules or compacts with one or more pharmaceutically acceptable excipients to form a blend; and compressing the blend to form a tablet.
  • the tablet is capable of dispersing within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 ⁇ m in accordance with the test for dispersible tablets defined in British Pharmacopoeia, 1988, volume II, page 895.
  • the tablet may include between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
  • the disintegrant may be selected from one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.
  • the disintegrant may be about 3% w/w to about 10% w/w of cross-linked polyvinylpyrrolidone.
  • the disintegrant may be up to about 10% w/w of sodium starch glycolate.
  • the disintegrant may be cross-linked polyvinylpyrrolidone and sodium starch glycolate being present at from about 3% w/w to about 10% w/w of the tablet.
  • the pharmaceutically acceptable excipients may be one or more of extragranular disintegrant, fillers, binders, flavours, lubricants and glidants.
  • the extragranular disintegrant may be one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low- substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof.
  • the filler may be one or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof.
  • the binder may be one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers like carbopols and combinations thereof.
  • the lubricant may be one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate and polyethylene glycol.
  • the glidant may be colloidal silicon dioxide.
  • the process may further include drying the granules prior to compressing into tablets.
  • the process may further include sizing the compacts prior to compressing into tablets.
  • the solvent used in forming the granules may be one or more of water, ethanol, methanol, isopropyl alcohol, dichloromethane, and acetone.
  • a method of treating epilepsy or bipolar disorder includes administering a water-dispersible tablet that includes granules or compacts.
  • the granules or compacts include lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants, the one or more disintegrants not being swellable clay disintegrants.
  • the tablet is capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 ⁇ m in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895.
  • Embodiments of the method may include one or more of the following or any of the features described above.
  • the tablet may include between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
  • lamotrigine refers to its free base or acid addition salt, such as its methanesulphonate and isothionate salts.
  • concentration may vary from about 2%w/w to about 90%w/w lamotrigine or a lamotrigine salt.
  • the intragranular disintegrants as used herein include one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and . combinations thereof.
  • the extragranular disintegrant may include swellable clays such as smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and like.
  • the disintegrant may be present in an aniount of about 1 %w/w to about 70%w/w, particularly about l%w/w to about 50%w/w, and more particularly about 1% to about 40%w/w of the tablet.
  • the tablet additionally may include one or more of fillers, binders, flavours, lubricants and glidants.
  • the fillers can be selected from one or more of the group consisting of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof.
  • the amount of filler can vary from about 2%w/w to about 90%w/w, particularly from about 10%w/w to about 75%w/w of the tablet.
  • the binders can be selected from one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyefhyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers like carbopols and combinations thereof.
  • the binder may be present in an amount of about 0. l%w/w to about 40%w/w, particularly about 0.1%w/w to about 30%w/w, and more particularly about 0.1%w/w to about 20%w/w of the tablet.
  • Flavours such as strawberry, raspberry, blackcurrant, orange, grape fruit and the like and sweeteners such as aspartame, saccharin sodium, lactose, dextrose, fructose, maltodextrin, maltose, mannitol and sorbitol can also be added.
  • the lubricants and glidants can be selected from one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate, polyethylene glycol, colloidal silicon dioxide and talc.
  • the lubricant may be present from about 0.1%w/w to about 10%w/w of the tablet while the glidant may be present from about 0.1 %w/w to about 3%w/w of the tablet.
  • lamotrigine dispersible tablets are prepared by:
  • step (ii) granulating the mixture of step (i) with a granulating liquid such as a binder solution or solvent(s) such as water, ethanol, methanol, isopropyl alcohol, dichloromethane, acetone and mixtures thereof;
  • a granulating liquid such as a binder solution or solvent(s) such as water, ethanol, methanol, isopropyl alcohol, dichloromethane, acetone and mixtures thereof;
  • step (iii) drying the granules of step (ii) and blending the granules with one or more extragranular excipients such as lubricant(s), glidant(s) and disintegrant(s); and
  • step (iv) compressing the mixture of step (iii) into a tablet using appropriate tooling.
  • lamotrigine dispersible tablets are prepared by (i) preparing a mixture of lamotrigine or a pharmaceutically acceptable salt thereof with one or more disintegrants, fillers, binders and other excipients; (ii) compacting the mixture of step (i) using compactor; (iii) sizing the compacts of step (ii) and blending them with extragranular excipients such as lubricant(s), glidant(s) and disintegrant(s); and (iv) compressing the mixture of step (iii) into a tablet using appropriate tooling.
  • the tablets prepared by these processes have sufficient hardness and less friability to withstand handling and storage. Typically, the tablet has a friability of 2% or less particularly 1% or less, and more particularly 0.5% or less.
  • the tablet disperses quickly in water to give a fine suspension which is free from chalkiness and provides the intended dose uniformly.
  • the tablets can also be swallowed as such like conventional tablets. The tablet disperses completely in water in about 2 minutes and particularly in about 1 minute.
  • Lamotrigine, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, calcium carbonate, saccharin sodium and povidone K-30 were sifted through a 30# mesh and mixed for 10 minutes to fonn a blend.
  • the blend was then granulated with a sufficient quantity of purified water to form granules.
  • the granules were dried in a fluid bed dryer and sifted through a 25# sieve.
  • Cross-linked polyvinylpyrrolidone, flavour, low- substituted hydroxypropylcellulose, microcrystalline cellulose, talc and colloidal silicon dioxide were sifted through a 40# sieve and mixed with the dried granules. This blend was then mixed with magnesium stearate and compressed using appropriate tooling.
  • Example 2 The tablets of Examples 2 and 3 were prepared by following the procedure of Example 1 except that sodium starch glycolate was used in place of cross-linked polyvinylpyrrolidone.
  • Lamotrigine, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, calcium carbonate, and povidone K-30 were sifted through a 30# mesh and mixed for 10 minutes to form a blend.
  • the blend was then compacted using a compactor.
  • the compacts were passed through a 25# sieve.
  • Cross-linked polyvinylpyrrolidone, flavour, low-substituted hydroxypropylcellulose, aspartame, microcrystalline cellulose, talc and colloidal silicon dioxide were sifted through a 36# sieve and mixed with the granules. This blend was then mixed with magnesium stearate and compressed using appropriate tooling.

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Abstract

The present invention relates to water-dispersible tablets of lamotrigine and pharmaceutically acceptable acid addition salts thereof. The water-dispersible tablet includes granules or compacts. The granules or compacts include lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants. The one or more disintegrants are not swellable clay disintegrants. The tablet is capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895. The invention also relates to processes for the preparation of such tablets.

Description

WATER DISPERSIBLE TABLETS OF LAMOTRIGINE
Technical Field of the Invention
The present invention relates to water-dispersible tablets of lamotrigine and pharmaceutically acceptable acid addition salts thereof. The invention also relates to processes for the preparation of such tablets.
Background of the Invention
Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine. Lamotrigine is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.
Conventional tablets are the most common delivery systems used for administering therapeutically active compounds. However, in certain cases their use is limited by the problems associated with certain patients, such as the elderly and children, who have difficulty in swallowing. Also, this same difficulty arises in dosing critically ill patients in whom the ability to swallow anything is compromised. The solution to these problems is a dispersible tablet which when placed in water disperses to give a suspension which is easily taken by the patient.
European Patent EP 685231 discloses a water-dispersible tablet that includes granules of 2% to 90% w/w lamotrigine and 0.25% to 40% w/w of a pharmaceutically acceptable swellable clay, such as smectite or attapulgite. The patent teaches ^e use of swellable clays as a disintegrant. Generally, the use of swellable clays in the manufacture of tablets is avoided due to their off-white appearance, which causes discoloration in tablets, and because clays are prone to microbial contamination due to their origin from natural sources. Moreover, the viscosity also may vary due to their origin. Further, when the suspension produced by these tablets is consumed, it may give a feeling of chalkiness in the mouth. These factors may affect patient compliance.
The inventors have surprisingly found that dispersible tablets of lamotrigine can be prepared without using intragranular swellable clays and nonetheless the tablet is capable of dispersing in water within a period of 3 minutes to provide a suspension which passes through a sieve screen with a mesh aperture of 710μm in accordance with the test-for dispersible tablets defined in the British Pharmacopoeia, 1988, volume II, page 895. Summary of the Invention
h one general aspect there is provided a water-dispersible tablet that includes granules or compacts, the granules or compacts including lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants. The one or more disintegrants are not swellable clay disintegrants. The tablet is capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895.
Embodiments of the tablet may include one or more of the following features. For example, the tablet may be between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
The disintegrant may be one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymefhyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof. In particular, the disintegrant may be cross-linked polyvinylpyrrolidone and the tablet may include between about 3% w/w and about 10% w/w cross-linked polyvinylpyrrolidone. The disintegrant may be sodium starch glycolate and the tablet may include up to about 10% w/w sodium starch glycolate. The disintegrant may be between about 3% w/w and about 10% w/w cross-linked polyvinylpyrrolidone and sodium starch glycolate. The disintegrant in particular may be cross-linked sodium carboxymethyl cellulose.
The tablet may further include one or more extragranular disintegrants, fillers, binders, flavours, lubricants and glidants. The extragranular disintegrant may be one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof. The filler may be one or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof. The binder may be one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanfh, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, and combinations thereof. In particular, the binder may be polyvinylpyrrolidone and/or hydroxypropylmethylcellulose.
The lubricant may be one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate and polyethylene glycol. In particular, the lubricant may be magnesium stearate. The glidant may be colloidal silicon dioxide.
In another general aspect there is provided a process for the preparation of a water- dispersible tablet of lamotrigine or a pharmaceutically acceptable salt thereof. The process includes preparing a mixture of lamotrigine or a pharmaceutically acceptable salt thereof with one or more disintegrants and optionally one or more phannaceutically acceptable excipients, the disintegrants not being a swellable clay disintegrant; granulating the mixture with a binder solution or solvent to form granules or compacting the mixture to form compacts; blending the granules or compacts with one or more pharmaceutically acceptable excipients to form a blend; and compressing the blend to form a tablet. The tablet is capable of dispersing within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia, 1988, volume II, page 895.
Embodiments of the process may include one or more of the following features. For example, the tablet may include between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
The disintegrant may be selected from one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof. In particular, the disintegrant may be about 3% w/w to about 10% w/w of cross-linked polyvinylpyrrolidone. The disintegrant may be up to about 10% w/w of sodium starch glycolate. The disintegrant may be cross-linked polyvinylpyrrolidone and sodium starch glycolate being present at from about 3% w/w to about 10% w/w of the tablet.
The pharmaceutically acceptable excipients may be one or more of extragranular disintegrant, fillers, binders, flavours, lubricants and glidants. The extragranular disintegrant may be one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low- substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof.
The filler may be one or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof. The binder may be one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers like carbopols and combinations thereof. The lubricant may be one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate and polyethylene glycol. The glidant may be colloidal silicon dioxide.
The process may further include drying the granules prior to compressing into tablets. The process may further include sizing the compacts prior to compressing into tablets. The solvent used in forming the granules may be one or more of water, ethanol, methanol, isopropyl alcohol, dichloromethane, and acetone.
In another general aspect there is provided a method of treating epilepsy or bipolar disorder. The method includes administering a water-dispersible tablet that includes granules or compacts. The granules or compacts include lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants, the one or more disintegrants not being swellable clay disintegrants. The tablet is capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895.
Embodiments of the method may include one or more of the following or any of the features described above. For example, the tablet may include between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description of the Invention
As used herein lamotrigine refers to its free base or acid addition salt, such as its methanesulphonate and isothionate salts. The concentration may vary from about 2%w/w to about 90%w/w lamotrigine or a lamotrigine salt.
The intragranular disintegrants as used herein include one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and . combinations thereof. Additionally, the extragranular disintegrant may include swellable clays such as smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and like. The disintegrant may be present in an aniount of about 1 %w/w to about 70%w/w, particularly about l%w/w to about 50%w/w, and more particularly about 1% to about 40%w/w of the tablet.
Besides these ingredients, the tablet additionally may include one or more of fillers, binders, flavours, lubricants and glidants.
The fillers can be selected from one or more of the group consisting of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof. The amount of filler can vary from about 2%w/w to about 90%w/w, particularly from about 10%w/w to about 75%w/w of the tablet. The binders can be selected from one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyefhyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers like carbopols and combinations thereof. The binder may be present in an amount of about 0. l%w/w to about 40%w/w, particularly about 0.1%w/w to about 30%w/w, and more particularly about 0.1%w/w to about 20%w/w of the tablet.
Flavours such as strawberry, raspberry, blackcurrant, orange, grape fruit and the like and sweeteners such as aspartame, saccharin sodium, lactose, dextrose, fructose, maltodextrin, maltose, mannitol and sorbitol can also be added.
The lubricants and glidants can be selected from one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate, polyethylene glycol, colloidal silicon dioxide and talc. The lubricant may be present from about 0.1%w/w to about 10%w/w of the tablet while the glidant may be present from about 0.1 %w/w to about 3%w/w of the tablet.
In one of the embodiments, lamotrigine dispersible tablets are prepared by
(i) preparing a mixture of lamotrigine or a pharmaceutically acceptable salt thereof with one or more of disintegrants, fillers, binders and other excipients;
(ii) granulating the mixture of step (i) with a granulating liquid such as a binder solution or solvent(s) such as water, ethanol, methanol, isopropyl alcohol, dichloromethane, acetone and mixtures thereof;
(iii) drying the granules of step (ii) and blending the granules with one or more extragranular excipients such as lubricant(s), glidant(s) and disintegrant(s); and
(iv) compressing the mixture of step (iii) into a tablet using appropriate tooling.
In another embodiment, lamotrigine dispersible tablets are prepared by (i) preparing a mixture of lamotrigine or a pharmaceutically acceptable salt thereof with one or more disintegrants, fillers, binders and other excipients; (ii) compacting the mixture of step (i) using compactor; (iii) sizing the compacts of step (ii) and blending them with extragranular excipients such as lubricant(s), glidant(s) and disintegrant(s); and (iv) compressing the mixture of step (iii) into a tablet using appropriate tooling.
The tablets prepared by these processes have sufficient hardness and less friability to withstand handling and storage. Typically, the tablet has a friability of 2% or less particularly 1% or less, and more particularly 0.5% or less. The tablet disperses quickly in water to give a fine suspension which is free from chalkiness and provides the intended dose uniformly. The tablets can also be swallowed as such like conventional tablets. The tablet disperses completely in water in about 2 minutes and particularly in about 1 minute.
The following examples are provided to enable one of ordinary skill in the art to prepare tablets of the invention and should not be construed as limiting the scope of the invention.
EXAMPLES 1-3
Figure imgf000008_0001
Procedure:
Example 1
Lamotrigine, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, calcium carbonate, saccharin sodium and povidone K-30 were sifted through a 30# mesh and mixed for 10 minutes to fonn a blend. The blend was then granulated with a sufficient quantity of purified water to form granules. The granules were dried in a fluid bed dryer and sifted through a 25# sieve. Cross-linked polyvinylpyrrolidone, flavour, low- substituted hydroxypropylcellulose, microcrystalline cellulose, talc and colloidal silicon dioxide were sifted through a 40# sieve and mixed with the dried granules. This blend was then mixed with magnesium stearate and compressed using appropriate tooling.
Examples 2 and 3
The tablets of Examples 2 and 3 were prepared by following the procedure of Example 1 except that sodium starch glycolate was used in place of cross-linked polyvinylpyrrolidone.
EXAMPLES 4-6
Figure imgf000009_0001
Procedure: Same as above EXAMPLE 7
Figure imgf000010_0001
Procedure:
Lamotrigine, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, calcium carbonate, and povidone K-30 were sifted through a 30# mesh and mixed for 10 minutes to form a blend. The blend was then compacted using a compactor. The compacts were passed through a 25# sieve. Cross-linked polyvinylpyrrolidone, flavour, low-substituted hydroxypropylcellulose, aspartame, microcrystalline cellulose, talc and colloidal silicon dioxide were sifted through a 36# sieve and mixed with the granules. This blend was then mixed with magnesium stearate and compressed using appropriate tooling.
While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims

We claim:
1. A water-dispersible tablet comprising granules or compacts, the granules or compacts comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants, the one or more disintegrants not being swellable clay disintegrants and the tablet being capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895.
2. The water-dispersible tablet according to claim 1, wherein the tablet comprises between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
3. The water-dispersible tablet according to claim 1 wherein the disintegrant comprises one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.
4. The water-dispersible tablet according to claim 3 wherein the disintegrant comprises cross-linked polyvinylpyrrolidone.
5. The water-dispersible tablet according to claim 4 wherein the tablet comprises between about 3% w/w and about 10% w/w cross-linked polyvinylpyrrolidone.
6. The water-dispersible tablet according to claim 3 wherein the disintegrant comprises sodium starch glycolate.
7. The water-dispersible tablet according to claim 6 wherein the tablet comprises up to about 10% w/w sodium starch glycolate.
8. The water-dispersible tablet according to claim 3, wherein the disintegrant comprises between about 3% w/w and about 10% w/w cross-linked polyvinylpyrrolidone and sodium starch glycolate.
9. The water-dispersible tablet according to claim 3 wherein the disintegrant comprises cross-linked sodium carboxymethyl cellulose.
10. The water-dispersible tablet according to claim 1 wherein the tablet further comprises one or more extragranular disintegrants, fillers, binders, flavours, lubricants and glidants.
11. The water-dispersible tablet according to claim 10 wherein the extragranular disintegrant comprises one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof.
12. The water-dispersible tablet according to claim 10 wherein the filler comprises one or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof.
13. The water-dispersible tablet according to claim 10 wherein the binder comprises one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, and combinations thereof.
14. The water-dispersible tablet according to claim 13 wherein the binder comprises polyvinylpyrrolidone.
15. The water-dispersible tablet according to claim 13 wherein the binder comprises hydroxypropylmethylcellulose.
16. The water-dispersible tablet according to claim 10 wherein the lubricant comprises one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate and polyethylene glycol.
17. The water-dispersible tablet according to claim 15 wherein the lubricant comprises magnesium stearate.
18. The water-dispersible tablet according to claim 10 wherein the glidant comprises colloidal silicon dioxide.
19. A process for the preparation of a water-dispersible tablet of lamotrigine or a pharmaceutically acceptable salt thereof, the process comprising: preparing a mixture of lamotrigine or a pharmaceutically acceptable salt thereof with one or more disintegrants and optionally one or more pharmaceutically acceptable excipients, the disintegrants not being a swellable clay disintegrant; granulating the mixture with a binder solution or solvent to form granules or compacting the mixture to form compacts; blending the granules or compacts with one or more pharmaceutically acceptable excipients to form a blend; and compressing the blend to form a tablet, wherein the tablet is capable of dispersing within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia, 1988, volume II, page 895.
20. The process according to claim 19, wherein the tablet comprises between about 2% w/w and about 90% w/w of lamotrigine or a phannaceutically acceptable salt thereof.
21. The process according to claim 19 wherein the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.
22. The process according to claim 21 wherein the disintegrant comprises about 3% w/w to about 10% w/w of cross-linked polyvinylpyrrolidone.
23. The process according to claim 21 wherein the disintegrant comprises up to about 10% w/w of sodium starch glycolate.
24. The process according to claim 21 wherein the disintegrant comprises cross-linked polyvinylpyrrolidone and sodium starch glycolate being present at from about 3% w/w to about 10% w/w of the tablet.
25. The process according to claim 19 wherein the pharmaceutically acceptable excipients comprise one or more of extragranular disintegrant, fillers, binders, flavours, lubricants and glidants.
26. The process according to claim 25 wherein the extragranular disintegrant comprises one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof.
27. The process according to claim 25 wherein the filler comprises one or more of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, dextrose, mannitol, sorbitol, xylitol and combinations thereof.
28. The process according to in claim 25 wherein the binder comprises one or more of polyvinylpyrrolidone, starch mucilage, pregelatinised starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers like carbopols and combinations thereof.
29. The process according to claim 25 wherein the lubricant comprises one or more of magnesium stearate, calcium stearate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, stearic acid, zinc stearate and polyethylene glycol.
30. The process according to claim 25 wherein the glidant comprises colloidal silicon dioxide.
31. The process according to claim 19, further comprising drying the granules prior to compressing into tablets.
32. The process according to claim 19, further comprising sizing the compacts prior to compressing into tablets.
33. The process according to claim 19 wherein the solvent comprises one or more of water, ethanol, methanol, isopropyl alcohol, dichloromethane, and acetone.
34. A method of treating epilepsy or bipolar disorder, the method comprising administering a water-dispersible tablet comprising granules or compacts, the granules or compacts comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more disintegrants, the one or more disintegrants not being swellable clay disintegrants and the tablet being capable of dispersing in water within a period of three minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710 μm in accordance with the test for dispersible tablets defined in British Pharmacopoeia 1988, volume II, page 895.
35. The method according to claim 34, wherein the tablet comprises between about 2% w/w and about 90% w/w of lamotrigine or a pharmaceutically acceptable salt thereof.
PCT/IB2004/001640 2003-05-20 2004-05-20 Water dispersible tablets of lamotrigine WO2004103340A1 (en)

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WO2005051350A2 (en) * 2003-10-28 2005-06-09 Torrent Pharmaceuticals Limited Water dispersible tablet
WO2005051350A3 (en) * 2003-10-28 2005-08-18 Torrent Pharmaceuticals Ltd Water dispersible tablet
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WO2009063484A3 (en) * 2007-08-03 2009-07-02 Alkem Lab Ltd Stable pharmaceutical composition of lamotrigine
WO2010070611A1 (en) * 2008-12-18 2010-06-24 Ranbaxy Laboratories Limited Atazanavir formulations
CN103933069B (en) * 2014-05-09 2016-10-26 山东司邦得制药有限公司 A kind of Fufang Anfenwanan capsules and preparation method thereof

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