WO2008018086A1 - Mouth dissolving pharmaceutical or nutraceutical composition - Google Patents

Mouth dissolving pharmaceutical or nutraceutical composition Download PDF

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Publication number
WO2008018086A1
WO2008018086A1 PCT/IN2006/000288 IN2006000288W WO2008018086A1 WO 2008018086 A1 WO2008018086 A1 WO 2008018086A1 IN 2006000288 W IN2006000288 W IN 2006000288W WO 2008018086 A1 WO2008018086 A1 WO 2008018086A1
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WO
WIPO (PCT)
Prior art keywords
composition
weight
granules
pharmaceutically acceptable
acceptable excipients
Prior art date
Application number
PCT/IN2006/000288
Other languages
French (fr)
Inventor
Purnima Dhanraj Amin
Pal Singh Partap Singh Pirthi
Namita Sham Rajadhyaksha
Satishkumar Pannalal Jain
Vinam Bharatbhai Mehta
Original Assignee
Bajaj Healthcare Limited
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.)
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Publication date
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Priority to PCT/IN2006/000288 priority Critical patent/WO2008018086A1/en
Publication of WO2008018086A1 publication Critical patent/WO2008018086A1/en

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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
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—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
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • This invention relates to a mouth dissolving pharmaceutical or nutraceutical composition.
  • the composition is formulated into various dosage forms such as pellets, granules or tablets.
  • This invention also relates to methods of making the mouth dissolving pharmaceutical or nutraceutical composition in various dosage forms such as pellets, granules or tablets.
  • mouth dissolving composition as used in the specification is intended to mean a composition, which disintegrates to form a non-gritty solution or slurry immediately upon contact with water or saliva.
  • Oral administration of medicaments and nutraceuticals is the most commonly used and preferred route, especially by pediatric and geriatric patients as they are easy to be taken orally and problems like choking which may occur while swallowing non-mouth dissolving solid dosage forms sucrt*as tablets or capsules do not occur with such compositions.
  • Mouth dissolving compositions are a ' liso preferred to liquid dosage as the latter is prone to problems like spillage or inaccuracies in dosages when taken from time to time, lesser stability as compared to solid dosage forms or more 'storage space requirement.
  • Rapidly dissolving tablets are known to be prepared by adding a pharmaceutical ingredietit%) a particulate support matrix. The resulting mixture is compressed into tablets.
  • the particulate ⁇ f ⁇ aMx comprises polypeptide components, bulking agents and a volatilizing agent. This method is very expensive and complex in that additional steps in fo ⁇ ning support matrix are required. Also, tablets formed by this method are very fragile and are to be coated thereby making the method costlier (XJS Patents Nos 5,635,210, 5,595,761, 5,807,576 and 5,587,180).
  • Porous tablets are known to be prepared by mixing the tablet components with a. liquid solvent or solid adjuvant that sublimes at temperatures, which do not adversely affect the properties of the tablet components.
  • the resulting mixture is introduced into an inert cooling medium ⁇ o solidify the solvent followed by pressing the mixture into tablets at temperatures below melting point of eutectic mixture of tablet component with solvent.
  • the solvent is evaporated from the tab ' le&sVby drying or lyophilization.
  • the process is very complex and difficult to carry out as the high water content in the mixture makes compression into tablets difficult and cumbersome (US Patents Nos 5,762,961, 5,720,974, 4,134,943 and 3,885,026).
  • US Patent No 6,149,938 describes a process for making mouth soluble tablets of pharmaceutical active consisting of granulating a polyalcohol, an active ingredient, an edible acid and an aque ⁇ j ⁇ s solution of water soluble or water insoluble polymer in a fluidized bed followed by drying 'the granules in the fluidized bed.
  • the tablets are effervescent and give unpleasant taste in mouth.
  • US Patent No 6,156,339 describes a process for the preparation of an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance which has an unacceptable taste which pr ⁇ ' d ⁇ sl comprises forming a solution or a suspension in a solvent of a water soluble or water dispersible carrier, a filler and the pharmaceutically active substance with the unacceptable taste in association with a lipid; fo ⁇ ning discrete units of the suspension or solution; and removing the solvent £rdfrf : t ⁇ fe discrete units under conditions whereby unit dosages are formed comprising a networky.of carrier/filler carrying a dosage of the pharmaceutically active substance in association with the lipid.
  • the process is very complex and requires sophisticated and expensive equipments. Also, the ' t ' ablets require special type of packaging and need to be handled carefully during dispensing and actf ⁇ al administration since they are prone to breakage.
  • US 5,437,837 describes a method for the preparation of a pharmaceutical composition of pb ' rous particles as reconsitutable powder, powder filled in capsule or tablets.
  • Stoichiometric amount of acid and base is mixed in a press to produce compact which is milled to form evenly distributed effervescent mixture and subsequently added to an active to form an active mixture.
  • the Ib 1 OVS mixture is wet granulated and dried. During drying the acid and base react due to heat and water present in the granules thereby releasing gas to form the porous particles.
  • the porous particles are milled to form a fine powder, which can be further compressed into tablets, or used as reconstitutable powder or filled in capsules as a quick dissolving powder.
  • the compression pressure causes rearrangement of particles to form a less porous structure because of which dissolution time increases.
  • EP 0,494,972 describes solid dosage forms adapted for direct oral administration (mouth), which
  • the solid dosage forms are tablets comprising at least one water or saliva activated effervescent disintegration agent in ill L.' -" ' an amount, which is effective to aid rapid disintegration of the tablets and also provide distinct sensation of effervescence upon disintegration of the tablets in the mouth. Tablets prepared by the above technique need to be handled carefully during dispensing and actual administration since they are prone to breakage. The effervescent tablets give unpleasant taste in mouth.
  • US 5464632 describes a rapidly disintegratable tablet for oral administration, the tablet comprising an active substance and a mixture of excipients, wherein said active substance is multiparticu ⁇ a ⁇ &and in the form of coated microcrystals, coated micrograhules or uncoated microgranules.
  • the mixturfej'of excipients is selected from the group consisting of at least one disintegrating agent and at least ojg'e swelling agent, which are responsible for the disintegration.
  • the disintegrating agent is selected frprn the group consisting of carboxymethylcellulose and insoluble reticulated Polyvinylpyrrolidone; qnd the swelling agent is selected from the group consisting of starch, modified starch', .anil microcrystalline cellulose and direct compression sugar.
  • US Patent No 6,596,311 describes a fast disintegrating tablet comprising a drug in a form, substantially water insoluble components in amount of 50-99.5% by weight, one or more "Water insoluble inorganic excipients in amount of 2-40% by weight, one or more disintegrants in amountW 0.5-30% by weight, and one or more substantially water soluble excipients in amount of 4- 16,%; by weight.
  • the disintegrating agent is selected from the group consisting of a natural starch, directly compressible starch, modified starch, cross-linked polyvinylpyrrolidone and modified cellul ⁇ sel'Sr combinations thereof.
  • US 20040258748 describes a process for preparing mouth dissolving dosage form whlb ' h disintegrates quickly in the mouth.
  • Active ingredient is blended with effervescent mixfifte comprising an acid source and a base to produce a tablet, which is subjected to moisture activation by exposing the tablet to controlled humidity or heat.
  • the process is critical at the plant scale as slight moisture can imitate the reaction between acid and base, releasing cog gas, which acts as disintegrating agent. Besides this, the effervescent tablet gives a burning sensation in the mouth? . '
  • Freeze drying processes are generally used to prepare fast disintegrating dosage forms.
  • the product obtained is characterized by a highly porous microstructure of the soluble supporting agent (i.e. mannitol, glycine, lactose or gelatins) in which the active is homogeneously dispersed. Therefore, the fast disintegrating tablets are generally very friable and
  • An object of the invention is to provide a mouth dissolving pharmaceutical or nutrace ⁇ tieal composition, which dissolves rapidly in the mouth.
  • Another object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which has low friability values and does not require '1 special type of packaging,
  • Another object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which can be in various dosage forms.
  • Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is simple and easy t ⁇ ' ⁇ arry out.
  • Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is economical.
  • Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is eco-friendly.
  • mouth dissolving pharmaceutical or neutraeeutjc'al composition comprising 1 to 70% by weight of at least one pharmaceutical or neutraceutical active and 30 to 99% by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as a super disintegrant in 1 to 30 % by weight Qf , the pharmaceutically acceptable excipients; at least one pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of >: the pharmaceutically acceptable excipients.
  • the pharmaceutical or neutraceutical composition of the invention is in solid dosage forms s ⁇ ' ⁇ lt-as pellets, granules or tablets.
  • the pharmaceutical active is, for example, selected from the group consisting of analgesics and 1 antiinflammatory agents such as aloxiprin, auranofm, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indometha ⁇ iih, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen 1 ; oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol or tromethamine; antihelminthics such as albendazole, bephenium hydroxynaphtrfoate, cam
  • anti-bacterial agents such ⁇ as alatrofloxacin, azithromycin, baclofen, benzathine penicillin, cinoxacin, ciprofloxacin 1 HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lomefloxacin, moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, piramycin, sulphabenzamide, sulphadoxine, sulphame
  • n on-essential fatty acids phytonadiol, vitamin A, vitamin B 2 , vitamin D, vitamin E or vitamih ⁇ K; or anti-benign prostate hypertrophy agents such as becaplermin, donepezil HCl, L-thryroxine ⁇ methoxsalen, verteporfin, physostigmine, pyridostigmine, raloxifene HCl, sibutramine J ⁇ Cl, sildenafil citrate, tacrine, tamsulosin HCl or tolterodine.
  • prostate hypertrophy agents such as becaplermin, donepezil HCl, L-thryroxine ⁇ methoxsalen, verteporfin, physostigmine, pyridostigmine, raloxifene HCl, sibutramine J ⁇ Cl, sildenafil citrate, tacrine, tamsulosin HCl or tolterodine.
  • the nutraceutical active is, for example, dietary or nutritional supplement also known as medical or functional or designer foods or phytochemicals and includes therapeutic foods, infant formulas, weight control foods or hypoallergic foods.
  • the neutraceutical active is, for example, selected' from the group consisting of herbs and botanicals such as capsicum, chamomile, cat's claw, echinacea, garlic, ginger, ginko, various ginseng, green tea, golden seal, kava kava, nettle, passion flower-j»saw palmetto, St.
  • John's wort or valerian mineral supplements such as calcium, copper, iodine, ' iron, magnesium, manganese, molybdenum, phosphorous, boron, selenium or zinc; weight l ⁇ bs> agents such as chromium picolinate or phenylpropanolamine; benzoin, fructo-oligosaccharides, glucosamine, grapeseed extract, guarana, inulin, phosphotidylserine, phytosterols, phytochemicals,' isoflavones, lecithin, lycopene, oligofructose, polyphenol or psyllium.
  • mineral supplements such as calcium, copper, iodine, ' iron, magnesium, manganese, molybdenum, phosphorous, boron, selenium or zinc
  • weight l ⁇ bs> agents such as chromium picolinate or phenylpropanolamine; benzoin, fructo-
  • the pharmaceutical or neutraceutical active can be of pleasant taste or non-bitter or can rle' of unpleasant taste or bitter and taste masked.
  • bitter pharmaceutical or neutraceutical active is taste masked by techniques known private aft using taste masking agents selected from the group consisting of flavours, sweeteners and atoihb acids such as fenchone, borneol, isoborneol, stevia based sweetner extract and glycerine, aneth ⁇ l-B 1 cyclodextrin complex and saccharin, sodium phenolate, anethole, eucalyptol and methyl salicylate, sodium citrate dihydrate, sodium saccharin, sodium glutamate and vanilla essence, sodium
  • taste masking agents selected from the group consisting of flavours, sweeteners and atoihb acids such as fenchone, borneol, isoborneol, stevia based sweetner extract and glycerine, aneth ⁇ l-B 1 cyclodextrin complex and saccharin, sodium phenolate, anethole, eucalyptol and methyl salicylate, sodium citrate di
  • lipids such as stearyl stearate, glycerol palmitostearaie, caraauba wax jan ' d magnesium aluminium silicate, glyceryl monostearate, gelatin and mixture of partially hydrogefia !
  • soyabean oil molten stearyl stearate, polyglycerine fatty acid esters, glycerine and chained triglycerides or homogenated suspensions of phospatidic acid or ⁇ -galactoglobulin; lecithin and lecithin like substances such as soyabean or phosphatidic acid, coating agents such as cellulose, shellac, L-hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer (Eudtfagit)', Hydroxypropyl Methylcellulose, Polyvinylpyrrolidone, cellulose acetate, Microcrystalline Cellulose, cellulose acetate butyrate, calcium gluconate and sodium alginate, carrageenan, macrogol-400, gelatin, carbopol, corn starch or macrogol-6000; protein; gelatins; prolamines (Zein); zeolitesT-ioh- exchange resins and complexing agents such as
  • the potassium salt of crosslinked acrylic polymer as super disintegrant is selected from Indion'4J4 (Ion Exchange India Ltd, Mumbai), Amberlite IRP-88 (Rohm & Haas (UK) Ltd., UK), Indion ⁇ £
  • the preferred potassium salt of crosslinked acrylic polymer as super disintegrant is Indion 414, which ⁇ Jias ⁇ a swelling index of 800. As the ionic radius of K + is high, the rate of water uptake by the composition is very high thereby resulting in fast disintegration thereof.
  • the partially pre-gelatinized starch ' l ⁇ as softening agent is Starch 1500 (Colorcon Asia Pvt Ltd, India).
  • the modified polysaccharide's softening agent is selected from Avicel RC 591 (micro-crystalline cellulose containing l l ⁇ jfo sodium carboxymethylcellulose by FMC Biopolymer, Denmark), Avicel RC 581 (microcrystalline cellulose containing 11-13% sodiumcarboxy methylcellulose by FMC Biopolymer, Denmark)-, Avicel CL 611 (microcrystalline cellulose containing sodium carboxymethylcellulose by ⁇ tMC Biopolymer, Denmark); preferably Avicel RC 591.
  • the water soluble channelizing agent is selected from polysorbates, poloxamers, sodium lauryl sulfate or water soluble sugars such as marihitoli lactose, dextrose, sucrose, maltose, glucose, fructose, sorbitol, maltitol, or xylitol.
  • the preferred channelizing agents are polysorbates or sodium lauryl sulfate or water soluble sugars su ⁇ iif as dextrose, mannitol, lactose, xylitol or sucrose.
  • the channelizing agents allow easy uptake of®2i ⁇ $3 iinnttoo tthhee ccoommposition and fo ⁇ n channels that facilitate rapid softening and disintegration of Sfite composition.
  • the other pharmaceutically acceptable excipients which can be used in the composition of jthe invention, include one or more disintegrants, sweeteners, salivating agents, colouring agents] flavouring agents, preservatives or formulating agents.
  • the disintegrating agents are selected from clays, celluloses, sodium starch glycolate, " starch 1 -, pregelatinised starch (Amigel, National 155), crosscarmellose sodium, microcrystalline c ' gllulqse (Avicel ), Polyvinylpyrrolidone cross linked, magnesium aluminum silicate, alginates or sb'dium alginate.
  • the disintegrants open up and disintegrate the composition upon contact with saliva.
  • the sweeteners render the composition palatable and are selected from sodium saccharin, aspartame 1 ; acesulfame potassium, monoammonium glycyrrhizinate (MAG), glycerine, polyols, lactitol,- cyclamate or sucralose or combinations thereof.
  • acesulfame potassium monoammonium glycyrrhizinate (MAG), glycerine
  • polyols lactitol,- cyclamate or sucralose or combinations thereof.
  • the salivation agents induce a sufficiently strong flow of saliva, which accelerates the actionf ⁇ f channelizing agents and dis integrants.
  • the salivating agents are selected from natural flavburrSKpE artificial flavours or weak or water-soluble organic acids such as citric acid.
  • Flavour can be solid or liquid flavor and is selected from but not limited to Orange flavor, Raspberry flavor, Chocolate flavor, Strawberry flavor or Pineapple flavor.
  • Coloring agents that can be used include all F D and C and / or D and C dyes and / of-llakes. Examples of coloring agents are Iron oxides, Carmoisine, Ponceau 4R, lake sunset yell ⁇ 'vsfpo ⁇ tartrazine.
  • the preservatives prevent microbial growth during storage of the composition and are selected'* ; frbm parahydroxybenzoates or alkyl esters or salts thereof, sodium benzoate, benzoic acid, edetic ⁇ atad; sorbic acid and salts, bronopol or the like.
  • the preservatives are parahydroxybenzoate ⁇ ! ⁇ >r alkyl esters thereof.
  • the formulating agents include diluents, binders, granulating agents, lubricating agents, tablettins: agents or spheronising agents.
  • the diluents are selected from calcium phosphate, calcium sulphate dihydrate, granular calcium lactate trihydrate, glyceryl palmitostearate, microcrystalline cellulose, kaolin, magnesium carbon ⁇ fe, magnesium oxide, hydrolysed starches such as emdex or celutab, inositol, amylose, starches ftf'ch/as corn, wheat or potato, calcium carbonate, calcium triphosphate or sodium chloride.
  • ffi ⁇ diluents are microcrystalline cellulose, kaolin, calcium phosphate, magnesium carbonate, magnesium oxide.
  • the granulating agents are selected from cellulose and derivatives thereof, starch and its deriva ⁇ ves- hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) pyrrolidone ' and derivatives thereof, or water.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC Polyvinylpyrrolidone or celluloses and derivatives thereof.
  • the lubricating agents are selected from calcium stearate, magnesium stearate, potassium stear,ate, sodium stearate, boric acid, hard paraffin, magnesium oxide, talc, stearic acid, colloidal silicon dioxide, polyethylene glycol 4000, corn starch, sodium lauryl sulphate, magnesium lauryl sulphate, or D L - leucine.
  • the lubricating agents are magnesium stearate, stearic acid or talc.
  • the tabletting agents are selected from calcium phosphate, magnesium carbonate, magnesium Qxifle, granular calcium lactate trihydrate, macrocrystalline cellulose (Avicel ® PH 101 and Avicel ® PH : .1.(32J, kaolin, hydrolysed starches such as Emdex or celutab, inositol, amylose, starches such as corn, wheat or potato, calcium carbonate.
  • the tabletting agents are microcrystalline cellulose (Ajgcel ® PH 101 and Avicel ® PH 102), kaolin, calcium phosphate, magnesium carbonate, magnesium oxide * ;, t
  • the binders are selected from acacia, tragacanth, gelatin, starch, methyl cellulose, magnesi ⁇ lfti aluminium silicate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, alginic ; .acid, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, Polyvinylpyrrolidone, polymethacrylates, dextrin, zein, hydrogenated vegetable oil, hydroxy ethyl cellulose, guar .gligi, maltodextrin, sodium alginate, water or ammonium calcium alginate. Most preferred birtfferr, r is HPMC or Polyvinylpyrrolidone eg. plasdone® K 29/32 or water.
  • the spheronizing agents are selected from microcrystalline cellulose.
  • Microcrystalline cellulose including all grades of Avicel ® (FMC BioPolymer, Denmark) such as but not limited to AvicetifPH 101, Avicel ® PH 102, Avicel ® PH 103, Avicel ® PH 105, Avicel ® PH 112, Avicel ® PH 113, Avjcfl ® PH 200, Avicel ® PH 301 and Avicel ® PH 302.
  • a method of making a mouth dissolving pharmaceutical or neutraceutical composition as pellets comprising i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceuticalHb ' r neutraceutical active with 30 to 99 % w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as ⁇ uper disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least.' ⁇ fe pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of pharmaceutically acceptable excipients and at least one water soluble channelizing agent, in
  • step (ii) dry mixing the mixture obtained by step (i) with at least one spheronization agent; iii a) mixing the mixture obtained by step (ii) with a binder solution; iv a) extruding and spheronising the composition obtained by step (iii a) to obtain pellets; and v a) drying the pellets obtained by step (iv a) at 35 to 100 0 C.
  • a method of making a mouth dissolving pharmaceutical or neutraceutical composition as granules comprising i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as sniper disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at leas,t prie pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channepzing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained in step (i) with at least one diluent; iii b) granulating the mixture of step (ii) with a binder solution; iv b) sieving the
  • a method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets comprising i) dry mixing at 25 to 45° C 1 to 70% by weight of at least one pharmaceutical ' kpr neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as ⁇ per disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least ' ⁇ ftfe pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by height of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained by step (i) with at least one tabletting agent and iii c) compressing the mixture obtained by step (ii) into tablets.
  • the dry mixing as per step (i) is carried out 25 to 35° C.
  • 10 to 60 % by weight of at least one pharmaceutical or neutraceutical active is dry mixed with 40 to 90 % w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 2 to 20 % by weight of the pharmaceutically acceptable excipients; at least one pre-gelatinized starch or modified polysaccharide as softening agent in 10 to 30 % ⁇ y weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 5 to 70 % by weight of pharmaceutically acceptable excipients.
  • step '( ⁇ ) or step (ii) can be carried out in a blender.
  • the mixing of step (iii a) can be carried out in a blender
  • The' granulation step (iii b) is carried out in a granulator.
  • the extrusion and spheronization of ' the composition as per step (iv a) can be carried out in extruder-spheronizer.
  • the drying of the pellets or granules as per step (v a) or (v b) can be carried out on a fluid bed dryer or tray dryer, preferably at 40 to 60° C.
  • the sieving of step (iv b) and (vi b) is carried out through meshes of 8 mesh arid-40 mesh sieve respectively.
  • the compression of the composition into tablets as per step (iii c) cari' " b ⁇ e carried out in a cadmach 8 station rotary machine.
  • a method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets comprising granulating the mixture obtained by step (i) with a solution op ⁇ ' granulating agent or binder followed by mixing the granules with a tabletting agent and compres ' sfii-g the granules into tablets.
  • the granules or pellets prepared according to the invention can be used for fortification ofllitj ⁇ iQs such as juices, milk, soy milk, etc and soft foods.
  • a mouth dissolving pharmaceutical or neutraceutical composition having very high dissolution or dispersion in the range of 5 to 65 seconds in water and/or upon contact with saliva and low friability in the range of 0.1 to 1%.
  • the composition caff £& in different solid dosage forms such as pellets, granules or tablets. Due to low friability, the ⁇ solid forms of the composition of the invention do not require special packaging or careful handling.
  • the steps of the methods of the invention for formulating the composition of the invention into arious solid dosage forms do not employ expensive equipments and machinery and are ; ⁇
  • ⁇ t
  • the mixture was further dry Mixed with 10% partially pregelatinized starch and 43.3% w/w dextrose in the blender.
  • the resulting powder was granulated with 20% w/w of sucrose solution comprising 50% w/w sucrose in water in,a granulator to obtain granules of calcium citrate and vitamin D3.
  • the granules were sieved through:8# sieve and dried in a Fluidized bed drier at 40 0 C.
  • the granules were further sieved through 20# jsfeive and collected on a 80# sieve.
  • Composition of calcium citrate and vitamin D3 as granules was prepared according to the Example 1.
  • Example 1 A and Example 1 B dispersed in 25 ml of each of water :a ⁇ d simulated saliva in 5-20 seconds and 1-2 minutes respectively.
  • the mixture was further dry mixed with 2% partially pregelatinized starch, 15% w/w Avicel ® PH 102, 6.3% w/w Pearlitol, 3% w/w talc and 1%- w/w magnesium stearate in a blender.
  • the resulting composition was compressed into tablets in, a cadmach 8 station rotary machine.
  • Composition of calcium citrate and vitamin D3 as tablets was prepared according to the Example' ! 2 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of pearlitol and partially pregelatinised starch.
  • Example 2A and 2B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
  • Friability was determined using 6 g of tablets of Example 2A and 2B in a Roche friabilator for 4 nim. at a speed of 25 rpm. The friability were as follows: Example 2 A : 0.36% Example 2 B : 0.72%
  • the mixture was further dry mixed with 7% w/w Avicel ® PH 101 and 10% w/w Avicel ® RC 591 in suitable blender.
  • the resulting mixture was granulated with water in a granulatorto obtain granules.
  • Composition of calcium citrate and vitamin D3 as pellets was prepared according to the Example 3A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and Avicel ® RC 591. o
  • Example 3 A and 3B 5 gms of the pellets of Example 3 A and 3B dispersed in 100 ml of water in 50 seconds and 3 imniues respectively.
  • the swelling index of the pellets of Example 3A and 3B in water and simulate saliva was 200-400% w/w and less than 100% w/w respectively.
  • Friability of 6 g of pellets of Example 3A and 3B was tested as in Example 2 and friability. was. ' as follows :
  • Example 3 A 0.13%
  • Example 3B 0.23%
  • Calcium citrate malate and vitamin D3 composition as granules.
  • Composition of calcium citrate malate and vitamin D3 as granules was prepared according, tp -the Example 4 A using starch glycolate instead of Indion 414 and Magnesium carbonate instead, of dextrose and partially pregelatinised starch.
  • Example 4 A and 4B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 1-2 minutes respectively.
  • the mixture was further dry mixed with 2% partially pregelatinized starch, 15% w/w Avicel ® PHl 02, 3% w/w talc and 1% w/w magnesium stearate in blender.
  • the resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
  • composition of calcium citrate malate and vitamin D3 as tablets was prepared according to 'the Example 5 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of Pearlitol and partially pregelatinised starch. Palatability Test
  • Example 5 A and Example 5 B dispersed in 100 ml of water in 1-2 minutes ana
  • Example 5 A and 5B disintegrate in lminute and 3-4 minutes respectively.
  • Friability of 6 g of tablets of Example 5A and 5B was tested as in Example 2 and the friability was as follows :
  • Example 5 A 0.32%
  • Example 5 B 0.33%
  • the mixture was further dry mixed with 10% w/w Avicel ® PH102 and 10% w/w Avicel ® RC 591 in blender.
  • the resulting mixture was granulated with water in a granulator to obtain granules.
  • the resulting granules were extruded and spheronised to obtain spherical pellets of calcium citrate malate and vitamin D3.
  • the pellets were dried on a fluid bed dryer at 40 0 C and fraction passing through 20# sieve arid collected on a 40# sieve was collected.
  • Composition of calcium citrate malate and vitamin D3 as pellets was prepared according to the Example 6 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and Avicel ® RC 591.
  • Example 6 A and 6 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
  • Friability of 6 g of pellets of Example 6A and 6B was tested as in Example 2 and the friability was /as follows :
  • Example ⁇ A 0.1%
  • Example 6 B 0.24%
  • Ferrous fumarate composition as granules
  • the resulting p ⁇ wtfer was granulated with 5 % w/w of sucrose solution comprising 50% w/w of sucrose in water in ' " a granulator to obtain granules of ferrous fumarate.
  • the granules were sieved through 8# sieve Md dried in a fluid bed dryer at 40 0 C.
  • the granules were further sieved through 20# sieve and collected on 80# sieve.
  • Composition of ferrous fumarate as granules was prepared according to the Example 7 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
  • Example 7 A and 7 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 70-90 seconds respectively.
  • the dry ⁇ mix was granulated with aqueous binding solution comprising of 3% Polyvinylpyrrolidone K29/32 and 5% HPMC of total weight in a granulator.
  • the granules were passed through 8# sieve and then ⁇ d ⁇ e * d in fluidized bed drier at 4O 0 C.
  • the dried granules were passed through 20 # sieve.
  • the granules w ' e ⁇ e then mixed with 3% talc and 1% w/w magnesium stearate in a blender.
  • the resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
  • Example 8 B Composition of ferrous fumarate as tablets was prepared according to the Example 8 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
  • Example 8 A and 8 B dispersed in 100 ml of water in 1-2 minutes and ⁇ minutes respectively.
  • Friability of 6 g of tablets of Example 8A and 8B was tested as in Example 2 and the friability was as follows :
  • Example 8 A 0.63 %
  • Example 8 B 0.68 %
  • the resulting mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone K29/32 and 5% w/w HPMC in l a granulator to obtain granules.
  • the resulting granules were extruded and spheronised to obtain spherical pellets of ferrous fumarate.
  • the pellets were dried in a fluid bed dryer at 40 0 C and fraction passing through 20# sieve and retained on a 40# sieve was collected.
  • Composition of ferrous fumarate as pellets was prepared according to the Example 9 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Av ⁇ ce ⁇ ® RC 591.
  • Example 9 A and 9 B dispersed in 100 ml of water in 60 seconds and 3 minutes respectively.
  • the swelling index of the pellets of Example 9 A and 9 B in water and simulate saliva was 200-450 % w/w and less than 120 % w/w respectively.
  • Friability of 6 g of pellets of Example 9 A and 9 B was tested and the friability was as follows Example 9 A : 0.21%
  • Example 9 B 0.25%
  • the resulting powder was granulated with 5% w/w of sucrose solution comprising 50% w/w dextrose in water in a granulator to obtain granules of carbonyl iron;
  • the granules were sieved through a 8# sieve and dried in a fluid bed dryer at 40 0 C.
  • the granules ⁇ ' were further sieved through a 20# sieve and collected on a 80# sieve.
  • Composition of carbonyl iron as granules was prepared according to the Example 10 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
  • Example 10 A and 10 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 80-90 seconds respectively.
  • the mixture vwas granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone and 5 % w/w hydroxyprcj ⁇ yl methyl cellulose in a granulator.
  • the granules were passed through 8# sieve and then dried in fluidized bed dryer at 4O 0 C.
  • the dried granules were passed through 20# sieve.
  • the granules were then mixed with 3% w/w talc and 1% w/w magnesium stearate in blender. The resulting composition .
  • Composition of carbonyl iron as tablets was prepared according to the Example 11 A using sodiur ⁇ starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol arid partially pregelatinised starch.
  • Example 11 A and 11 B dispersed in 100 ml of water in 60-90 seconds ari ⁇ !4-5 minutes respectively.
  • Example H A 0.45 %
  • Example H B 0.23 %
  • ⁇ resulting mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone K29/32 afitt 5% w/w HPMC in a granulator to obtain granules.
  • the resulting granules were extruded and spheronised to obtain spherical pellets of carbonyl iron.
  • the pellets were dried in fluid bed dryer at 4O 0 C and sieved through a 2Q# sieve and collected on a 40# sieve.
  • Composition of carbonyl iron as spherical pellets was prepared according to the Example 12 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avicel ® RC 591.
  • Example 12 A and 12 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
  • the swelling index of the pellets of each of Example 12 A and 12 B in water and simulated saliva was 200-500% w/w and less than 150% w/w respectively.
  • Example 12 A 0.29 %
  • Example 12 B 0.24% o
  • Chlorpheniramine maleate composition as granules
  • the resulting powder was granulated with 5 % w/w of sucrose solution comprising 5Q%[-w/w sucrose in water in a granulator to obtain granules of chlorpheniramine maleate.
  • the granules 1 were sieved through a 8# sieve and dried in fluid bed dryer at 40°C. The granules were further sie ' Ved through a 20# sieve and collected on 80# sieve.
  • Composition of chlorpheniramine maleate as granules was prepared according to the Example 13 J A' using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead' of mannitol and partially pregelatinised starch.
  • Example 13 A and 13 B dispersed in 25 ml of each of water and simulated saliva in 5-15 seconds and 50-60 seconds respectively.
  • the mixture was further dry rriixed with 20% w/w Avicel ® PHlOl.
  • the resultant mixture was granulated using aqueous solution of 5% HPMC in a granulator.
  • the granules were passed through 8# sieve and dried in fluidized bed dryer at 4O 0 C
  • the dried granules were passed through 20#.
  • the granules were then mixed with 3% w/w ' MB and 1% w/w magnesium stearate in blender.
  • the resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
  • Composition of chlorpheniramine maleate as tablet was prepared according to the Example. 14 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and partially pregelatinised starch.
  • Example 14 A and 14 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
  • Example 14 A Friability of 6 g of tablets of Example 14 A and 14 B was tested as in Example 2 and the friability was as follows : Example 14 A : 0.59 % Example 14 B : 0.67 %
  • the mixture was further dry mixed with 10% w/w Avicel ® PH 101 and 15% w/w Avicel ® RC 591 in blender.
  • the resulting mixture ' w&s granulated with aqueous solution of 5% w/w HPMC in a granulator to obtain granules.
  • the resulting granules were extruded and spheronised to obtain spherical pellets of chlorpheniramine maleate.
  • the pellets were dried in fluid bed dryer at 40 0 C and sieved through a 20# sieve and collected on a 40# sieve.
  • Composition of chlorpheniramine maleate as spherical pellets was prepared according to. the Example 15 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and Avicel ® RC 591.
  • Example 15 A and 15 B Palatability of the pellets of Example 15 A and 15 B was tested on 25 volunteers as in Example 1 arid the scoring were as follows: Pellets of Example 15 A: 3-4 Pellets of Example 15 B: 1-2 Dispersion test and swelling index
  • Example 15 A and 15 B dispersed in 100 ml of water in 40 seconds, and 3 minutes respectively.
  • the swelling index of the pellets of Example 15 A and 15 B in water and simulated saliva was 200- 600 % w/w and less than 300 % w/w respectively.
  • Example 15 A 0.29 %
  • Example 15 B 0.12%
  • 10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially prege latinized starch, 59.3% w/w xylitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C, The resulting powder was granulated with aqueous solution of 5% w/w of sucrose and 3% ' iw/w Polyvinylpyrrolidone solution in a granulator to obtain granules of loratidine. The granules ⁇ w'dre sieved through a 8# sieve and dried in a fluid bed dryer at 40 0 C. The granules were further sieved
  • Composition of loratidine as granules was prepared according to the Example 16 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and partially pregelatinised starch.
  • Example 16 A and 16 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 60-70 seconds respectively.
  • 10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mur ⁇ bai). 10% partially pregelatinized starch, 62.3% w/w of Pearlitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 1% colloidal silicon dioxide, 3% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in ⁇ - cadmach 8 station rotary machine.
  • Composition of loratidine as tablet was prepared according to the Example 17 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of Pearlitol and partially pregelatinised starch.
  • Example 17 A and 17 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
  • Example 17 A Friability of 6 g of tablets of Example 17 A and Example 17 B was tested as in Example 2 and the friability was as follows : Example 17 A : 0.42 % Example 17 B : 0.59 %
  • 10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 47.3% w/w xylitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour,T% ' w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0-02% w/w sodium propyl parab ' en in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel ® PH 101 and 15% w/w Avicel ® RC 591 in blender.
  • the resulting mixture * was granulated with aqueous solution of 5% w/w Polyvinylpyrrolidone in a granulator to obtain granules " .
  • the resulting granules were extruded and spheronised to obtain spherical pellets of loratidine. ⁇
  • the pellets were dried in fluid bed dryer at 4O 0 C and sieved through a 20# sieve and collected on a 4O# sieve.
  • Composition of loratidine as spherical pellets was prepared according to the Example 18 A using sodium starch glycolate instead of Indion 414 and calcium phosphate, dibasic instead of xylit ⁇ l and Avicel ® RC 591. Palatability Test
  • Example 18 A and 18 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
  • the swelling index of the pellets of Example 18 A and 18 B in water and simulated saliva was 200- 400% w/w and less than 100% w/w respectively.
  • Example 18 A Friability of 6 g of tablets of Example 18 A and Example 18 B was tested as in Example 2 and the friability was as follows : Example 18 A : 0.27% Example 18 B : 0.30 %
  • composition of paracetamol as granules was prepared according to the Example 19 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
  • Example 19 A and 19 B dispersed in 25 ml of each of water ana simumtpa saliva in 5-20 seconds and 60-70 seconds respectively.
  • composition of paracetamol as tablet was prepared according to the Example 20 A using sodium
  • Example 20 A and 20 B dispersed in 100 ml of water in 1-2 minutes an,d-i5.?6 minutes respectively.
  • Friability of 6 g of tablets of Example 20 A and Example 20 B was tested as in Example 2 and, the . friability was as follows : Example 20 A : 0.79 % Example 20 B : 0.82 %
  • the mixture was further dry mixed with 10% w/w Avicel ® PH 101 and 10% Avicel ® RC 591 in a blender.
  • the resulting mixture was granulated with water in a granulator to obtain granules.
  • the resulting granules were extruded and spheronised in an extruder and spheronizer to obtain spherical pellets of paracetamol.
  • the pellets were dried / in fluid bed dryer at 4O 0 C and sieved through a 20# sieve and collected on a 40# sieve.
  • composition of paracetamol as pellets was prepared according to the Example 21 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and A vice! ® RC 591.
  • Example 21 A Palatability of the pellets of Examples 21 A and 21 B was tested on 25 volunteers as in Example " -i 1 and the scoring were as follows: Pellets of Example 21 A: 4-5 Pellets of Example 21 B: 2-3
  • Example 21 A and 21 B dispersed in 100 ml of water in 60 seconds and 4 minutes respectively.
  • the swelling index of the pellets of Example 21 A and 21 B was 200-400% w/w and less than 100% w/w respectively.
  • Example 21 A Friability of 6 g of tablets of Example 21 A and Example 21 B was tested as in Example 2 and "the friability was as follows : Example 21 A : 0.18% Example 21 B: 0.29%
  • the resulting powder was granulated with 20% w/w sucrose solution comprising 50% w/w of sucrose in water in a granulator to obtain granules of ofloxacin.
  • the granules were sieved through a 8# sieve and dried in a fluid bed dryer at 40 0 C.
  • the granules " were further sieved through a 80# sieve.
  • composition of ofloxacin as granules was prepared according to the Example 22 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
  • Example 22 A and 22 B dispersed in 25 ml of each of water and simulated saliva in 5-10 seconds and 60-70 seconds respectively.
  • ' i ⁇ " range of 25 to 35° C.
  • the mixture was further dry mixed with 3% w/w talc and 1% w/w magnesium stearate in a blender.
  • the resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
  • Composition of ofloxacin as tablet was prepared according to the Example 23 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
  • Example 23 A and 23 B dispersed in 100 ml of water in 60-70 seconds and.3-4 minutes respectively.
  • the resulting mixture was granulated with aqueous 5% w/w HPMC solution in a granulator to obtain granules.
  • the resulting granules were extruded and spheronised to obtain spherical pellets" of ,
  • the pellets were dried in fluid bed dryer at 4O 0 C and sieved through a 20# sieve and collected on a 40# sieve.
  • composition of ofloxacin as spherical pellets was prepared according to the Example 24 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose arid Avicel ® RC 591 partially pregelatinised starch.
  • Example 24 A and 24 B dispersed in 100 ml of water in 50 seconds ' and 3 minutes respectively.
  • the swelling index of the pellets of Example 24 A and 24 B was 200-400% w/w and less than 100% w/w respectively. ⁇ •
  • Example 24 A Friability of 6 g of tablets of Example 24 A and Example 24 B was tested as in Example 2 and the friability was as follows : Example 24 A : 0.13 % Example 24 B : 0.29 %
  • the resulting powder was granulated with 12.5% w/w sucrose solution comprising " 5'0% w/w of sucrose in water in a granulator to obtain granules of azithromycin.
  • the granules were sieved through a 8# sieve and dried in fluid bed dryer at 4O 0 C.
  • the granules were further sieved through' a 80# sieve.
  • Composition of Azithromycin as granules was prepared according to the Example 25 A using sodium starch glycQlate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and partially pregelatinised starch.
  • Example 25 A and 25 B dispersed in 25 ml of each of water and simulated saliva in 5-10 seconds and 50-60 seconds respectively.
  • the mixture was further dry mixed with 10% w/w Avicel ® PH 102, 2% w/w talc and 1% w/w magnesium stearate in a blender.
  • the resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
  • Composition of Azithromycin as tablet was prepared according to the Example 26 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
  • Example 26A and 26B dispersed in 100 ml of water in 1-2 minutes and :4-5 minutes respectively.
  • Example 26 A Friability of 6 g of tablets of Example 26 A and Example 26 B was tested as in Example 2 and the friability was as follows : Example 26 A : 0.23% Example 26 B : 0.25%
  • the mixture was further dry mixed witfr JQ% w/w Avicel ® PH 101 and 12% w/w Avicel ® RC 591 in a blender.
  • the resulting mixture was granulated with aqueous 5% w/w HPMC solution in a granulator to obtain granules.
  • the resultirig granules were extruded and Spheronized to obtain spherical pellets of azithromycin.
  • the pellets were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
  • Composition of Azithromycin as spherical pellets was prepared according to the Example 27 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and Avicel ® RC 591.
  • Example 27 A and 27 B dispersed in 100 ml of water in 50 seconds and.3 minutes respectively.
  • the swelling index of the pellets of Example 27 A and 27 B was 200-400% w/w and less than'lQ0% w/w respectively.
  • Example 27 A 0.25 %
  • Example 27 B 0.29%

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Abstract

Mouth dissolving pharmaceutical or neutraceutical composition comprising 1 to 70 % by weight of at least one pharmaceutical or neutraceutical active and 30 to 99 % by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least one pre- gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of 'the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of the pharmaceutically acceptable excipients. Potassium salt of crosslinked acrylic polymer as superdisintegrant is preferably Indion (414). The partially pre-gelatinized starch and 'the modified polysaccharide as softening agent are preferably Starch (1500) and Avicel RC (591) respectively. The water soluble channelizing agent is preferably selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including xylitol or sucrose. The composition can be in the form of pellets, granules or tablets. Also methods of making the composition as pellets, granules or tablets are also disclosed.

Description

TITLE OF INVENTION Mouth dissolving pharmaceutical or nutraceutical composition
FIELD OF THE INVENTION
This invention relates to a mouth dissolving pharmaceutical or nutraceutical composition. The composition is formulated into various dosage forms such as pellets, granules or tablets. This invention also relates to methods of making the mouth dissolving pharmaceutical or nutraceutical composition in various dosage forms such as pellets, granules or tablets.
The term mouth dissolving composition as used in the specification is intended to mean a composition, which disintegrates to form a non-gritty solution or slurry immediately upon contact with water or saliva.
BACKGROUND OF THE INVENTION
Oral administration of medicaments and nutraceuticals is the most commonly used and preferred route, especially by pediatric and geriatric patients as they are easy to be taken orally and problems like choking which may occur while swallowing non-mouth dissolving solid dosage forms sucrt*as tablets or capsules do not occur with such compositions. Mouth dissolving compositions are a'liso preferred to liquid dosage as the latter is prone to problems like spillage or inaccuracies in dosages when taken from time to time, lesser stability as compared to solid dosage forms or more 'storage space requirement.
Rapidly dissolving tablets are known to be prepared by adding a pharmaceutical ingredietit%) a particulate support matrix. The resulting mixture is compressed into tablets. The particulate ϊfϊaMx comprises polypeptide components, bulking agents and a volatilizing agent. This method is very expensive and complex in that additional steps in foπning support matrix are required. Also, tablets formed by this method are very fragile and are to be coated thereby making the method costlier (XJS Patents Nos 5,635,210, 5,595,761, 5,807,576 and 5,587,180).
US Patents Nos 4,305,502, 4,371516 and 5,738,875 describe a freeze dying process to prepare\an amorphous and porous dosage form which dissolves rapidly. However, such formulations are^ery expensive and require sophisticated technologies. The tablets prepared by the method disclosed!, in these patents are difficult to handle and require special packaging.
Porous tablets are known to be prepared by mixing the tablet components with a. liquid solvent or solid adjuvant that sublimes at temperatures, which do not adversely affect the properties of the tablet components. The resulting mixture is introduced into an inert cooling medium ^o solidify the solvent followed by pressing the mixture into tablets at temperatures below melting point of eutectic mixture of tablet component with solvent. The solvent is evaporated from the tab'le&sVby drying or lyophilization. The process is very complex and difficult to carry out as the high water content in the mixture makes compression into tablets difficult and cumbersome (US Patents Nos 5,762,961, 5,720,974, 4,134,943 and 3,885,026).
US Patent No 6,149,938, describes a process for making mouth soluble tablets of pharmaceutical active consisting of granulating a polyalcohol, an active ingredient, an edible acid and an aqueόjύs solution of water soluble or water insoluble polymer in a fluidized bed followed by drying 'the granules in the fluidized bed. The tablets are effervescent and give unpleasant taste in mouth.
US Patent No 6,156,339 describes a process for the preparation of an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance which has an unacceptable taste which prό'dέsl comprises forming a solution or a suspension in a solvent of a water soluble or water dispersible carrier, a filler and the pharmaceutically active substance with the unacceptable taste in association with a lipid; foπning discrete units of the suspension or solution; and removing the solvent £rdfrf:tϊfe discrete units under conditions whereby unit dosages are formed comprising a networky.of carrier/filler carrying a dosage of the pharmaceutically active substance in association with the lipid. The process is very complex and requires sophisticated and expensive equipments. Also, the't'ablets require special type of packaging and need to be handled carefully during dispensing and actfϊal administration since they are prone to breakage.
US 5,437,837 describes a method for the preparation of a pharmaceutical composition of pb'rous particles as reconsitutable powder, powder filled in capsule or tablets. Stoichiometric amount of acid and base is mixed in a press to produce compact which is milled to form evenly distributed effervescent mixture and subsequently added to an active to form an active mixture. The Ib1OVS mixture is wet granulated and dried. During drying the acid and base react due to heat and water present in the granules thereby releasing gas to form the porous particles. The porous particles. are milled to form a fine powder, which can be further compressed into tablets, or used as reconstitutable powder or filled in capsules as a quick dissolving powder. The compression pressure causes rearrangement of particles to form a less porous structure because of which dissolution time increases.
EP 0,494,972 describes solid dosage forms adapted for direct oral administration (mouth), which
' ..t'v1 substantially completely disintegrates upon contact with water and / or saliva. The solid dosage forms are tablets comprising at least one water or saliva activated effervescent disintegration agent in ill L.' -"' an amount, which is effective to aid rapid disintegration of the tablets and also provide distinct sensation of effervescence upon disintegration of the tablets in the mouth. Tablets prepared by the above technique need to be handled carefully during dispensing and actual administration since they are prone to breakage. The effervescent tablets give unpleasant taste in mouth.
US 5464632 describes a rapidly disintegratable tablet for oral administration, the tablet comprising an active substance and a mixture of excipients, wherein said active substance is multiparticuϊaϊ&and in the form of coated microcrystals, coated micrograhules or uncoated microgranules. The mixturfej'of excipients is selected from the group consisting of at least one disintegrating agent and at least ojg'e swelling agent, which are responsible for the disintegration. The disintegrating agent is selected frprn the group consisting of carboxymethylcellulose and insoluble reticulated Polyvinylpyrrolidone; qnd the swelling agent is selected from the group consisting of starch, modified starch', .anil microcrystalline cellulose and direct compression sugar.
US Patent No 6,596,311 describes a fast disintegrating tablet comprising a drug in a
Figure imgf000004_0001
form, substantially water insoluble components in amount of 50-99.5% by weight, one or more "Water insoluble inorganic excipients in amount of 2-40% by weight, one or more disintegrants in amountW 0.5-30% by weight, and one or more substantially water soluble excipients in amount of 4- 16,%; by weight. The disintegrating agent is selected from the group consisting of a natural starch, directly compressible starch, modified starch, cross-linked polyvinylpyrrolidone and modified cellulόsel'Sr combinations thereof.
US 20040258748 describes a process for preparing mouth dissolving dosage form whlb'h disintegrates quickly in the mouth. Active ingredient is blended with effervescent mixfifte comprising an acid source and a base to produce a tablet, which is subjected to moisture activation by exposing the tablet to controlled humidity or heat. The process is critical at the plant scale as slight moisture can imitate the reaction between acid and base, releasing cog gas, which acts as disintegrating agent. Besides this, the effervescent tablet gives a burning sensation in the mouth? .'
Freeze drying processes are generally used to prepare fast disintegrating dosage forms. Depending dri the manufacturing process, the product obtained is characterized by a highly porous microstructure of the soluble supporting agent (i.e. mannitol, glycine, lactose or gelatins) in which the active is homogeneously dispersed. Therefore, the fast disintegrating tablets are generally very friable and
■ '. ' vήfev require special packaging and are to be carefully handled. Freeze drying also increases the production cost because of the long duration of each freeze drying cycle (normally from 24 'tp^§8. hours). The complexity of the industrial plants is another important factor, which prejudices the large scale use of this technology for the development of rapidly disintegrating tablets. Moreover, the thermal shocks, as a direct consequence of each freeze drying cycle, might physically modify the physico-chemical properties of the outer membrane of the microencapsulated particles.
OBJECTS OF INVENTION
An object of the invention is to provide a mouth dissolving pharmaceutical or nutraceύtieal composition, which dissolves rapidly in the mouth.
Another object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which has low friability values and does not require'1 special type of packaging, |3αfl careful handling.
Another object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which can be in various dosage forms.
Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is simple and easy tσ'όarry out.
Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is economical.
Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is eco-friendly.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided mouth dissolving pharmaceutical or neutraeeutjc'al composition comprising 1 to 70% by weight of at least one pharmaceutical or neutraceutical active and 30 to 99% by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as a super disintegrant in 1 to 30 % by weight Qf , the pharmaceutically acceptable excipients; at least one pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of>:the pharmaceutically acceptable excipients.
The pharmaceutical or neutraceutical composition of the invention is in solid dosage forms sύ'έlt-as pellets, granules or tablets.
The pharmaceutical active is, for example, selected from the group consisting of analgesics and1 antiinflammatory agents such as aloxiprin, auranofm, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethaέiih, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen1; oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol or tromethamine; antihelminthics such as albendazole, bephenium hydroxynaphtrfoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxaijtel embonate, praziquantel, pyrantel embonate or thiabendazole; anti-arrhythmic agents such.»p amiodarone HCl, disopyramide, flecainide acetate or quinidine sulfate; anti-asthma agents suchi%!> zileuton, zafirlukast, terbutaline sulfate, montelukast or albuterol; anti-bacterial agents suchμas alatrofloxacin, azithromycin, baclofen, benzathine penicillin, cinoxacin, ciprofloxacin 1HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lomefloxacin, moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, piramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiaziηe,
Figure imgf000007_0001
lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, niofetil mycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citr'ajξ, teniposide, testolactone, topotecan HCl or toremifene citrate; anti-protozoal agents sικ?hH as tovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furόδte,
n
Figure imgf000008_0001
on-essential fatty acids, phytonadiol, vitamin A, vitamin B2, vitamin D, vitamin E or vitamih^K;
Figure imgf000009_0001
or anti-benign prostate hypertrophy agents such as becaplermin, donepezil HCl, L-thryroxine^ methoxsalen, verteporfin, physostigmine, pyridostigmine, raloxifene HCl, sibutramine JϊCl, sildenafil citrate, tacrine, tamsulosin HCl or tolterodine.
The nutraceutical active is, for example, dietary or nutritional supplement also known as medical or functional or designer foods or phytochemicals and includes therapeutic foods, infant formulas, weight control foods or hypoallergic foods. The neutraceutical active is, for example, selected' from the group consisting of herbs and botanicals such as capsicum, chamomile, cat's claw, echinacea, garlic, ginger, ginko, various ginseng, green tea, golden seal, kava kava, nettle, passion flower-j»saw palmetto, St. John's wort or valerian; mineral supplements such as calcium, copper, iodine, ' iron, magnesium, manganese, molybdenum, phosphorous, boron, selenium or zinc; weight lθbs> agents such as chromium picolinate or phenylpropanolamine; benzoin, fructo-oligosaccharides, glucosamine, grapeseed extract, guarana, inulin, phosphotidylserine, phytosterols, phytochemicals,' isoflavones, lecithin, lycopene, oligofructose, polyphenol or psyllium.
The pharmaceutical or neutraceutical active can be of pleasant taste or non-bitter or can rle' of unpleasant taste or bitter and taste masked.
The bitter pharmaceutical or neutraceutical active is taste masked by techniques known inutile aft using taste masking agents selected from the group consisting of flavours, sweeteners and atoihb acids such as fenchone, borneol, isoborneol, stevia based sweetner extract and glycerine, anethόl-B1 cyclodextrin complex and saccharin, sodium phenolate, anethole, eucalyptol and methyl salicylate, sodium citrate dihydrate, sodium saccharin, sodium glutamate and vanilla essence, sodium
Λ" l bicarbonate, citric acid and lemon flavor, monosodium glycyrrhizinate, starch, lactose and irtaήήitόl or glycine alanine, lipids such as stearyl stearate, glycerol palmitostearaie, caraauba wax jan'd magnesium aluminium silicate, glyceryl monostearate, gelatin and mixture of partially hydrogefia!ted soyabean oil, molten stearyl stearate, polyglycerine fatty acid esters, glycerine and chained triglycerides or homogenated suspensions of phospatidic acid or β-galactoglobulin; lecithin and lecithin like substances such as soyabean or phosphatidic acid, coating agents such as cellulose, shellac, L-hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer (Eudtfagit)', Hydroxypropyl Methylcellulose, Polyvinylpyrrolidone, cellulose acetate, Microcrystalline Cellulose, cellulose acetate butyrate, calcium gluconate and sodium alginate, carrageenan, macrogol-400, gelatin, carbopol, corn starch or macrogol-6000; protein; gelatins; prolamines (Zein); zeolitesT-ioh- exchange resins and complexing agents such as cyclodextrin, Hydroxypropyl β- cyclodextrin, Ii^CJU, Indion CRP 244, Indion CRP 254, Amberlite IRP 69, Indion 234; effervescent agents such as"ci|ric acid, fumaric acid, maleic acid, tartaric acid or sodium bicarbonate ; wax; benecoat BJ^II-6.0 phosphatidic acid or tannic acid.
The potassium salt of crosslinked acrylic polymer as super disintegrant is selected from Indion'4J4 (Ion Exchange India Ltd, Mumbai), Amberlite IRP-88 (Rohm & Haas (UK) Ltd., UK), Indion^£| (Ion Exchange India Ltd., India) or Indion 294 (Ion Exchange India Ltd., India). The preferred potassium salt of crosslinked acrylic polymer as super disintegrant is Indion 414, whichΛJias^a swelling index of 800. As the ionic radius of K+ is high, the rate of water uptake by the composition is very high thereby resulting in fast disintegration thereof. The partially pre-gelatinized starch'lϊas softening agent is Starch 1500 (Colorcon Asia Pvt Ltd, India). The modified polysaccharide's softening agent is selected from Avicel RC 591 (micro-crystalline cellulose containing l løβjfo sodium carboxymethylcellulose by FMC Biopolymer, Denmark), Avicel RC 581 (microcrystalline cellulose containing 11-13% sodiumcarboxy methylcellulose by FMC Biopolymer, Denmark)-, Avicel CL 611 (microcrystalline cellulose containing sodium carboxymethylcellulose by^tMC Biopolymer, Denmark); preferably Avicel RC 591. The water soluble channelizing agent is selected from polysorbates, poloxamers, sodium lauryl sulfate or water soluble sugars such as marihitoli lactose, dextrose, sucrose, maltose, glucose, fructose, sorbitol, maltitol, or xylitol. The preferred channelizing agents are polysorbates or sodium lauryl sulfate or water soluble sugars suάiif as dextrose, mannitol, lactose, xylitol or sucrose. The channelizing agents allow easy uptake of®2i<$3 iinnttoo tthhee ccoommposition and foπn channels that facilitate rapid softening and disintegration of Sfite composition.
The other pharmaceutically acceptable excipients, which can be used in the composition of jthe invention, include one or more disintegrants, sweeteners, salivating agents, colouring agents] flavouring agents, preservatives or formulating agents.
The disintegrating agents are selected from clays, celluloses, sodium starch glycolate," starch1-, pregelatinised starch (Amigel, National 155), crosscarmellose sodium, microcrystalline c'gllulqse (Avicel ), Polyvinylpyrrolidone cross linked, magnesium aluminum silicate, alginates or sb'dium alginate. The disintegrants open up and disintegrate the composition upon contact with saliva. The sweeteners render the composition palatable and are selected from sodium saccharin, aspartame1; acesulfame potassium, monoammonium glycyrrhizinate (MAG), glycerine, polyols, lactitol,- cyclamate or sucralose or combinations thereof.
The salivation agents induce a sufficiently strong flow of saliva, which accelerates the actionfύf channelizing agents and dis integrants. The salivating agents are selected from natural flavburrSKpE artificial flavours or weak or water-soluble organic acids such as citric acid.
The colours and flavours add aesthetic appeal and flavour to the composition. Flavour can be solid or liquid flavor and is selected from but not limited to Orange flavor, Raspberry flavor, Chocolate flavor, Strawberry flavor or Pineapple flavor.
Coloring agents that can be used include all F D and C and / or D and C dyes and / of-llakes. Examples of coloring agents are Iron oxides, Carmoisine, Ponceau 4R, lake sunset yellό'vsfpoϊ tartrazine.
The preservatives prevent microbial growth during storage of the composition and are selected'*;frbm parahydroxybenzoates or alkyl esters or salts thereof, sodium benzoate, benzoic acid, edetic^atad; sorbic acid and salts, bronopol or the like. Preferably the preservatives are parahydroxybenzoate^! ϊ>r alkyl esters thereof.
The formulating agents include diluents, binders, granulating agents, lubricating agents, tablettins: agents or spheronising agents.
The diluents are selected from calcium phosphate, calcium sulphate dihydrate, granular calcium lactate trihydrate, glyceryl palmitostearate, microcrystalline cellulose, kaolin, magnesium carbonϊfe, magnesium oxide, hydrolysed starches such as emdex or celutab, inositol, amylose, starches ftf'ch/as corn, wheat or potato, calcium carbonate, calcium triphosphate or sodium chloride. Preferably^ ffiϊ§ diluents are microcrystalline cellulose, kaolin, calcium phosphate, magnesium carbonate, magnesium oxide.
The granulating agents are selected from cellulose and derivatives thereof, starch and its derivaϊϊves- hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) pyrrolidone ' and derivatives thereof, or water. Preferably the granulating agents are water, hydroxypropyl methylcellulose (HPMC), Polyvinylpyrrolidone or celluloses and derivatives thereof.
The lubricating agents are selected from calcium stearate, magnesium stearate, potassium stear,ate, sodium stearate, boric acid, hard paraffin, magnesium oxide, talc, stearic acid, colloidal silicon dioxide, polyethylene glycol 4000, corn starch, sodium lauryl sulphate, magnesium lauryl sulphate, or D L - leucine. Preferably the lubricating agents are magnesium stearate, stearic acid or talc.
The tabletting agents are selected from calcium phosphate, magnesium carbonate, magnesium Qxifle, granular calcium lactate trihydrate, macrocrystalline cellulose (Avicel® PH 101 and Avicel® PH:.1.(32J, kaolin, hydrolysed starches such as Emdex or celutab, inositol, amylose, starches such as corn, wheat or potato, calcium carbonate. Preferably the tabletting agents are microcrystalline cellulose (Ajgcel® PH 101 and Avicel® PH 102), kaolin, calcium phosphate, magnesium carbonate, magnesium oxide*;, t
The binders are selected from acacia, tragacanth, gelatin, starch, methyl cellulose, magnesiϊlfti aluminium silicate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, alginic;.acid, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, Polyvinylpyrrolidone, polymethacrylates, dextrin, zein, hydrogenated vegetable oil, hydroxy ethyl cellulose, guar .gligi, maltodextrin, sodium alginate, water or ammonium calcium alginate. Most preferred birtfferr,ris HPMC or Polyvinylpyrrolidone eg. plasdone® K 29/32 or water.
The spheronizing agents are selected from microcrystalline cellulose. Microcrystalline cellulose including all grades of Avicel® (FMC BioPolymer, Denmark) such as but not limited to AvicetifPH 101, Avicel® PH 102, Avicel® PH 103, Avicel® PH 105, Avicel® PH 112, Avicel® PH 113, Avjcfl® PH 200, Avicel® PH 301 and Avicel® PH 302.
According to the invention there is provided a method of making a mouth dissolving pharmaceutical or neutraceutical composition as pellets, the method comprising i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceuticalHb'r neutraceutical active with 30 to 99 % w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as^uper disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least.'φϊfe pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of pharmaceutically acceptable excipients and at least one water soluble channelizing agent, in
2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained by step (i) with at least one spheronization agent; iii a) mixing the mixture obtained by step (ii) with a binder solution; iv a) extruding and spheronising the composition obtained by step (iii a) to obtain pellets; and v a) drying the pellets obtained by step (iv a) at 35 to 1000C.
According to the invention there is provided a method of making a mouth dissolving pharmaceutical or neutraceutical composition as granules, the method comprising i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as sniper disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at leas,t prie pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channepzing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained in step (i) with at least one diluent; iii b) granulating the mixture of step (ii) with a binder solution; iv b) sieving the granules obtained by step (iii b); v b) drying the granules of step (iv b) at 35 to 100° C; and vi b) sieving the granules obtained by step (v b).
According to the invention there is provided a method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets, the method comprising i) dry mixing at 25 to 45° C 1 to 70% by weight of at least one pharmaceutical' kpr neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as^ύper disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least 'όftfe pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by height of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained by step (i) with at least one tabletting agent and iii c) compressing the mixture obtained by step (ii) into tablets.
Preferably, the dry mixing as per step (i) is carried out 25 to 35° C. Preferably, 10 to 60 % by weight of at least one pharmaceutical or neutraceutical active is dry mixed with 40 to 90 % w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 2 to 20 % by weight of the pharmaceutically acceptable excipients; at least one pre-gelatinized starch or modified polysaccharide as softening agent in 10 to 30 %φy weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 5 to 70 % by weight of pharmaceutically acceptable excipients. The mixing of step '(ϊ) or step (ii) can be carried out in a blender. The mixing of step (iii a) can be carried out in a blender The' granulation step (iii b) is carried out in a granulator. The extrusion and spheronization of'the composition as per step (iv a) can be carried out in extruder-spheronizer. The drying of the pellets or granules as per step (v a) or (v b) can be carried out on a fluid bed dryer or tray dryer, preferably at 40 to 60° C. The sieving of step (iv b) and (vi b) is carried out through meshes of 8 mesh arid-40 mesh sieve respectively. The compression of the composition into tablets as per step (iii c) cari'"b~e carried out in a cadmach 8 station rotary machine.
A method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets where the method comprises granulating the mixture obtained by step (i) with a solution opά' granulating agent or binder followed by mixing the granules with a tabletting agent and compres'sfii-g the granules into tablets.
The granules or pellets prepared according to the invention can be used for fortification ofllitjϋiQs such as juices, milk, soy milk, etc and soft foods.
According to the invention, there is provided a mouth dissolving pharmaceutical or neutraceutical composition having very high dissolution or dispersion in the range of 5 to 65 seconds in water and/or upon contact with saliva and low friability in the range of 0.1 to 1%. The composition caff £& in different solid dosage forms such as pellets, granules or tablets. Due to low friability, the^ solid forms of the composition of the invention do not require special packaging or careful handling. The steps of the methods of the invention for formulating the composition of the invention into arious solid dosage forms do not employ expensive equipments and machinery and are;ι|ϊδt
Figure imgf000016_0001
invention is also efficient and economical for the above reasons.
The following experimental examples are illustrative of the invention but not limitative of the scope thereof.
Example 1
Calcium citrate and vitamin D3 composition as granule
[Example IA]
20% w/w of calcium citrate and 0-0061% w/w of vitamin D3 were dry mixed with 3% w/wlndibn
414 (Ion Exchange India Ltd, Mumbai). 1 % w/w of sodium saccharin, 1.5% w/w of orange fJa'YOi&'A
■ Y.rS % w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry Mixed with 10% partially pregelatinized starch and 43.3% w/w dextrose in the blender. The resulting powder was granulated with 20% w/w of sucrose solution comprising 50% w/w sucrose in water in,a granulator to obtain granules of calcium citrate and vitamin D3. The granules were sieved through:8# sieve and dried in a Fluidized bed drier at 40 0C. The granules were further sieved through 20# jsfeive and collected on a 80# sieve.
[Example 1 B]
Composition of calcium citrate and vitamin D3 as granules was prepared according to the Example 1. A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and partially pregelatinised starch. o
Palatability Test
Palatability of the dosages of Examples IA and IB was tested on 25 volunteers using a scoring scale of 0-5 where 0 stood for high unpalatability and 5 stood for high palatability. The scores given byithe volunteers were as follows: Granules of Example 1 A: 4-5 Granules of Example I B: 1-2
Dispersion test
5 gms of the granules of Example 1 A and Example 1 B dispersed in 25 ml of each of water :aηd simulated saliva in 5-20 seconds and 1-2 minutes respectively.
Example 2
Calcium citrate and vitamin D3 composition as tablets
[Example 2 A]
60% w/w of calcium citrate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/w Inchon 414 (Ion Exchange India Ltd, Mumbai). 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 2.0% w/w of orange flavor, 2% w/w of lake sutisel yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blendέf#at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 2% partially pregelatinized starch, 15% w/w Avicel® PH 102, 6.3% w/w Pearlitol, 3% w/w talc and 1%- w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in, a cadmach 8 station rotary machine.
[Example 2 B]
Composition of calcium citrate and vitamin D3 as tablets was prepared according to the Example'!2 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 2 A and 2 B was tested on 25 volunteers as in Example 1 >a'nd the scoring were as follows: Tablets of Example 2 A: 3-4 Tablets of Example 2 B: 1-2
Dispersion test
2 tablets of each of Example 2A and 2B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
Six tablets of each of Example 2A and 2B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability was determined using 6 g of tablets of Example 2A and 2B in a Roche friabilator for 4 nim. at a speed of 25 rpm. The friability were as follows: Example 2 A : 0.36% Example 2 B : 0.72%
Example 3
Calcium citrate and vitamin D3 composition as pellets
[Example 3 A]
60% w/w of calcium citrate and 0.0061 % w/w of vitamin D3 were dry mixed with 10% w/wTndion 414 (Ion Exchange India Ltd, Mumbai). 5.99% dextrose, 0.8% w/w sodium lauryl sulfate, 1%'W/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 2.0% w/w of orange flavor, '2% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 7% w/w Avicel® PH 101 and 10% w/w Avicel® RC 591 in suitable blender. The resulting mixture was granulated with water in a granulatorto obtain granules. The resulting granulomere
' V.- -' . extruded and spheronised to obtain spherical pellets of calcium citrate and vitamin D3. The pellets were dried in a fluid bed dryer at 40 0C and fraction passing through 20# sieve and retained on a 40# sieve was collected.
[Example 3 B]
Composition of calcium citrate and vitamin D3 as pellets was prepared according to the Example 3A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and Avicel® RC 591. o
Palatability Test
Palatability of the pellets of Examples 3 A and 3 B was tested on 25 volunteers as in Example ,lt and the scoring were as follows: Pellets of Example 3 A: 4-5 Pellets of Example 3 B: 1-2
Dispersion test and swelling index
5 gms of the pellets of Example 3 A and 3B dispersed in 100 ml of water in 50 seconds and 3 imniues respectively.
The swelling index of the pellets of Example 3A and 3B in water and simulate saliva was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of pellets of Example 3A and 3B was tested as in Example 2 and friability. Was.'as follows :
Example 3 A : 0.13% Example 3B : 0.23%
Example 4
Calcium citrate malate and vitamin D3 composition as granules.
[Example 4 A]
Figure imgf000019_0001
citrate malate and vitamin D3. The granules were sieved through 8# sieve and dried in a bed drier at 40°C. The granules were further sieved through 20# sieve and collected on 80# sieve.-' * [Example 4 B]
Composition of calcium citrate malate and vitamin D3 as granules was prepared according, tp -the Example 4 A using starch glycolate instead of Indion 414 and Magnesium carbonate instead, of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 4 A and 4 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Granules of Example 4 A: 4-5 Granules of Example 4 B: 1-2
Dispersion test
5 gms of the granules of Example 4 A and 4B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 1-2 minutes respectively.
Example 5
Calcium citrate malate and vitamin D3 composition as tablets
[Example 5 A]
60% w/w of calcium citrate malate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 6.3% w/w pearlitol and 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 1.5% w/wiof orange flavor, 1% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 2% partially pregelatinized starch, 15% w/w Avicel® PHl 02, 3% w/w talc and 1% w/w magnesium stearate in blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 5 B]
Composition of calcium citrate malate and vitamin D3 as tablets was prepared according to 'the Example 5 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of Pearlitol and partially pregelatinised starch. Palatability Test
Palatability of the tablets of Examples 5 A and 5 B was tested on 25 volunteers as in Example -I1 and the scoring were as follows: Tablets of Example 5 A: 3-4 Tablets of Example 5 B: 1-2
Dispersion test
2 tablets of each of Example 5 A and Example 5 B dispersed in 100 ml of water in 1-2 minutes ana
5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 5 A and 5B disintegrate in lminute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 5A and 5B was tested as in Example 2 and the friability was as follows :
Example 5 A : 0.32%
Example 5 B : 0.33%
Example 6
Calcium citrate malate and vitamin D3 composition as pellets
[Example 6 A]
60% w/w of calcium citrate malate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/# Indion 414 (Ion Exchange India Ltd, Mumbai). 2.99% w/w dextrose and 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 2.0% w/w of orange flavor, 2% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH102 and 10% w/w Avicel® RC 591 in blender. The resulting mixture was granulated with water in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of calcium citrate malate and vitamin D3. The pellets were dried on a fluid bed dryer at 40 0C and fraction passing through 20# sieve arid collected on a 40# sieve was collected. [Example 6 B]
Composition of calcium citrate malate and vitamin D3 as pellets was prepared according to the Example 6 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Examples 6 A and 6 B was tested on 25 volunteers as in Example.1 and the scoring were as follows:
Pellets of Example 6 A: 4-5
Pellets of Example 6 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 6 A and 6 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 6 A and 6 B in water and simulate saliva wasj^OO^
400% w/w and less than 100% w/w.
Friability test
Friability of 6 g of pellets of Example 6A and 6B was tested as in Example 2 and the friability was /as follows :
Example β A : 0.1% Example 6 B : 0.24%
Example 7
Ferrous fumarate composition as granules
[Example 7 A]
12.66% w/w of ferrous fumarate was dry mixed with 12% w/w Indion 414 (Ion Exchange India-Lid, Mumbai). 10% partially pregelatinized starch, 51.14 % w/w dextrose, 2% w/w aspartame, 5%>w/w chocolate flavour, 2% w/w red iron oxide, 0.18% w/w sodium methyl paraben and 0.02%. w/w sodium propyl paraben in blender at temperature in the range of 25 to 35° C. The resulting pόwtfer was granulated with 5 % w/w of sucrose solution comprising 50% w/w of sucrose in water in'" a granulator to obtain granules of ferrous fumarate. The granules were sieved through 8# sieve Md dried in a fluid bed dryer at 400C. The granules were further sieved through 20# sieve and collected on 80# sieve.
[Example 7 B]
Composition of ferrous fumarate as granules was prepared according to the Example 7 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 7 A and 7 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Granules of Example 7 A: 4-5 Granules of Example 7 B: 1-3
Dispersion test
5 gms of the granules of Example 7 A and 7 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 70-90 seconds respectively.
Example 8
Ferrous fumarate composition as tablets '■>
[Example 8 A]
30.4% w/w of ferrous fumarate was dry mixed with 10% w/w Indion (Ion Exchange India Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate and 20% w/w dextrose, 2 % w/w aspartame, 5%J^/w chocolate flavour, 2% w/w red iron oxide, 0.18% w/w sodium methyl paraben and 0.02%uw/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 3% partially pregelatinized starch, 15% w/w Avicel® PHlOl. The dry^mix was granulated with aqueous binding solution comprising of 3% Polyvinylpyrrolidone K29/32 and 5% HPMC of total weight in a granulator. The granules were passed through 8# sieve and then<dπe*d in fluidized bed drier at 4O0C. The dried granules were passed through 20 # sieve. The granules w'eϊe then mixed with 3% talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 8 B] Composition of ferrous fumarate as tablets was prepared according to the Example 8 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Payability Test
Palatability of the tablets of Examples 8 A and 8 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Tablet of Example 8 A: 4-5 Tablet of Example 8 B: 1-3
Dispersion test
2 tablets of each of Example 8 A and 8 B dispersed in 100 ml of water in 1-2 minutes and^ό minutes respectively.
Disintegration Test
6 tablets of each of Example 8 A disintegrate in 50 seconds and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 8A and 8B was tested as in Example 2 and the friability was as follows :
Example 8 A : 0.63 %
Example 8 B : 0.68 %
Example 9
Ferrous fumarate composition as pellets
[Example 9 A]
30.4% w/w of ferrous fumarate was dry mixed with 10% w/w Indion (Ion Exchange India^ Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate and 17% dextrose, 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone K29/32 and 5% w/w HPMC inla granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of ferrous fumarate. The pellets were dried in a fluid bed dryer at 40 0C and fraction passing through 20# sieve and retained on a 40# sieve was collected.
[Example 9 B]
Composition of ferrous fumarate as pellets was prepared according to the Example 9 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avϊceϊ® RC 591.
Palatability Test
Palatability of the pellets of Examples 9 A and 9 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Pellets of Example 9 A: 4-5 Pellets of Example 9 B: 1-3
Dispersion test and swelling index
5 gms of the pellets of Example 9 A and 9 B dispersed in 100 ml of water in 60 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 9 A and 9 B in water and simulate saliva was 200-450 % w/w and less than 120 % w/w respectively.
Friability test
Friability of 6 g of pellets of Example 9 A and 9 B was tested and the friability was as follows Example 9 A : 0.21% Example 9 B : 0.25%
Example 10
Carbonyl iron composition as granules
[Example 10A]
7.5% w/w of carbonyl iron was dry mixed with 12% w/w Indion 414 (Ion Exchange IndiaVEtd, Mumbai). 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w lake red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% partially pregelatinized staζch, 56.3% w/w dextrose. The resulting powder was granulated with 5% w/w of sucrose solution comprising 50% w/w dextrose in water in a granulator to obtain granules of carbonyl iron; The granules were sieved through a 8# sieve and dried in a fluid bed dryer at 400C. The granules^'were further sieved through a 20# sieve and collected on a 80# sieve.
[Example 10B]
Composition of carbonyl iron as granules was prepared according to the Example 10 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Payability Test
Palatability of the granules of Examples 10 A and 10 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Granules of Example 10 A: 3-4 Granules of Example 10 B : 1 -2
Dispersion test
5 gms of the granules of Example 10 A and 10 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 80-90 seconds respectively.
Example 11
Carbonyl iron composition as tablets '■
[Example 11 A]
7.5% w/w of carbonyl iron was dry mixed with 12% w/w Indion 414 (Ion Exchange India, Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate, 38.9% w/w mannitol, 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w lake brown, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% partially pregelatinized starch, 10% w/w Avicel® PHlOl. The mixture, vwas granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone and 5 % w/w hydroxyprcj^yl methyl cellulose in a granulator. The granules were passed through 8# sieve and then dried in fluidized bed dryer at 4O0C. The dried granules were passed through 20# sieve. The granules were then mixed with 3% w/w talc and 1% w/w magnesium stearate in blender. The resulting composition .
was compressed into tablets in a cadmach 8 station rotary machine.
[Example 11 B]
Composition of carbonyl iron as tablets was prepared according to the Example 11 A using sodiurή starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol arid partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 11 A and 11 B was tested on 25 volunteers as in Example* 1 scoring were as follows: Tablets of Example 11 A: 3-4 Tablets of Example 11 B: 1-2
Dispersion test
2 tablets of each of Example 11 A and 11 B dispersed in 100 ml of water in 60-90 seconds ari<Ϊ!4-5 minutes respectively.
Disintegration Test
6 tablets of each of Example 11 A and 11 B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 11 A and 11 B was tested as in Example 2 and the friability was as follows : Example H A : 0.45 % Example H B : 0.23 %
Example 12
Carbonyl iron composition as pellets
[Example 12 A]
7.5% w/w of carbonyl iron was dry mixed with 12% w/w Indion 414 (Ion Exchange India -'Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate and 37.9% w/w dextrose, 2% w/w aspartame, 5% 1V^w chocolate flavour, 2% w/w lake red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% wfw sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixtu'r|'w.as further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. ^ resulting mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone K29/32 afitt 5% w/w HPMC in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of carbonyl iron. The pellets were dried in fluid bed dryer at 4O0C and sieved through a 2Q# sieve and collected on a 40# sieve.
[Example 12 B]
Composition of carbonyl iron as spherical pellets was prepared according to the Example 12 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Examples 12 A and 12 B was tested on 25 volunteers as in Example 1 . and the scoring were as follows: Pellets of Example 12 A: 3-4 Pellets of Example 12 B: 1-2
Dispersion test and swelling index
5 gms of the pellets of Example 12 A and 12 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of each of Example 12 A and 12 B in water and simulated saliva was 200-500% w/w and less than 150% w/w respectively.
Friability test
Friability of 6 g of pellets of Example 12 A and 12 B was tested as in Example 2 and the friability was as follows : Example 12 A : 0.29 % Example 12 B : 0.24% o
Example 13
Chlorpheniramine maleate composition as granules
[Example 13 A]
7.5% w/w of chlorpheniramine maleate was dry mixed with 10 % w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 60.7% w/w mannitol, 0.4% w/w sodium lauryl sulfate and 0.2% , -.w/w Polysorbate 80, 2% w/w aspartame, 2% w/w pineapple flavour, 2% w/w lake tartrazine, 0.18%
Figure imgf000029_0001
sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in 'the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w partially pregelatinised starch. The resulting powder was granulated with 5 % w/w of sucrose solution comprising 5Q%[-w/w sucrose in water in a granulator to obtain granules of chlorpheniramine maleate. The granules1 were sieved through a 8# sieve and dried in fluid bed dryer at 40°C. The granules were further sie'Ved through a 20# sieve and collected on 80# sieve.
[Example 13 B]
Composition of chlorpheniramine maleate as granules was prepared according to the Example 13 J A' using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead' of mannitol and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 13 A and 13 B was tested on 25 volunteers as in Example'1! and the scoring were as follows: Granules of Example 13 A: 3-4 Granules of Example 13 B: 1-2
Dispersion test
5 gms of the granules of Example 13 A and 13 B dispersed in 25 ml of each of water and simulated saliva in 5-15 seconds and 50-60 seconds respectively.
Example 14
Chlorpheniramine maleate composition as tablets
[Example 14 A]
7.5% w/w of chlorpheniramine maleate was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 40.7% w/w mannitol and 0.4% w/w sodium lauryl sulfate and 0.2%!iwM Polysorbate 80, 2% w/w aspartame, 2% w/w pineapple flavour, 2% w/w lake tartrazine, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben, 6% w/w partially pregelatinised starch in a blender at temperature in the range of 25 to 35° C. The mixture was further dry rriixed with 20% w/w Avicel® PHlOl. The resultant mixture was granulated using aqueous solution of 5% HPMC in a granulator. The granules were passed through 8# sieve and dried in fluidized bed dryer at 4O0C The dried granules were passed through 20#. The granules were then mixed with 3% w/w' MB and 1% w/w magnesium stearate in blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 14 B]
Composition of chlorpheniramine maleate as tablet was prepared according to the Example. 14 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 14 A and 14 B was tested on 25 volunteers as in Example^! and the scoring were as follows: Tablets of Example 14 A: 3-4 Tablets of Example 14 B: 1-2
Dispersion test
2 tablets of each of Example 14 A and 14 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 14 A and 14 B disintegrate in lminute and 3-4 minutes respectively;- •
Friability test
Friability of 6 g of tablets of Example 14 A and 14 B was tested as in Example 2 and the friability was as follows : Example 14 A : 0.59 % Example 14 B : 0.67 %
Example 15
Chlorpheniramine maleate composition as pellets
[Example 15 A]
7.5% w/w of chlorpheniramine maleate was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 43.7% w/w mannitol, 0.4% w/w sodium lauryl sulfate and 0.2%vtw/w Polysorbate 80, 2% w/w aspartame, 2% w/w pineapple flavour, 2% w/w lake tartrazine, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben, 2% w/w Pregelatinised starcή' in"' a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture', w&s granulated with aqueous solution of 5% w/w HPMC in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of chlorpheniramine maleate. The pellets were dried in fluid bed dryer at 400C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 15 B]
Composition of chlorpheniramine maleate as spherical pellets was prepared according to. the Example 15 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Example 15 A and 15 B was tested on 25 volunteers as in Example 1 arid the scoring were as follows: Pellets of Example 15 A: 3-4 Pellets of Example 15 B: 1-2 Dispersion test and swelling index
5 gms of the pellets of Example 15 A and 15 B dispersed in 100 ml of water in 40 seconds, and 3 minutes respectively.
The swelling index of the pellets of Example 15 A and 15 B in water and simulated saliva was 200- 600 % w/w and less than 300 % w/w respectively.
Friability test
Friability of 6 g of pellets of Example 15 A and Example 15 B was tested as in Example 2 and .the friability was as follows : Example 15 A : 0.29 % Example 15 B :0.12%
Example 16
Loratidine composition as granules
[Example 16 A]
10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially prege latinized starch, 59.3% w/w xylitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C, The resulting powder was granulated with aqueous solution of 5% w/w of sucrose and 3%'iw/w Polyvinylpyrrolidone solution in a granulator to obtain granules of loratidine. The granules^w'dre sieved through a 8# sieve and dried in a fluid bed dryer at 400C. The granules were further sieved through a 20# sieve and collected on a 80# sieve.
[Example 16 B]
Composition of loratidine as granules was prepared according to the Example 16 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 16 A and 16 B was tested on 25 volunteers as in Example' I and the scoring were as follows: Granules of Example 16 A: 4-5 Granules of Example 16 B: 2-3
Dispersion test
5 gms of the granules of Example 16 A and 16 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 60-70 seconds respectively.
Example 17
Loratidine composition as tablets
[Example 17 A]
10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Murηbai). 10% partially pregelatinized starch, 62.3% w/w of Pearlitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 1% colloidal silicon dioxide, 3% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in β- cadmach 8 station rotary machine.
[Example 17 B]
Composition of loratidine as tablet was prepared according to the Example 17 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of Pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 17 A and 17 B was tested on 25 volunteers as in Example -1 and the scoring were as follows: Tablets of Example 17 A: 4-5 Tablets of Example 17 B: 2-3 Dispersion test
2 tablets of each of Example 17 A and 17 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 17 A and 17 B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 17 A and Example 17 B was tested as in Example 2 and the friability was as follows : Example 17 A : 0.42 % Example 17 B : 0.59 %
Example 18
Loratidine composition as pellets
[Example 18 A]
10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 47.3% w/w xylitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour,T%' w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0-02% w/w sodium propyl parab'en in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture* was granulated with aqueous solution of 5% w/w Polyvinylpyrrolidone in a granulator to obtain granules". The resulting granules were extruded and spheronised to obtain spherical pellets of loratidine.^ The pellets were dried in fluid bed dryer at 4O0C and sieved through a 20# sieve and collected on a 4O# sieve.
[Example 18 B]
Composition of loratidine as spherical pellets was prepared according to the Example 18 A using sodium starch glycolate instead of Indion 414 and calcium phosphate, dibasic instead of xylitόl and Avicel® RC 591. Palatability Test
Palatability of the pellets of Examples 18 A and 18 B was tested on 25 volunteers as in Example <l and the scoring were as follows: Pellets of Example 18 A: 4-5 Pellets of Example 18 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 18 A and 18 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 18 A and 18 B in water and simulated saliva was 200- 400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 18 A and Example 18 B was tested as in Example 2 and the friability was as follows : Example 18 A : 0.27% Example 18 B : 0.30 %
Example 19
Paracetamol composition as granules
[Example 19 A]
12.5% w/w of paracetamol taste masked using 12.5% w/w Crosslmked Polyvinylpyrrolidone was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 43.8% w/w dextrose, 2% wfw orange flavour, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w partially pregelatinized starch. The resulting powder was granulated with aqueous solution of 5% sucrose and 5% HPMC in a granulator to obtain granules .yof paracetamol. The granules were sieved through a 8# sieve and dried in fluid bed dryer at 4O0C; T;he granules were further sieved through a 40# sieve. [Example 19 B]
Composition of paracetamol as granules was prepared according to the Example 19 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 19 A and 19 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Granules of Example 19 A: 4-5 Granules of Example 19 B: 2-3
Dispersion test
5 gms of the granules of Example 19 A and 19 B dispersed in 25 ml of each of water ana simumtpa saliva in 5-20 seconds and 60-70 seconds respectively.
Example 20
Paracetamol composition as tablets
[Example 20 A]
25% w/w of paracetamol taste masked using 25% w/w Crosslinked Polyvinylpyrrolidone was, dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 4% partially pregelatinized starch, 31.8% w/w Pearlitol, 2% w/w aspartame and 2% w/w sodium sacharin, 2% w/w orange flavor, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w:.sodj[um propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further ^dry mixed with 2% w/w talc in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 20 B]
Composition of paracetamol as tablet was prepared according to the Example 20 A using sodium
...t: starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch. Payability Test
Palatability of the tablets of Examples 20 A and 20 B was tested on 25 volunteers as in Example. 1- and the scoring were as follows: Tablets of Example 20 A: 4-5 Tablets of Example 20 B: 2-3
Dispersion test
2 tablets of each of Example 20 A and 20 B dispersed in 100 ml of water in 1-2 minutes an,d-i5.?6 minutes respectively.
Disintegration Test
6 tablets of each of Example 20 A and 20 B disintegrate in lminute and 3-4 minutes respectively, y
Friability test
Friability of 6 g of tablets of Example 20 A and Example 20 B was tested as in Example 2 and, the . friability was as follows : Example 20 A : 0.79 % Example 20 B : 0.82 %
Example 21
Paracetamol composition as pellets
[Example 21 A]
12.5% w/w of paracetamol taste masked using 12.5% w/w Crosslinked Polyvinylpyrrolidone was 'dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 38.8% w/w dextrose, 2% w/w aspartame and 2% w/w sodium saccharin, 2% w/w orange flavor and 3% w/w citric acid, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in. a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 10% Avicel® RC 591 in a blender. The resulting mixture was granulated with water in a granulator to obtain granules. The resulting granules were extruded and spheronised in an extruder and spheronizer to obtain spherical pellets of paracetamol. The pellets were dried /in fluid bed dryer at 4O0C and sieved through a 20# sieve and collected on a 40# sieve. [Example 21 B]
Composition of paracetamol as pellets was prepared according to the Example 21 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and A vice!® RC 591.
Palatability Test
Palatability of the pellets of Examples 21 A and 21 B was tested on 25 volunteers as in Example" -i1 and the scoring were as follows: Pellets of Example 21 A: 4-5 Pellets of Example 21 B: 2-3
Dispersion test and swelling index
5 gms of pellets of Example 21 A and 21 B dispersed in 100 ml of water in 60 seconds and 4 minutes respectively.
The swelling index of the pellets of Example 21 A and 21 B was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 21 A and Example 21 B was tested as in Example 2 and" the friability was as follows : Example 21 A : 0.18% Example 21 B: 0.29%
Example 22
Ofloxacin composition as granules
[Example 22 A]
2.5% w/w of ofloxacin taste masked using 5% w/w ion exchange resin was dry mixed with 3%W/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially pregelatinized starch, 54.3%' w/w dextrose, 1% w/w aspartame, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18%i :^w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in-.ϊhe range of 25 to 35° C. The resulting powder was granulated with 20% w/w sucrose solution comprising 50% w/w of sucrose in water in a granulator to obtain granules of ofloxacin. The granules were sieved through a 8# sieve and dried in a fluid bed dryer at 400C. The granules": were further sieved through a 80# sieve.
[Example 22 B]
Composition of ofloxacin as granules was prepared according to the Example 22 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 22 A and 22 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Granules of Example 22 A: 4-5 Granules of Example 22 B: 2-3
Dispersion test
5 gms of the granules of Example 22 A and 22 B dispersed in 25 ml of each of water and simulated saliva in 5-10 seconds and 60-70 seconds respectively.
Example 23
Ofloxacin composition as tablets
[Example 23 A]
20% w/w of ofloxacin taste masked using 40% w/w ion exchange resin was dry mixed with: 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 2% partially pregelatinized starch, 18.8;%lw/w Pearlitol, 2% w/w aspartame, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18%; w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the
' iϊ": range of 25 to 35° C. The mixture was further dry mixed with 3% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 23 B]
Composition of ofloxacin as tablet was prepared according to the Example 23 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
Payability Test
Palatability of the Tablets of Examples 23 A and 23 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Tablets of Example 23 A: 4-5 Tablets of Example 23 B; 2-3
Dispersion test
2 tablets of each of Example 23 A and 23 B dispersed in 100 ml of water in 60-70 seconds and.3-4 minutes respectively.
Disintegration Test
6 tablets of each of Example 23 A and 23 B disintegrate in 50-60 seconds and 2-3 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 23 A and Example 23 B was tested as in Example 2 aridiϊhe friability was as follows : Example 23 A : 0.66 % Example 23 B : 0.49 %
Example 24
Ofloxacin composition as pellets
[Example 24 A]
5% w/w of ofloxacin taste masked using 10% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 41.8% w/w dextrose, 2% w/w aspartame, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 12% w/w Avicel® RC 591 in a blender. The resulting mixture was granulated with aqueous 5% w/w HPMC solution in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets" of ,
ofloxacin. The pellets were dried in fluid bed dryer at 4O0C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 24 B]
Composition of ofloxacin as spherical pellets was prepared according to the Example 24 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose arid Avicel® RC 591 partially pregelatinised starch.
Payability Test
Palatability of the pellets of Examples 24 A and 24 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Pellets of Example 24 A: 4-5 Pellets of Example 24 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 24 A and 24 B dispersed in 100 ml of water in 50 seconds' and 3 minutes respectively.
The swelling index of the pellets of Example 24 A and 24 B was 200-400% w/w and less than 100% w/w respectively. ■ •
Friability test
Friability of 6 g of tablets of Example 24 A and Example 24 B was tested as in Example 2 and the friability was as follows : Example 24 A : 0.13 % Example 24 B : 0.29 %
Example 25
Azithromycin composition as granules
[Example 25 A]
10% w/w of azithromycin taste masked using 30% w/w ion exchange resin was dry mixed with ϊb°/o w/w Indion 414 (Ion Exchange India Ltd., Mumbai). 5% partially pregelatinized starch, 1% Ww sodium sachharin and 0.5% w/w monoammonium glycyrrhizinate, 2% w/w strawberry flavour, 2% w/w lake ponceau red, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben'iή a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 26.8'% w/w xylitol. The resulting powder was granulated with 12.5% w/w sucrose solution comprising"5'0% w/w of sucrose in water in a granulator to obtain granules of azithromycin. The granules were sieved through a 8# sieve and dried in fluid bed dryer at 4O0C. The granules were further sieved through' a 80# sieve.
[Example 25 B]
Composition of Azithromycin as granules was prepared according to the Example 25 A using sodium starch glycQlate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 25 A and 25 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Granules of Example 25 A. 4-5 Granules of Example 25 B: 2-3
Dispersion test
5 gms of the granules of Example 25 A and 25 B dispersed in 25 ml of each of water and simulated saliva in 5-10 seconds and 50-60 seconds respectively.
Example 26
Azithromycin composition as tablets
[Example 26 A]
10% w/w of azithromycin taste masked using 30% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai. 3% partially pregelatinized starch, 28 3% 1Ww Pearlitol, 1% w/w sodium sachharin and 0.5% w/w monoammonium glycyrrhizinate, 2% w/w strawberry flavour (salivating agent), 2% w/w lake ponceau red (colouring agent), 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben (preservative) in a blendef at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 102, 2% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 26 B]
Composition of Azithromycin as tablet was prepared according to the Example 26 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 26 A and 26 B was tested on 25 volunteers as in Exaiηplp ,1 and the scoring were as follows: Tablets of Example 26A: 4-5 Tablets of Example 26B: 2-3
Dispersion test
2 tablets of each of Example 26A and 26B dispersed in 100 ml of water in 1-2 minutes and :4-5 minutes respectively.
Disintegration Test
6 tablets of each of Example 26A and 26B disintegrate in 1 minute and 3-4 minutes respectively:
Friability test
Friability of 6 g of tablets of Example 26 A and Example 26 B was tested as in Example 2 and the friability was as follows : Example 26 A : 0.23% Example 26 B : 0.25%
Example 27
Azithromycin composition as pellets
[Example 27 A]
10% w/w of azithromycin taste masked using 30% w/w ion exchange resin was dry mixed with.10% w/w Indion 414 (Ion Exchange India Ltd., Mumbai). 17.3% w/w xylitol, 1% w/w sodium sachMfin and 0.5% w/w monoammonium glycyrrhizinate, 2% w/w strawberry flavour, 2% w/w lake ponceau red, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben (preservative) : in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed witfr JQ% w/w Avicel® PH 101 and 12% w/w Avicel® RC 591 in a blender. The resulting mixture ;Was granulated with aqueous 5% w/w HPMC solution in a granulator to obtain granules. The resultirig granules were extruded and Spheronized to obtain spherical pellets of azithromycin. The pellets, were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 27 B]
Composition of Azithromycin as spherical pellets was prepared according to the Example 27 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Examples 27 A and 27 B was tested on 25 volunteers as in Example-'l and the scoring were as follows: Pellets of Example 27 A: 4-5 Pellets of Example 27 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 27 A and 27 B dispersed in 100 ml of water in 50 seconds and.3 minutes respectively.
The swelling index of the pellets of Example 27 A and 27 B was 200-400% w/w and less than'lQ0% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 27 A and Example 27 B was tested as in Example 2 and/the friability was as follows : Example 27 A : 0.25 % Example 27 B : 0.29%

Claims

CLAIMS :
1) Mouth dissolving pharmaceutical or neutraceutical composition comprising 1 to 7θVό'k$ weight of at least one pharmaceutical or neutraceutical active and 30 to 99% by weighif'^f pharmaceutically acceptable excipients including at least one potassium salt of cross liiύced acrylic polymer as super disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least one partially pre-gelatinized starch or modified polysaccharide as a softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water- soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients.
2) Mouth dissolving composition as claimed in claim 1, wherein the potassium salt' of crosslinked acrylic polymer is Indion 414.
3) Mouth dissolving composition as claimed in claim 1, wherein the partially pre-gelatihized starch is Starch 1500.
4) Mouth dissolving composition as claimed in claim 1, wherein the modified polysaccharide's Avicel RC 591.
5) Mouth dissolving composition as claimed in claim 1, wherein the water soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or water soluble sugars sucn'^as dextrose, mannitol including xylitol or sucrose.
6) Mouth dissolving composition as claimed in claim 1, which comprises granules.
7) Mouth dissolving composition as claimed in claim 1, which comprises tablets.
8) Mouth dissolving composition as claimed in claim 1, which comprises pellets.
9) A method of making a mouth dissolving pharmaceutical or neutraceutical compositiόn^'as pellets, the method comprising ' ';ϊ- ;'- i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical,- -or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at ϊeasj one partially pre-gelatinized starch or modified polysaccharide as a softening agent in 5 to,50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained by step (i) with at least one spheronization agent;
Figure imgf000046_0001
iii a) mixing the mixture obtained by step (ii) with a binder solution; ' ■„ , , „ iv a) extruding and spheronising the composition obtained by step (iii a) to obtain pellets; and v a) drying the pellets obtained by step (iv a) at 35 to 1000C.
10)A method of making mouth dissolving composition as claimed in claim 9, wherein the potassium salt of crosslinked acrylic polymer is Indion 414.
H)A method of making mouth dissolving composition as claimed in claim 9, wherein; -$αe partially pre-gelatinized starch is Starch 1500.
12) A method of making mouth dissolving composition as claimed in claim 9, wherein; !-ϊhe modified polysaccharide is Avicel RC 591. '
13) A method of making mouth dissolving composition as claimed in claim 9, wherein the ater soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including xylitol or sucrose
14) A method of making a mouth dissolving pharmaceutical or neutraceutical composition ,as granules, the method comprising i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical,; or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer a's'Super disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at lea'st-otϊe partially pre-gelatinized starch or modified polysaccharide as a softening agent in 5 to 50 r% by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; ii) dry mixing the mixture obtained in step (i) with at least one diluent; iii b) mixing the mixture of step (ii) with a binder solution to form granules; iv b) sieving the granules obtained by step (iii b); v b) drying the granules of step (iv b) at 35 to 100° C; and vi b) sieving the granules obtained by step (v b).
15) A method of making mouth dissolving composition as claimed in claim 14, whereiii'^he potassium salt of crosslinked acrylic polymer is Indion 414.
16) A method of making mouth dissolving composition as claimed in claim 14, wherein: -the partially pre-gelatinized starch is Starch 1500.
17) A method of making mouth dissolving composition as claimed in claim 14, whereifi the modified polysaccharide is Avicel RC 591.
18) A method of making mouth dissolving composition as claimed in claim 14, wherein the water soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or^Vater soluble sugars such as dextrose, mannitoϊ including pearlitol, xylitol or sucrose
19) A method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets, the method comprising <-'Λbh i ) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as
Figure imgf000047_0001
disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least one partially pre-gelatinized starch or modified polysaccharide as a softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water "'soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients; V/Λ "; ii) dry mixing the mixture obtained by step (i) with at least one tabletting agent and at least one lubricating agent; and iii c) compressing the mixture obtained by step (ii) into tablets. 2O) A method of making mouth dissolving composition as claimed in claim 19, wherein •„ the potassium salt of crosslinked acrylic polymer is Indion 414.
2I) A method of making mouth dissolving composition as claimed in claim 19, wherein the partially pre-gelatinized starch is Starch 1500.
22) A method of making mouth dissolving composition as claimed in claim 19, wherein , the modified polysaccharide is Avicel RC 591.
23) A method of making mouth dissolving composition as claimed in claim 19, wherein thejvater soluble channelizing agent is selected from.polysorbates or sodium lauryl sulfate or w#tør soluble sugars such as dextrose, mannitol including xylitol or sucrose.
24) A method of making a mouth dissolving pharmaceutical or neutraceutical composition' as tablets as claimed in claim 19, wherein the dry mixture obtained by step (i) is granulated wϊth solution of a granulating agent or binder followed by mixing the granules with a tabletting agent and compressing the granules into tablets.
PCT/IN2006/000288 2006-08-10 2006-08-10 Mouth dissolving pharmaceutical or nutraceutical composition WO2008018086A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009130715A1 (en) * 2008-04-25 2009-10-29 Cadila Healtcare Limited Rapidly disintegrating oral compositions of tramadol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999044580A1 (en) * 1998-03-06 1999-09-10 Eurand International S.P.A. Fast disintegrating tablets
WO2003063831A2 (en) * 2002-02-01 2003-08-07 Pfizer Products Inc. Immediate release dosage forms containing solid drug dispersions
WO2006046111A1 (en) * 2004-10-26 2006-05-04 Nycomed Pharma As Use of xylitol as an anti-chalk acting agent in compositions for oral use containing a calcium-containing compound as an active substance
WO2006072878A1 (en) * 2005-01-07 2006-07-13 Ranbaxy Laboratories Limited Oral dosage forms of sertraline having controlled particle size and processes for their preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999044580A1 (en) * 1998-03-06 1999-09-10 Eurand International S.P.A. Fast disintegrating tablets
WO2003063831A2 (en) * 2002-02-01 2003-08-07 Pfizer Products Inc. Immediate release dosage forms containing solid drug dispersions
WO2006046111A1 (en) * 2004-10-26 2006-05-04 Nycomed Pharma As Use of xylitol as an anti-chalk acting agent in compositions for oral use containing a calcium-containing compound as an active substance
WO2006072878A1 (en) * 2005-01-07 2006-07-13 Ranbaxy Laboratories Limited Oral dosage forms of sertraline having controlled particle size and processes for their preparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009130715A1 (en) * 2008-04-25 2009-10-29 Cadila Healtcare Limited Rapidly disintegrating oral compositions of tramadol

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