[go: up one dir, main page]

US20090208576A1 - Orally Disintegrating Tablets - Google Patents

Orally Disintegrating Tablets Download PDF

Info

Publication number
US20090208576A1
US20090208576A1 US12/293,857 US29385707A US2009208576A1 US 20090208576 A1 US20090208576 A1 US 20090208576A1 US 29385707 A US29385707 A US 29385707A US 2009208576 A1 US2009208576 A1 US 2009208576A1
Authority
US
United States
Prior art keywords
agents
orally disintegrating
directly compressible
hydrochloride
composite
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US12/293,857
Inventor
Anilkumar S. Gandhi
Pradnya Bagde
Hetal N. Morvekar
Pratibha S. Pilgaonkar
Maharukh T. Rustomjee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rubicon Research Pvt Ltd
Original Assignee
Rubicon Research Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rubicon Research Pvt Ltd filed Critical Rubicon Research Pvt Ltd
Assigned to RUBICON RESEARCH PRIVATE LIMITED reassignment RUBICON RESEARCH PRIVATE LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAGDE, PRADNYA M., MRS., GANDHI, ANILKUMAR, DR., MORVEKAR, HETAL N., DR., PILGAONKAR, PRATIBHA, MRS., RUSTOMJEE, MAHARUKH, MRS.
Publication of US20090208576A1 publication Critical patent/US20090208576A1/en
Abandoned legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention provides a tablet with optimal mechanical strength, which when placed in the oral cavity rapidly dissolves or disintegrates without water preferably within about 60 seconds.
  • the present invention relates to composites produced by co-processing of at least one water-soluble excipient and at least one water insoluble excipient such as calcium silicate and their use in orally disintegrating tablets.
  • Freeze drying is one common process for producing many commercial fast dissolving tablets wherein a cake or wafer is prepared by freeze drying a solution or suspension of the medicament and suitable excipients in water or other solvents. Such systems dissolve very rapidly on the tongue, due to their high affinity for moisture and a very high porosity.
  • U.S. Pat. No. 5,298,261 discloses freeze-drying a slurry or paste comprising an active ingredient and excipients placed in blister packets.
  • PCT application WO 97/36879 discloses vacuum drying, at room temperature or a slightly elevated temperature, a suspension including the active drug, a sugar alcohol, PEG 6000, talc, sweeteners and flavors in preformed blisters.
  • freeze-drying process suffers from several disadvantages, primary among these is that solutions employed for freeze-drying are aqueous and, therefore, not suited for water sensitive medicaments. It is also limited to low dose actives. The process itself is typically laborious, costly and time-consuming. Finally, the resultant dosage forms, in addition to being hygroscopic, tend to be very soft and, therefore, require special moisture- and impact-resistant packaging and require careful handling.
  • U.S. Pat. No. 5,464,632 claims use of high levels of disintegrants such as 16% starch 1500 and 13.3% crospovidone for disintegration time of 35 seconds to 45 seconds. However, such tablets have a chalky or dry feel when placed in the mouth.
  • U.S. Pat. No. 5,178,878 discloses a rapidly dissolving oral formulation that requires an extragranular microparticulate active in conjunction with an effervescent agent incorporated into a tableted matrix in order to achieve rapid oral disintegration. Many fast-dissolving tablets are also formulated by the inclusion of effervescent compounds.
  • U.S. Pat. No. 5,178,878 and WO 91/04757 disclose the addition of an effervescent couple (such as sodium bicarbonate and citric acid) to a tablet. Exposure of such tablet to moisture results in contact and chemical reaction between the effervescent couple which leads to gas production and tablet disintegration.
  • tablets which include effervescent pairs are highly sensitive to moisture and require a specific, very costly plant including special handling equipment, controlled-humidity environments and special moisture resistant packaging and also such preparations have an unpleasant mouth feel.
  • Another orally disintegrating technique is spray drying technology as explained in U.S. Pat. Nos. 5,958,471 and 6,165,511, which includes preparing an aqueous solution of more than 80% of one or more non-hygroscopic polyols and spraying the resulting mixture into an air stream.
  • the resulting composition of the spray-drying process contains a filamentous structure.
  • PCT application WO03051338A1 relates to a method for producing a directly compressible and highly compactible composition by co-spray drying of mannitol and sorbitol solution resulting in nonfilamentous microstructure. Both these patents describe use of highly concentrated aqueous solutions, which are to be maintained and sprayed at high temperature thus demanding special equipment.
  • EP 1145711 describes the preparation of flash-melt dosage forms that disintegrated in the mouth in less than 25 second. They consist of granules composed of a superdisintegrant (4-8%), a dispersing agent such as calcium silicate (20-70%), a distributing agent selected from amorphous silica, fumed silica, diatomaceous earth, talc, kaolin, magnesium aluminum trisilicate, and a binder (10 to 50% by weight). A larger amount of binder although may produce stronger tablets, the disintegration time tend to increase. To counter this, a large amount of dispersing and distributing agent is included in the formulation which increases the weight of the tablet and also the cost of the formulation may increase.
  • a superdisintegrant 4-8%
  • a dispersing agent such as calcium silicate (20-70%)
  • a distributing agent selected from amorphous silica, fumed silica, diatomaceous earth, talc, kaolin, magnesium aluminum trisilicate
  • PCT application WO03045844A1 relates to synthetic calcium metasilicate which when incorporated in a solid product significantly increases the disintegration rate of the formed product, when contacted by a substantially aqueous environment.
  • the reduction in disintegration time with calcium silicate is more pronounced with immediate release tablets as tablets prepared with calcium silicate has low porosity leading to increased disintegration time in oral cavity.
  • use of calcium silicate with conventional equipments leads to discoloration of the final dosage form due to interaction of calcium silicate with some metals.
  • Calcium silicate due to its hydrophobic and static nature results in blends with very poor flow properties causing weight and content variation during compression into tablets. Further, it also imparts a chalky taste to the dosage form.
  • composites made by co-processing of at least one water soluble excipient and at least one water insoluble excipient such as calcium silicate leads to a formulation that rapidly disintegrates or dissolves on in the mouth.
  • Tablets made with these excipients are robust (e.g., low friability, low ejection forces, hardness) enough to be processed in high speed tableting machines and shipped in low cost packages, and at the same time retain rapid disintegration or dissolution properties.
  • the tablets have a pleasant mouth feel and good mechanical strength and such tablets also do not require special handling or packaging conditions.
  • It is another object of the present invention is to prepare composites by spray drying having porosity of greater than 50%
  • a directly compressible composite for orally disintegrating tablets comprising at least one water-soluble excipient and calcium silicate prepared by co-processing.
  • an orally disintegrating tablet formulation having optimal mechanical strength comprising
  • Solid pharmaceutical dosage forms that rapidly dissolve or disintegrate in a glass of water or in the gastrointestinal tract have been known in the art for many years.
  • the obvious advantages of the convenience of carrying dosage forms that will dissolve or effervesce in water to release medicaments are well known. Rapid disintegration technology is among the most exciting recent developments in the pharmaceutical industry.
  • Orally Disintegrating Tablets are tablets that disintegrate/dissolve in the mouth rapidly without administering extra water. These dosage forms provide the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation.
  • Such dosage forms due to their ease of administration and pleasant mouth feel, may encourage patients especially children, the elderly and schizophrenic patients who have difficulty in swallowing conventional tablets to adhere to daily medication regimens and also allow the luxury of much more accurate dosing than oral liquids. Yet another situation where such tablets would be useful is where water may not be readily available to assist in swallowing the tablet in specific conditions.
  • Co-processed excipient refers to an excipient composite in which at least two excipients are present in close proximity to each other. In one of the embodiments such excipient composite may have one excipient incorporated in the particle structure of the other.
  • Porosity is a measure of void spaces within the material and is measured as a fraction (between 0 to 1) or as a percentage value (between 0 to 100%). Porosity is the ratio of void space to bulk volume. It can be determined using the following formula
  • wicking time as used here provides time (seconds) taken for water to wick into the tablet and completely wet the tablet core.
  • the wicking time test is used to evaluate the performance of orally disintegrating tablets.
  • the wicking time determination is carried out in a petri plate ( ⁇ 10 cm in diameter).
  • the plate is layered with tissue papers of 0.25 mm thick.
  • the tissue paper is wetted with 10 ml water (preferably colored using a water soluble dye) and allowed to soak for 30 sec.
  • a tablet is then placed on the wetted tissue paper and the time taken by water to reach the surface of tablet and completely wet it is recorded as the ‘wicking time’.
  • the test may be appropriately modified for tablets having weight of more than 200 mg.
  • mouth dissolution time provides time (seconds) taken for tablet to completely dissolve in the mouth determined in and by human volunteers.
  • lag time provides time (seconds) taken for tablet to soften and start disintegrating after being placed on the tongue determined in and by human volunteers.
  • in vitro disintegration time refers to the time taken for complete disintegration of the tablet as determined using the USP disintegration apparatus.
  • Composites are blend of excipients obtained by co-processing of at least one water soluble excipient and at least one water insoluble excipient.
  • the water soluble excipients according to the embodiments of the invention are excipients that are soluble in water.
  • the preferred examples include water soluble carbohydrates, salt or a polyhydric alcohol or its derivative.
  • the water soluble carbohydrates can be a monosaccharide, disaccharide, oligosaccharide or polysaccharide.
  • Examples include but not limited to monosaccharides such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, allose, altrose, glucose, mannose, fructose, gulose, idose, galactose, talose and sorbitol; disaccharides such as maltose, lactose, cellobiose, sucrose, mannitol and trehalose; oligosaccharides such as raffinose, stachyose, and dextrates; or polysaccharides such as maltodextrins, starch, glycogen, cellulose, chitin, callose, galactomannan, xylan and laminarin
  • the saccharide is preferably at least one selected from mannitol, lactose, saccharose, trehalose, xylitol and erythritol.
  • the saccharide is mannitol.
  • water soluble excipients can be employed alone or in combination.
  • the water soluble excipients also include but are not limited to polyhydric alcohols like propylene glycol, polyethylene glycol, glycerin or their derivatives, salts such as sodium chloride or water soluble cellulose derivatives.
  • the water insoluble excipients according to the embodiments of the invention are excipients that are not soluble in water.
  • excipients include but are not limited to inorganic salts such as calcium silicate-ortho, meta and alpha triclinic forms thereof, magnesium trisilicate-ortho and meta forms thereof or light anhydrous silicic acid, mica, synthetic aluminum silicate, silicon dioxide, magnesium aluminum silicate, magnesium metasilicate aluminate, celluloses such as microcrystalline cellulose, crystalline cellulose, cellulose derivatives, vinylpyrolidone derivatives, colloidal silicon dioxide etc.
  • the preferred water insoluble agent is calcium metasilicate.
  • the most preferred water insoluble agent is calcium silicate marketed by Huber as Rxcipient FM1000 having an aspect ratio of about 1:1 to about 2.5:1 and an oil absorption of from about 20 ml/100 gm to 220 ml/100 gm. It is a unique physical form of Calcium Silicate, which reduces the disintegration time of a dosage form.
  • water soluble and insoluble excipients may be present in the composites in the ratio of 1:50 to 50:1.
  • the ratio can be 1:30 to 30:1 and more preferably 1:20 to 20:1.
  • any process that ensures close proximity of water insoluble excipient and water soluble excipient can be employed. Such process would ensure intimate contact of water insoluble excipients and water soluble excipients.
  • Some of the preferred processes ensure complete or partial covering of the water insoluble excipient by water soluble excipient can be employed for the preparation of the composites.
  • the non-limiting processes may include physical mixing, wet mixing, complexation, precipitation, spray drying, lyophilization, microencapsulation, spray congealing, hot melt, gas antisolvent or rapid evaporation of supercritical solvent methods employed with supercritical fluid processing.
  • the preferred method for preparing composites is spray drying.
  • Spray drying is an industrial process involving particle formation and drying. It is highly suited for the continuous production of dry solids in either powder, granulate or agglomerate form from liquid feedstocks as solutions, emulsions and pumpable suspensions. Therefore, spray drying is an ideal process where the end-product must comply with precise quality standards regarding particle size distribution, residual moisture content, bulk density, and particle shape.
  • Spray drying involves the atomization of a liquid feedstock into a spray of droplets and contacting the droplets with hot air in a drying chamber. The sprays are produces by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions. Powder is discharged continuously from the drying chamber. Operating conditions and dryer design are selected according to the drying characteristics of the product and powder specification.
  • feed composition feed viscosity, density, feed spray rate, inlet temperature, outlet temperature, temperature difference, atomization pressure, vacuum, residence time. All these parameters can be varied in order to achieve the desired product.
  • the process employed comprise of preparation of the slurry of water-soluble and water insoluble excipient which was homogenized using overhead stirrer, homogenizer etc.
  • the feed can be preheated during stirring before being fed to the spray drying chamber.
  • a single fluid nozzle or a two-fluid nozzle can be employed.
  • the feed may also be sprayed using a rotating disk.
  • the drying of the particles could be achieved using any of the methods such as co-current flow, counter current flow or mixed flow.
  • the total solid content of the feed could vary from about 2-75%, preferably from 5-60% and more preferably from 10-50%.
  • the composites of at least one water soluble excipient and at least one water insoluble excipient such as calcium silicate may have certain desirable properties.
  • the moisture content of the composite as determined using loss on drying is preferably less than 2%.
  • the porosity of the composite plays a crucial role in the performance of the orally disintegrating tablet. In order to have disintegration time of less than 60 seconds, the porosity of the composite should be at least about 50%.
  • Another parameter which determines the wicking time, disintegration time in oral cavity and lag time is the particle size distribution of the composite. This parameter also determines the flow of the blend ready for compression into tablets. It is desirable that not less than 40% of particles are less than 150 microns.
  • active ingredient refers to one or more compounds that have some pharmacological property.
  • active ingredient AI
  • Active ingredients can be included in the said compositions as such or coated with suitable taste masking agent.
  • the compositions of the invention contain at least one suitable pharmaceutical active ingredient or nutraceutical active ingredients.
  • Examples of pharmaceutical ingredients that can be used include, but are not limited to gastrointestinal function conditioning agents anti-inflammatory agents, including, but not limited to aceclofenac, diclofenac, ibuprofen flubiprofen, piroxicam, sulindac, and celecoxib; analgesics, including, but not limited to acetaminophen, fentanyl, tramadol and aspirin; agents for erectile dysfunction therapy, including, but not limited to sildenafil and apomorphine; anti-migraines, including, but not limited to sumatriptan, rizatriptan, zolmitriptan, naratriptan and ergotamin; antihistaminic agents, including, but not limited to loratadine, fexofenadine, pseudoephedrine and cetirizine; cardiovascular agents, including, but not limited to nitroglycerine and isosorbide dinitrate; diuretics, including, but not
  • nutraceutical ingredients include, but are not limited to any ingredient that is thought to have a beneficial effect on human health.
  • Such ingredients include coenzyme Q-10, chondroitoin, echinacea, ephedra, glucosamine, garlic, ginkgo biloba, ginseng, grape seed extract, guarana, hawthorn, herbs, kava, kola nut, lutein, St. John's wort, vinpocetine, and yohimbe.
  • the active ingredient may be present in any form such as its normal form, taste masked form, enteric or controlled release form.
  • the taste masking can be carried out by any of the processes known in the art, not limiting to complexation with cyclodextrins, ion exchange resins or any other suitable agents. Taste masking can also be achieved by coating with water soluble or insoluble polymers or polymers having pH dependent solubility or waxes. Both the enteric release and controlled release may demand for coating of active ingredient or its granules with suitable retardants or polymers.
  • the active ingredient may be incorporated in the formulation in the powder form, granules, pellets, beads or any other form.
  • the tablets of the invention may include in addition to the composite and an active ingredient, one or more binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners colorants, diluents, souring agents, suitable taste masking agents, viscosity builders, glidants or lubricants, solubilizers, and stabilizers.
  • compositions of the invention also include at least one super disintegrant selected from but not limited to natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems.
  • Preferred disintegrants in the invention include crospovidone and natural, modified or pregelatinized starch.
  • the amount of superdisintegrant employed in the composition is about 2-50% by weight of the said dosage form.
  • binders examples include starch, pregelatinized starch, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.
  • suitable diluents include starch, dicalcium phosphate, microcrystalline cellulose and the like.
  • compositions of the invention may also include a glidant selected from colloidal silica, silica gel, precipitated silica, or combinations thereof.
  • glidant selected from colloidal silica, silica gel, precipitated silica, or combinations thereof.
  • the said compositions may also include salivating agents such as but not limited to micronised polyethylene glycol preferably of molecular weight 4000, sodium chloride or precipitated micronised silica to improve the disintegration properties of the said compositions.
  • compositions of the invention also include at least one sweetening agent selected from aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; one or more flavors e.g., mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, magnasweet 135, key lime flavor, grape flavor trusil art 511815, fruit extracts and colours or dyes.
  • sweetening agent selected from aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate
  • flavors e.g., mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, magnasweet 135, key lime flavor, grape flavor trusil art 511815, fruit extracts and colours
  • solid dosage form may refer to tablets, capsules, granules, powders etc. However the most preferred dosage form is tablet.
  • tablet is construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/melt granulation.
  • the preferred process is direct compression which involves compression of drug-excipient blend after mixing them for a definite time period.
  • the tablet may vary in shape such as oval, triangle, almond, peanut, parallelogram, round, pentagonal, hexagonal, and trapezoidal.
  • the preferred shapes are round, oval and parallelogram forms.
  • the performance of the orally disintegrating tablets can be evaluated using a number of parameters namely wicking time, disintegration time in oral cavity, in vitro disintegration time, lag time etc.
  • both the wicking time and disintegration time in oral cavity are less than 60 seconds and the lag time is less than 10 seconds.
  • compositions of orally disintegrating tablets using composites and spray dried mannitol A Ingredients mg/tablet mg/tablet Spray dried mannitol of example 2 45.0 — Co-processed composite of example 2 — 50.0 Starch 23.0 23.0 Microcrystalline cellulose 10.0 10.0 Croscarmellose sodium 3.5 3.5 Calcium silicate 10.0 5.0 Aspartame 1.5 1.5 Colloidal silicon dioxide 0.8 0.8 Flavor 0.5 0.5 Polyethylene Glycol 5.0 5.0 Flavor 0.2 0.2 Sodium stearyl fumarate 0.5 0.5 Total 100.0 100.0
  • compositions of orally disintegrating tablets using composite of example 4 Ingredients mg/tablet Coprocessed composite of example 4 55.0 Starch 23.0 Microcrystalline cellulose 5.0 Croscarmellose sodium 3.5 Calcium silicate 5.0 Aspartame 1.5 Colloidal silicon dioxide 0.8 Flavor 0.5 Polyethylene Glycol 5.0 Flavor 0.2 Sodium stearyl fumarate 0.5 Total 100.0
  • the test is carried out to determine the rate of water uptake by the orally disintegrating tablets.
  • Five circular tissue papers of about 10-cm diameter were placed in a petridish with a 10-cm diameter.
  • a tablet (100 mg weight) was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablets by capillary action was noted as the wicking time.
  • Wicking time suggest that the spray dried composites exhibits lesser wicking time indicating rapid disintegration of these tablets. Between spray dried mannitol and the composite of the present invention, the composite gives much reduced wicking time.
  • compositions of orally disintegrating tablets Ingredients mg/tablet mg/tablet Clonazepam 0.5 — Loratadine — 10.0 Composite of example 3 55.0 45.0 Starch 22.5 18.0 Croscarmellose sodium 3.5 4.0 Calcium silicate 5.0 5.0 Aspartame 1.5 2.0 Colloidal silicon dioxide 0.8 0.8 Flavor 5.0 0.5 Polyethylene Glycol 0.2 4.2 Sodium stearyl fumarate 0.5 0.5 Total 90.0 90.0
  • the drug and the composite was mixed to get a premix.
  • This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets. All the tablets had good mouth feel and disintegrated in mouth within 60 sec.
  • the drug and the composite was mixed to get a premix.
  • This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets.
  • the drug and the composite was mixed to get a premix.
  • This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets having a lag time of less than 5 sec.
  • the drug and the composite were mixed to get a premix.
  • This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets. Tablets had desired wicking time of about 55 sec and a good mouth feel.
  • the ingredients were sieved through 40# sieve along with taste-masked drug.
  • the sieved mix was blended to homogenize, lubricated and compressed to obtain 130 mg tablets of the following properties:
  • the ingredients were sieved through 40# sieve along with taste-masked drug.
  • the sieved mix was blended to homogenize, lubricated and compressed to obtain 100 mg tablets of the following properties:
  • the ingredients were sieved through 40# sieve along with taste-masked drug.
  • the sieved mix was blended to homogenize, lubricated and compressed to obtain 210 mg tablets of the following properties:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention describes a directly compressible composite prepared by co-processing a water-soluble excipient and calcium silicate. The present invention further describes the incorporation of the co-processed composite into a tablet formulation. The orally disintegrating tablets are of optimal mechanical strength and disintegrate within 60 seconds in the oral cavity.

Description

    FIELD OF INVENTION
  • The present invention provides a tablet with optimal mechanical strength, which when placed in the oral cavity rapidly dissolves or disintegrates without water preferably within about 60 seconds.
  • More particularly, the present invention relates to composites produced by co-processing of at least one water-soluble excipient and at least one water insoluble excipient such as calcium silicate and their use in orally disintegrating tablets.
    • BACKGROUND AND PRIOR ART
  • Design of an orally disintegrating tablet requires a significant amount of research work in order to develop a process that maintains enough porosity inside the compressed tablets for fast dissolving or fast melting while maintaining the mechanical strength of the tablet. Orally disintegrating dosage forms are known in the art and some of the most commonly used techniques are incorporated herein by reference. Current technologies involved in many patents as well as existing commercial fast-dissolving tablets utilize complicated processing techniques such as freeze-drying, molding and sublimation or use of specialized excipients such as effervescent couple, highly micronized agents or the likes.
  • Freeze drying is one common process for producing many commercial fast dissolving tablets wherein a cake or wafer is prepared by freeze drying a solution or suspension of the medicament and suitable excipients in water or other solvents. Such systems dissolve very rapidly on the tongue, due to their high affinity for moisture and a very high porosity. U.S. Pat. No. 5,298,261 discloses freeze-drying a slurry or paste comprising an active ingredient and excipients placed in blister packets. PCT application WO 97/36879 discloses vacuum drying, at room temperature or a slightly elevated temperature, a suspension including the active drug, a sugar alcohol, PEG 6000, talc, sweeteners and flavors in preformed blisters. However, the freeze-drying process suffers from several disadvantages, primary among these is that solutions employed for freeze-drying are aqueous and, therefore, not suited for water sensitive medicaments. It is also limited to low dose actives. The process itself is typically laborious, costly and time-consuming. Finally, the resultant dosage forms, in addition to being hygroscopic, tend to be very soft and, therefore, require special moisture- and impact-resistant packaging and require careful handling.
  • U.S. Pat. No. 5,464,632 claims use of high levels of disintegrants such as 16% starch 1500 and 13.3% crospovidone for disintegration time of 35 seconds to 45 seconds. However, such tablets have a chalky or dry feel when placed in the mouth.
  • U.S. Pat. No. 5,178,878 discloses a rapidly dissolving oral formulation that requires an extragranular microparticulate active in conjunction with an effervescent agent incorporated into a tableted matrix in order to achieve rapid oral disintegration. Many fast-dissolving tablets are also formulated by the inclusion of effervescent compounds. U.S. Pat. No. 5,178,878 and WO 91/04757 disclose the addition of an effervescent couple (such as sodium bicarbonate and citric acid) to a tablet. Exposure of such tablet to moisture results in contact and chemical reaction between the effervescent couple which leads to gas production and tablet disintegration. However, tablets which include effervescent pairs are highly sensitive to moisture and require a specific, very costly plant including special handling equipment, controlled-humidity environments and special moisture resistant packaging and also such preparations have an unpleasant mouth feel.
  • Another orally disintegrating technique is spray drying technology as explained in U.S. Pat. Nos. 5,958,471 and 6,165,511, which includes preparing an aqueous solution of more than 80% of one or more non-hygroscopic polyols and spraying the resulting mixture into an air stream. The resulting composition of the spray-drying process contains a filamentous structure. Similarly PCT application WO03051338A1 relates to a method for producing a directly compressible and highly compactible composition by co-spray drying of mannitol and sorbitol solution resulting in nonfilamentous microstructure. Both these patents describe use of highly concentrated aqueous solutions, which are to be maintained and sprayed at high temperature thus demanding special equipment.
  • Another approach to develop orally disintegrating dosage form involves optimal selection of excipients which would result in desired disintegration time. These are typically compressed dosage forms. EP 1145711 describes the preparation of flash-melt dosage forms that disintegrated in the mouth in less than 25 second. They consist of granules composed of a superdisintegrant (4-8%), a dispersing agent such as calcium silicate (20-70%), a distributing agent selected from amorphous silica, fumed silica, diatomaceous earth, talc, kaolin, magnesium aluminum trisilicate, and a binder (10 to 50% by weight). A larger amount of binder although may produce stronger tablets, the disintegration time tend to increase. To counter this, a large amount of dispersing and distributing agent is included in the formulation which increases the weight of the tablet and also the cost of the formulation may increase.
  • PCT application WO03045844A1 relates to synthetic calcium metasilicate which when incorporated in a solid product significantly increases the disintegration rate of the formed product, when contacted by a substantially aqueous environment. The reduction in disintegration time with calcium silicate is more pronounced with immediate release tablets as tablets prepared with calcium silicate has low porosity leading to increased disintegration time in oral cavity. However use of calcium silicate with conventional equipments leads to discoloration of the final dosage form due to interaction of calcium silicate with some metals. Calcium silicate due to its hydrophobic and static nature results in blends with very poor flow properties causing weight and content variation during compression into tablets. Further, it also imparts a chalky taste to the dosage form.
  • In general, there are numerous other examples of specific formulations that utilize one or more of the techniques or mechanisms discussed above. Majority of these techniques possess one or more of the above enumerated disadvantages to some extent such as tedious and complex method of manufacturing, special packaging and storage requirements, high cost, limitation on drug load etc. Thus, there continues to be a need for a formulation that mitigates or eliminates these disadvantages. The desired features of such dosage form include quick disintegrability in an oral cavity, a pleasant mouth feel and optimal mechanical strength even in storage under a humidifying conditions.
  • It was surprisingly found that composites made by co-processing of at least one water soluble excipient and at least one water insoluble excipient such as calcium silicate, leads to a formulation that rapidly disintegrates or dissolves on in the mouth. Tablets made with these excipients are robust (e.g., low friability, low ejection forces, hardness) enough to be processed in high speed tableting machines and shipped in low cost packages, and at the same time retain rapid disintegration or dissolution properties. The tablets have a pleasant mouth feel and good mechanical strength and such tablets also do not require special handling or packaging conditions.
    • OBJECT OF INVENTION
  • It is an object of the present invention to develop an orally disintegrating tablet with a disintegration time of less than 60 seconds in the oral cavity.
  • It is yet another object of the present invention to develop orally disintegrating tablets using composites prepared by co-processing.
  • It is further an object of the present invention to prepare composites by co-processing of at least one water soluble excipients and at least one water insoluble excipients such as calcium silicate and their use in orally disintegrating tablets.
  • It is further an object of the present invention to prepare composites by co-processing of at least one water soluble excipients and at least one water insoluble excipients such as calcium silicate by spray drying.
  • It is another object of the present invention is to prepare composites by spray drying having porosity of greater than 50%
  • It is an object of the present invention to prepare composites by co-processing of calcium silicate and mannitol by spray drying and their use in orally disintegrating tablets.
  • It is yet another object of the present invention to develop an orally disintegrating tablet with a wicking time of less than 60 seconds.
  • It is yet another object of the present invention to develop an orally disintegrating tablet with a lag time of less than 10 seconds.
  • It is yet another object of the present invention to develop an orally disintegrating tablet with hardness of at least 10N.
    • SUMMARY OF INVENTION
  • According to a broad aspect of the invention is provided a directly compressible composite for orally disintegrating tablets comprising at least one water-soluble excipient and calcium silicate prepared by co-processing.
  • According to another aspect of the invention is provided an orally disintegrating tablet formulation having optimal mechanical strength comprising
      • a. at least one pharmaceutically active ingredient or a nutraceutical agent
      • b. composites produced by co-processing of mannitol and calcium silicate.
      • c. At least one other excipient.
        such that the tablet has optimal mechanical strength and a disintegration time of about 60 sec in the oral cavity.
    DETAILED DESCRIPTION
  • Solid pharmaceutical dosage forms that rapidly dissolve or disintegrate in a glass of water or in the gastrointestinal tract have been known in the art for many years. The obvious advantages of the convenience of carrying dosage forms that will dissolve or effervesce in water to release medicaments are well known. Rapid disintegration technology is among the most exciting recent developments in the pharmaceutical industry. Orally Disintegrating Tablets are tablets that disintegrate/dissolve in the mouth rapidly without administering extra water. These dosage forms provide the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation. Such dosage forms due to their ease of administration and pleasant mouth feel, may encourage patients especially children, the elderly and schizophrenic patients who have difficulty in swallowing conventional tablets to adhere to daily medication regimens and also allow the luxury of much more accurate dosing than oral liquids. Yet another situation where such tablets would be useful is where water may not be readily available to assist in swallowing the tablet in specific conditions.
  • The term ‘Co-processed excipient’ as used here refers to an excipient composite in which at least two excipients are present in close proximity to each other. In one of the embodiments such excipient composite may have one excipient incorporated in the particle structure of the other.
  • The term ‘porosity’ as used here is a measure of void spaces within the material and is measured as a fraction (between 0 to 1) or as a percentage value (between 0 to 100%). Porosity is the ratio of void space to bulk volume. It can be determined using the following formula

  • Porosity=(Bulk volume−True volume)/Bulk volume
  • The term ‘wicking time’ as used here provides time (seconds) taken for water to wick into the tablet and completely wet the tablet core. The wicking time test is used to evaluate the performance of orally disintegrating tablets. The wicking time determination is carried out in a petri plate (˜10 cm in diameter). The plate is layered with tissue papers of 0.25 mm thick. The tissue paper is wetted with 10 ml water (preferably colored using a water soluble dye) and allowed to soak for 30 sec. A tablet is then placed on the wetted tissue paper and the time taken by water to reach the surface of tablet and completely wet it is recorded as the ‘wicking time’. The test may be appropriately modified for tablets having weight of more than 200 mg.
  • The term ‘mouth dissolution time’ as used here provides time (seconds) taken for tablet to completely dissolve in the mouth determined in and by human volunteers.
  • The term ‘lag time’ as used here provides time (seconds) taken for tablet to soften and start disintegrating after being placed on the tongue determined in and by human volunteers.
  • The term ‘in vitro disintegration time’ as used here refer to the time taken for complete disintegration of the tablet as determined using the USP disintegration apparatus.
    • Composites
  • Composites are blend of excipients obtained by co-processing of at least one water soluble excipient and at least one water insoluble excipient.
  • The water soluble excipients according to the embodiments of the invention are excipients that are soluble in water. The preferred examples include water soluble carbohydrates, salt or a polyhydric alcohol or its derivative. The water soluble carbohydrates can be a monosaccharide, disaccharide, oligosaccharide or polysaccharide. Examples include but not limited to monosaccharides such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, allose, altrose, glucose, mannose, fructose, gulose, idose, galactose, talose and sorbitol; disaccharides such as maltose, lactose, cellobiose, sucrose, mannitol and trehalose; oligosaccharides such as raffinose, stachyose, and dextrates; or polysaccharides such as maltodextrins, starch, glycogen, cellulose, chitin, callose, galactomannan, xylan and laminarin The saccharide is preferably at least one selected from mannitol, lactose, saccharose, trehalose, xylitol and erythritol. Preferably, the saccharide is mannitol. These water soluble excipients can be employed alone or in combination. The water soluble excipients also include but are not limited to polyhydric alcohols like propylene glycol, polyethylene glycol, glycerin or their derivatives, salts such as sodium chloride or water soluble cellulose derivatives.
  • The water insoluble excipients according to the embodiments of the invention are excipients that are not soluble in water. These excipients include but are not limited to inorganic salts such as calcium silicate-ortho, meta and alpha triclinic forms thereof, magnesium trisilicate-ortho and meta forms thereof or light anhydrous silicic acid, mica, synthetic aluminum silicate, silicon dioxide, magnesium aluminum silicate, magnesium metasilicate aluminate, celluloses such as microcrystalline cellulose, crystalline cellulose, cellulose derivatives, vinylpyrolidone derivatives, colloidal silicon dioxide etc. The preferred water insoluble agent is calcium metasilicate. The most preferred water insoluble agent is calcium silicate marketed by Huber as Rxcipient FM1000 having an aspect ratio of about 1:1 to about 2.5:1 and an oil absorption of from about 20 ml/100 gm to 220 ml/100 gm. It is a unique physical form of Calcium Silicate, which reduces the disintegration time of a dosage form.
  • These water soluble and insoluble excipients may be present in the composites in the ratio of 1:50 to 50:1. Preferably the ratio can be 1:30 to 30:1 and more preferably 1:20 to 20:1.
  • Any process that ensures close proximity of water insoluble excipient and water soluble excipient can be employed. Such process would ensure intimate contact of water insoluble excipients and water soluble excipients. Some of the preferred processes ensure complete or partial covering of the water insoluble excipient by water soluble excipient can be employed for the preparation of the composites. The non-limiting processes may include physical mixing, wet mixing, complexation, precipitation, spray drying, lyophilization, microencapsulation, spray congealing, hot melt, gas antisolvent or rapid evaporation of supercritical solvent methods employed with supercritical fluid processing. The preferred method for preparing composites is spray drying.
  • Spray drying is an industrial process involving particle formation and drying. It is highly suited for the continuous production of dry solids in either powder, granulate or agglomerate form from liquid feedstocks as solutions, emulsions and pumpable suspensions. Therefore, spray drying is an ideal process where the end-product must comply with precise quality standards regarding particle size distribution, residual moisture content, bulk density, and particle shape. Spray drying involves the atomization of a liquid feedstock into a spray of droplets and contacting the droplets with hot air in a drying chamber. The sprays are produces by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions. Powder is discharged continuously from the drying chamber. Operating conditions and dryer design are selected according to the drying characteristics of the product and powder specification.
  • There are a number of variables in the spray drying process which include feed composition, feed viscosity, density, feed spray rate, inlet temperature, outlet temperature, temperature difference, atomization pressure, vacuum, residence time. All these parameters can be varied in order to achieve the desired product.
  • The process employed comprise of preparation of the slurry of water-soluble and water insoluble excipient which was homogenized using overhead stirrer, homogenizer etc. The feed can be preheated during stirring before being fed to the spray drying chamber. For spraying this dispersion a single fluid nozzle or a two-fluid nozzle can be employed. Alternatively the feed may also be sprayed using a rotating disk. The drying of the particles could be achieved using any of the methods such as co-current flow, counter current flow or mixed flow. The total solid content of the feed could vary from about 2-75%, preferably from 5-60% and more preferably from 10-50%.
  • The composites of at least one water soluble excipient and at least one water insoluble excipient such as calcium silicate may have certain desirable properties. The moisture content of the composite as determined using loss on drying is preferably less than 2%. The porosity of the composite plays a crucial role in the performance of the orally disintegrating tablet. In order to have disintegration time of less than 60 seconds, the porosity of the composite should be at least about 50%. Another parameter which determines the wicking time, disintegration time in oral cavity and lag time is the particle size distribution of the composite. This parameter also determines the flow of the blend ready for compression into tablets. It is desirable that not less than 40% of particles are less than 150 microns.
    • Active Ingredients
  • As used herein, the term “active ingredient” or “active agent” refers to one or more compounds that have some pharmacological property. There is no limitation to the active ingredient (AI) that can be used with the present invention. Active ingredients can be included in the said compositions as such or coated with suitable taste masking agent. The compositions of the invention contain at least one suitable pharmaceutical active ingredient or nutraceutical active ingredients. Examples of pharmaceutical ingredients that can be used include, but are not limited to gastrointestinal function conditioning agents anti-inflammatory agents, including, but not limited to aceclofenac, diclofenac, ibuprofen flubiprofen, piroxicam, sulindac, and celecoxib; analgesics, including, but not limited to acetaminophen, fentanyl, tramadol and aspirin; agents for erectile dysfunction therapy, including, but not limited to sildenafil and apomorphine; anti-migraines, including, but not limited to sumatriptan, rizatriptan, zolmitriptan, naratriptan and ergotamin; antihistaminic agents, including, but not limited to loratadine, fexofenadine, pseudoephedrine and cetirizine; cardiovascular agents, including, but not limited to nitroglycerine and isosorbide dinitrate; diuretics, including, but not limited to furocemide and spironolactone; anti-hypertensive agents, including, but not limited to propranolol, amlodipine, felodipine, nifedipine, captoprile, ramiprile, atenolol, and diltiazem; anti-hypolipidemic agents, including, but not limited to simvistatin, atrovastatin, and pravastatin; anti-ulcer agents, including, but not limited to cimietidine, ranitidine, famotidine, omeprazole, esomeprazole, rabeprazole and lansoprazol; anti emetics, including, but not limited to meclizine hydrochloride, ondansetron, granisetron, ramosetron, and tropisetron; anticoagulants such as ticlopidine hydrochloride, dicumarol, or warfarin potassium; antiepileptics such as phenyloin sodium, and lamotrigine, anti-asthmatic agents, including, but not limited to aminophylline, theophylline, terbutaline, fenoterol, formoterol, and ketotifen; brain metabolism altering drugs such as meclofenoxate hydrochloride; minor tranquilizers such as oxazolam, diazepam, clonazepam, clotiazepam, medazepam, temazepam, fludiazepam, nitrazepam, alprazolam, lorazepam or chlordiazepoxide; anti-depressants, including, but not limited to fluoxetine, mirtazepine, escitalopram and sertraline; drugs for treatment of parkinson's disease or restless leg syndrome such as ropinirole hydrochloride; drug for alzheimer's disease such as memantine; drugs for schizophrenia such as risperidone, olanzepine and aripiprazole; oral antibacterial and antifungal agents such as penicillin, ampicillin, amoxicillin, cephalexin, erythromycin ethylsuccinate, acampicillin hydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline, erythromycin, fluconazole, itraconazole, ketoconazole, miconazole or terbinafine; synthetic antibacterial agents such as nalidixic acid, piromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, or sulfamethoxazole trimethoprim; antipasmodics such as propantheline bromide, atropine sulfate, oxapium bromide, timepidium bromide, antitussive, anti-asthmatic agents; muscle relaxants such as chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorozoxazone, phenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, or dantrolene sodium; oral antidiabetic agents such as glibenclamide, tolbutamide, or glymidine sodium; circulatory agents such as ubidecarenone or ATP-2Na; iron preparations such as ferrous sulfate or dried ferrous sulfate; vitamins such as vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K or folic acid; pollakiuria remedies such as flavoxate hydrochloride, oxybutynin hydrochloride, terodiline hydrochloride, or 4-diethylamino-1,1-dimethyl-2-butynyl (I)-a-cyclohexyl-oc-phenylglycolate hydrochloride; angiotensin-converting enzyme inhibitors such as enalapril maleate, anti-viral agents such as trisodium phosphonoformate, didanosine, dideoxycytidine, azido-deoxythymidine, didehydro-deoxythymidine, adefovir dipivoxil, abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir or stavudine.
  • Examples of nutraceutical ingredients include, but are not limited to any ingredient that is thought to have a beneficial effect on human health. Such ingredients include coenzyme Q-10, chondroitoin, echinacea, ephedra, glucosamine, garlic, ginkgo biloba, ginseng, grape seed extract, guarana, hawthorn, herbs, kava, kola nut, lutein, St. John's wort, vinpocetine, and yohimbe.
  • The active ingredient may be present in any form such as its normal form, taste masked form, enteric or controlled release form. The taste masking can be carried out by any of the processes known in the art, not limiting to complexation with cyclodextrins, ion exchange resins or any other suitable agents. Taste masking can also be achieved by coating with water soluble or insoluble polymers or polymers having pH dependent solubility or waxes. Both the enteric release and controlled release may demand for coating of active ingredient or its granules with suitable retardants or polymers.
  • The active ingredient may be incorporated in the formulation in the powder form, granules, pellets, beads or any other form.
  • The tablets of the invention may include in addition to the composite and an active ingredient, one or more binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners colorants, diluents, souring agents, suitable taste masking agents, viscosity builders, glidants or lubricants, solubilizers, and stabilizers.
  • The compositions of the invention also include at least one super disintegrant selected from but not limited to natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems. Preferred disintegrants in the invention include crospovidone and natural, modified or pregelatinized starch. The amount of superdisintegrant employed in the composition is about 2-50% by weight of the said dosage form.
  • Examples of suitable binders include starch, pregelatinized starch, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts. Examples of suitable diluents include starch, dicalcium phosphate, microcrystalline cellulose and the like.
  • Examples of the lubricant include but not limited to magnesium stearate, calcium stearate, stearic acid, talc, and sodium fumarate stearate. The compositions of the invention may also include a glidant selected from colloidal silica, silica gel, precipitated silica, or combinations thereof. The said compositions may also include salivating agents such as but not limited to micronised polyethylene glycol preferably of molecular weight 4000, sodium chloride or precipitated micronised silica to improve the disintegration properties of the said compositions.
  • In addition to above excipients, the compositions of the invention also include at least one sweetening agent selected from aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; one or more flavors e.g., mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, magnasweet 135, key lime flavor, grape flavor trusil art 511815, fruit extracts and colours or dyes. There is no limitation on color or flavor that is useful in the present invention, and these characteristics will likely be chosen based on the age of the patient consuming the solid dosage form.
  • The term “solid dosage form” may refer to tablets, capsules, granules, powders etc. However the most preferred dosage form is tablet. The term tablet is construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/melt granulation. The preferred process is direct compression which involves compression of drug-excipient blend after mixing them for a definite time period.
  • The tablet may vary in shape such as oval, triangle, almond, peanut, parallelogram, round, pentagonal, hexagonal, and trapezoidal. The preferred shapes are round, oval and parallelogram forms.
  • The performance of the orally disintegrating tablets can be evaluated using a number of parameters namely wicking time, disintegration time in oral cavity, in vitro disintegration time, lag time etc. As per various embodiments of the present invention, both the wicking time and disintegration time in oral cavity are less than 60 seconds and the lag time is less than 10 seconds.
  • While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations.
    • EXAMPLES Example 1 Orally Disintegrating Tablets Produced by Physical Mixing
  • TABLE 1
    Composition of orally disintegrating tablets
    Ingredients mg/tablet
    Mannitol 45.0
    Maize starch 23.0
    Microcrystalline cellulose 10.0
    Croscarmellose sodium 3.5
    Calcium silicate 10.0
    Aspartame 1.5
    Colloidal silicon dioxide 0.8
    Flavor 0.2
    Polyethylene Glycol 5.0
    Sodium stearyl fumarate 0.5
    Total 100.0
  • All excipients except lubricant were blended in a blender to get a uniform mass. The mass was lubricated and compressed into tablets having following parameters:
  •
    Hardness (N) 10-30
    Friability (%) 1.5%
    In vitro Disintegration time (sec)  5-10
    Disintegration time in oral cavity (sec) 20-30

    Tablets with desired friability and disintegration time were obtained.
    • Example 2 (a) Co-Processing of Mannitol and Calcium Silicate by Spray Drying
  • 180 gms of mannitol was dissolved in water at about 80° C. temperature. In this solution 20 gms of calcium silicate was added and stirred to get a uniform mass. The mass was sprayed in the spray dryer under following conditions:
  •
    Inlet Temperature 180-200° C.
    Outlet Temperature 80-120° C.
    Nozzle diameter 1 mm
    Feed rate 150-200 ml/Hr
    Atomisation pressure 0.7-1.2 Kg/cm2

    The composites obtained were free flowing with bulk density in the range of 0.3-0.5 gm/cc and having about 75% of particles below 150 microns.
    • (b) Spray Drying of Mannitol
  • Mannitol alone was also spray dried under above mentioned conditions.
    • Example 3 Co-Processing of Mannitol, Sorbitol and Calcium Silicate by Spray Drying
  • 160 gms of mannitol and 20 gms of sorbitol were dissolved in water at 70-75° C. temperature. In this solution 20 gms of calcium silicate was added and stirred to get a uniform mass. The mass was sprayed in the spray dryer under following conditions:
  •
    Inlet Temperature 180-200° C.
    Outlet Temperature 70-100° C.
    Nozzle diameter 1 mm
    Feed rate 150-200 ml/Hr
    Atomisation pressure 3-4 Kg/cm2

    The composites obtained were free flowing with bulk density of 0.4-0.5 gm/cc
    • Example 4 Co-Processing of Mannitol, Microcrystalline Cellulose and Calcium Silicate by Spray Drying
  • 160 gms of mannitol was dissolved in water at about 70° C. temperature. In this solution 20 gms of calcium silicate and 20 gms of microcrystalline cellulose were added and stirred to get a uniform mass. The mass was sprayed in the spray dryer under same conditions as given in example 2. The composites obtained were free flowing with bulk density of 0.4 gm/cc.
    • Example 5 Co-Processing of Mannitol and Calcium Silicate by Spray Drying
  • 240 g Mannitol was dissolved in 4.0 liter water at room temperature. In this solution 560 g of calcium silicate was added and stirred to get a homogeneous mass. The mass was sprayed in the spray dryer under following conditions:
  •
    Inlet Temperature 200-220° C.
    Outlet Temperature 80-120° C.
    Nozzle diameter 2.0 mm
    Feed rate 70-90 ml/min
    Atomisation pressure 0.2 Kg/cm2

    The composites obtained were free flowing with bulk density of 0.55-0.65 gm/cc and moisture content of less than 1.0% determined by loss on drying. About 90% of the particles were of size less than 150 microns and the composite had a desirable porosity of 63%.
    • Example 6 Co-Processing of Mannitol and Calcium Silicate by Spray Drying
  • 600.0 g Mannitol was dissolved in 3.0 liter water at room temperature. In this solution 600.0 g of calcium silicate was added and stirred to get a uniform mass. The mass was sprayed in the spray dryer under following conditions:
  •
    Inlet Temperature 200-205° C.
    Outlet Temperature 105-125° C.
    Nozzle diameter 2.0 mm
    Feed rate 70-90 ml/min
    Atomisation pressure 0.2 Kg/cm2

    The composites obtained had moisture content of less than 1%, porosity of 65% and were free flowing with bulk density of 0.6-0.8 gm/cc
    • Example 7 Co-Processing of Mannitol, Calcium Silicate and Polyethylene Glycol by Spray Drying
  • 340.0 g Mannitol and 20.0 g of Polyethylene glycol were dissolved in 2.0 liter water at room temperature. In this solution 40.0 gms of calcium silicate was added and stirred to get a uniform mass. The mass was sprayed in the spray dryer under following conditions:
  •
    Inlet Temperature 200-205° C.
    Outlet Temperature 105-125° C.
    Nozzle diameter 2.0 mm
    Feed rate 70-90 ml/Hr
    Atomisation pressure 0.2 Kgf/cm2

    The composites obtained were free flowing with bulk density of 0.5-0.7 gm/cc and moisture content 0.5%. The porosity of the composite was 61%.
    • Example 8 Co-Processing of Mannitol and Calcium Silicate by Spray Drying Using a Rotary Disc
  • 900.0 g Mannitol was dissolved in 5.0 liter water at room temperature. In this solution 100.0 gms of calcium silicate was added and stirred to get a uniform mass. The mass was sprayed in the spray dryer under following conditions:
  •
    Inlet Temperature 200-205° C.
    Outlet Temperature 85-95° C.
    Rotary disc radius 6.0 cm
    Rotary disc speed 24000 rpm
    Feed rate 70-90 ml/Hr

    The composites obtained possessed bulk density of 0.45-0.55 gm/cc and had a good flow. The moisture content was about 0.6% with about 95% of particles below 150 microns.
    • Example 9 Tablet Formulation Using Composite of Mannitol and Calcium Silicate and Spray Dried Mannitol
  • TABLE 2
    Compositions of orally disintegrating tablets
    using composites and spray dried mannitol
    A B
    Ingredients mg/tablet mg/tablet
    Spray dried mannitol of example 2 45.0 —
    Co-processed composite of example 2 — 50.0
    Starch 23.0 23.0
    Microcrystalline cellulose 10.0 10.0
    Croscarmellose sodium 3.5 3.5
    Calcium silicate 10.0 5.0
    Aspartame 1.5 1.5
    Colloidal silicon dioxide 0.8 0.8
    Flavor 0.5 0.5
    Polyethylene Glycol 5.0 5.0
    Flavor 0.2 0.2
    Sodium stearyl fumarate 0.5 0.5
    Total 100.0 100.0
  • All excipients except lubricant were blended in a blender to get a uniform mass. The mass was lubricated and compressed into tablets having following parameters:
  • A B
    Hardness (N) 10-20 10-20
    Friability (%) 0.85 1.0
    In vitro Disintegration time (sec) 15-20  5-10
    Disintegration time in oral cavity (sec) 40-50 25-40

    Robust tablets were obtained with low friability and desired disintegration time.
    • Example 10 Tablet Formulation Using Composite of Mannitol, Microcrystalline Cellulose and Calcium Silicate
  • TABLE 3
    Compositions of orally disintegrating
    tablets using composite of example 4
    Ingredients mg/tablet
    Coprocessed composite of example 4 55.0
    Starch 23.0
    Microcrystalline cellulose 5.0
    Croscarmellose sodium 3.5
    Calcium silicate 5.0
    Aspartame 1.5
    Colloidal silicon dioxide 0.8
    Flavor 0.5
    Polyethylene Glycol 5.0
    Flavor 0.2
    Sodium stearyl fumarate 0.5
    Total 100.0
  • All excipients except lubricant were blended in a blender to get a uniform mass. The mass was lubricated and compressed into tablets having following parameters:
  •
    Hardness (N) 10-20
    Friability (%) 0.8-0.9
    In vitro Disintegration time (sec)  8-12
    Disintegration time in oral cavity (sec) 30-40

    Robust tablets were obtained with low friability and desired disintegration time.
    • Example 11 Wicking Test
  • The test is carried out to determine the rate of water uptake by the orally disintegrating tablets. Five circular tissue papers of about 10-cm diameter were placed in a petridish with a 10-cm diameter. Ten milliliters of water containing eosin, a water-soluble dye, was added to the petridish. A tablet (100 mg weight) was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablets by capillary action was noted as the wicking time.
  • TABLE 4
    Wicking time of various orally disintegrating tablets
    Formulation Wicking Time (sec)
    Example 1 15-20
    Example 9A 35-40
    Example 9B 18-20
    Example 10 20-22
  • Wicking time suggest that the spray dried composites exhibits lesser wicking time indicating rapid disintegration of these tablets. Between spray dried mannitol and the composite of the present invention, the composite gives much reduced wicking time.
    • Example 12 Orally Disintegrating Tablets of Drugs Having No Bitter Taste
  • TABLE 4
    Compositions of orally disintegrating tablets
    Ingredients mg/tablet mg/tablet
    Clonazepam 0.5 —
    Loratadine — 10.0
    Composite of example 3 55.0 45.0
    Starch 22.5 18.0
    Croscarmellose sodium 3.5 4.0
    Calcium silicate 5.0 5.0
    Aspartame 1.5 2.0
    Colloidal silicon dioxide 0.8 0.8
    Flavor 5.0 0.5
    Polyethylene Glycol 0.2 4.2
    Sodium stearyl fumarate 0.5 0.5
    Total 90.0 90.0
  • The drug and the composite was mixed to get a premix. This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets. All the tablets had good mouth feel and disintegrated in mouth within 60 sec.
    • Example 13 Orally Disintegrating Tablets of Tramadol Hydrochloride
  • Ingredients mg/tablet
    Taste masked tramadol equivalent to 50 mg 108.0
    tramadol hydrochloride
    Composite of example 3 57.0
    Starch 18.0
    Microcrystalline cellulose 14.0
    Croscarmellose sodium 4.5
    Sucralose 0.25
    Aspartame 2.0
    Colloidal silicon dioxide 0.8
    Polyethylene Glycol 4.0
    Flavor 0.75
    Sodium stearyl fumarate 0.5
    Total 210
  • The drug and the composite was mixed to get a premix. This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets.
  • All the tablets had good mouth feel and disintegrated in mouth within 60 sec.
    • Example 14 Orally Disintegrating Tablets of Taste Masked Donepezil
  • Ingredients mg/tablet
    Taste masked Donepezil equivalent to 45.0
    10 mg Donepezil
    Composite of example 3 60.0
    Starch 18.0
    Microcrystalline cellulose 10.0
    Croscarmellose sodium 5.5
    Calcium silicate 5.0
    Aspartame 3.0
    Colloidal silicon dioxide 0.8
    Sodium chloride 3.5
    Flavor 0.2
    Sodium stearyl fumarate 0.5
    Total 150.0
  • The drug and the composite was mixed to get a premix. This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets having a lag time of less than 5 sec.
    • Example 15 Orally Disintegrating Tablets of High Dose Bitter Drug Paracetamol
  • Ingredients mg/tablet
    Taste masked paracetamol equivalent to 200
    125 mg of paracetamol
    Coprocessed composite of example 2 100
    Starch 45
    Microcrystalline cellulose 25
    Croscarmellose sodium 7.0
    Calcium silicate 10
    Aspartame 4.0
    Colloidal silicon dioxide 1.5
    Polyethylene Glycol 5.5
    Flavor 1.5
    Sodium chloride 4.0
    Sodium stearyl fumarate 1.5
    Total 405
  • The drug and the composite were mixed to get a premix. This premix was further mixed with other inactive ingredients, lubricated and compressed into tablets. Tablets had desired wicking time of about 55 sec and a good mouth feel.
    • Example 16 Taste-Masked Aripiprazole Incorporated in Tablets Along with Spray-Dried ODT Excipient Prepared in Example 5
  • Ingredients (mg/tablet)
    Taste-masked Aripiprazole 30.0
    Equivalet to 10.0 mg Aripiprazole
    ODT Excipient (example 5) 60.0
    Maize starch 18.0
    Microcrystalline cellulose 6.0
    PEG 4000 5.0
    Polyplasdone 7.5
    Aspartame 1.0
    Peppermint 0.5
    Blue FD & C 0.2
    Magnesium stearate 1.0
    Aerosil 200 0.8
    Total 130.0
    • Process:
  • The ingredients were sieved through 40# sieve along with taste-masked drug. The sieved mix was blended to homogenize, lubricated and compressed to obtain 130 mg tablets of the following properties:
  •
    Hardness (N) 15-22
    Friability (%) 0.75
    Disintegration time (sec) 15
    Disintegration time in oral cavity (sec) 30-40

    Tablets had desired disintegration time of about 30-40 sec in oral cavity and a good mouth feel. The lag time was about 4 seconds
    • Example 17 Taste-Masked Ropinirole Incorporated in Tablets Comprising Physical Mix of Spray-Dried Mannitol and Calcium Silicate in the Ratio 9:1
  • Ingredients (mg/tablet)
    Taste-masked ropinirole 10.0
    equivalent to 2.5 mg ropinirole
    Coprocessed excipient of example 6 30.0
    Xylitol 17.0
    Maize starch 8.0
    Microcrystalline cellulose 10.0
    PEG 4000 5.0
    Polyplasdone 7.5
    Aspartame 2.0
    Peppermint 0.5
    Blue FD & C 0.2
    Magnesium stearate 1.0
    Aerosil 200 8.8
    Total 100.0
    • Process:
  • The ingredients were sieved through 40# sieve along with taste-masked drug. The sieved mix was blended to homogenize, lubricated and compressed to obtain 100 mg tablets of the following properties:
  •
    Hardness (N) 20-25
    Friability (%) 0.5
    Wicking time (sec) 30
    Disintegration time in oral cavity (sec) 30
    • Example 18 Orally Disintegrating Tablets of Enteric Coated Esomeprazole
  • Ingredients (mg/tablet)
    Enteric-coated esomeprazole pellets equivalent to 35.0
    20 mg esomeprazole
    ODT Excipient (example 7) 140.0
    Silicified Microcrystalline cellulose 60.0
    PEG 4000 5.0
    Polyplasdone 7.5
    Aspartame 0.45
    Peppermint 0.25
    Magnesium stearate 1.0
    Aerosil 200 0.8
    Total 250.0
    • Process:
  • The ingredients were sieved through 40# sieve along and was blended to homogenize, lubricated and compressed to obtain 250 mg tablets of the following properties:
  •
    Hardness (N) 40
    Friability (%) 0.6
    Wicking time (sec) 45
    Disintegration time in oral cavity (sec) 50
    • Example 19 Orally Disintegrating Tablets of Memantine
  • Ingredients (mg/tablet)
    Taste-masked memantine 40.0
    equivalent to 20.0 mg memantine
    ODT Excipient (example 7) 115.0
    Pregelatinised starch 18.0
    Powdered cellulose 24.0
    Sodium chloride 2.0
    Polyplasdone 7.5
    Sodium saccharine 1.0
    Orange flavor 0.5
    Blue FD & C 0.2
    Magnesium stearate 1.0
    Aerosil 200 0.8
    Total 210.0
    • Process:
  • The ingredients were sieved through 40# sieve along with taste-masked drug. The sieved mix was blended to homogenize, lubricated and compressed to obtain 210 mg tablets of the following properties:
  •
    Hardness (N) 45
    Friability (%) 0.3
    Wicking time (sec) 48
    Disintegration time in oral cavity (sec) 40-50

Claims (35)

1. A directly compressible composite for an orally disintegrating tablet comprising at least one water-soluble excipient and calcium silicate prepared by co-processing.
2. A directly compressible composite as claimed in claim 1, wherein the water soluble excipient is a carbohydrate, a water soluble salt or a polyhydric alcohol or its derivative.
3. A directly compressible composite as claimed in claim 2, wherein the water soluble carbohydrate is a monosaccharide, disaccharide, oligosaccharide or polysaccharide.
4. A directly compressible composite as claimed in claim 3, wherein the monosaccharide is xylose, glucose, mannose, fructose, galactose, and sorbitol.
5. A directly compressible composite as claimed in claim 3, wherein the disaccharide is maltose, lactose, cellobiose, sucrose, mannitol and trehalose.
6. A directly compressible composite as claimed in claim 3, wherein the oligosaccharide is raffinose and dextrates.
7. A directly compressible composite as claimed in claim 3, wherein the polysaccharide is maltodextrins.
8. A directly compressible composite as claimed in claim 2, wherein the water soluble salt is sodium chloride.
9. A directly compressible composite as claimed in claim 2, wherein the water soluble polyhydric alcohol is propylene glycol, polyethylene glycol and glycerin.
10. A directly compressible composite as claimed in claim 1, wherein calcium silicate has an aspect ratio of about 1:1 to about 2.5:1 and an oil absorption of from about 20 ml/100 gm to 220 ml/100 gm.
11. A directly compressible composite as claimed in claim 1 wherein the ratio of at least one water-soluble excipient and calcium silicate is from about 50:1 to about 1:50.
12. A directly compressible composite as claimed in claim 1 wherein the ratio of at least one water-soluble excipient and calcium silicate is preferably from about 30:1 to about 1:30 and more preferably from about 20:1 to about 1:20.
13. A directly compressible composite as claimed in claim 1 wherein the composite has not less than 40% of particles less than 150 microns.
14. A directly compressible composite as claimed in claim 1 wherein the composite has loss on drying of less than 2% w/w.
15. A directly compressible composite as claimed in claim 1 wherein the composite has porosity of at least about 50%.
16. A method for producing a directly compressible composite as claimed in claim 1, wherein co-processing involves processes such as physical mixing, wet mixing, complexation, precipitation, spray drying, lyophilization, microencapsulation, spray congealing, hot melt, gas antisolvent or rapid evaporation of supercritical solvent methods employed with supercritical fluid processing.
17. A method for producing a directly compressible composite as claimed in claim 1, wherein co-processing involves spray drying.
18. A method for producing a directly compressible composite as claimed in claim 1, wherein the spray drying method comprises:
a. Dissolving the water soluble excipient in water.
b. Adding calcium silicate with stirring to solution of step-a.
c. Homogenising the blend to make it uniform.
d. Drying the mixture in an air stream,
e. Forming the co-processed excipient.
19. A method for producing a directly compressible composite wherein the spray drying method comprises:
a. Dissolving mannitol in water.
b. Adding calcium silicate under stirring to solution of step-a.
c. Homogenising the blend to make it uniform.
d. Drying the mixture in an air stream,
e. Forming the co-processed excipient.
20. An orally disintegrating tablet formulation having optimal mechanical strength comprising
a. at least one pharmaceutically active ingredient or a nutraceutical agent
b. composites produced by co-processing of at least one water soluble excipient and calcium silicate.
c. At least one other excipient.
such that the tablet has optimal mechanical strength and a disintegration time of about 60 seconds in the oral cavity,
21. An orally disintegrating tablet as claimed in claim 20, wherein the active ingredient is selected from gastrointestinal function conditioning agents anti-inflammatory agents, including, but not limited to aceclofenac, ibuprofen, diclofenac, flubiprofen, piroxicam, sulindac, and celecoxib; analgesics, including, but not limited to acetaminophen, fentanyl, tramadol and aspirin; agents for erectile dysfunction therapy, including, but not limited to sildenafil and apomorphine; anti-migraines, including, but not limited to sumatriptan, rizatriptan, zolmitriptan, naratriptan and ergotamin; antihistaminic agents, including, but not limited to loratadine, fexofenadine, pseudoephedrine and cetirizine; cardiovascular agents, including, but not limited to nitroglycerine and isosorbide dinitrate; diuretics, including, but not limited to furocemide and spironolactone; anti-hypertensive agents, including, but not limited to propranolol, amlodipine, felodipine, nifedipine, captoprile, ramiprile, atenolol, and diltiazem; anti-hypolipidemic agents, including, but not limited to simvistatin, atrovastatin, and pravastatin; anti-ulcer agents, including, but not limited to cimietidine, ranitidine, famotidine, omeprazole, esomeprazole, rabeprazole and lansoprazol; anti emetics, including, but not limited to meclizine hydrochloride, ondansetron, granisetron, ramosetron, and tropisetron; anticoagulants such as ticlopidine hydrochloride, dicumarol, or warfarin potassium; antiepileptics such as phenyloin sodium, and lamotrigine, anti-asthmatic agents, including, but not limited to aminophylline, theophylline, terbuttaline, fenoterol, formoterol, and ketotifen; brain metabolism altering drugs such as meclofenoxate hydrochloride; minor tranquilizers such as oxazolam, diazepam, clonazepam, clotiazepam, medazepam, temazepam, fludiazepam, nitrazepam, alprazolam, lorazepam or chlordiazepoxide; anti-depressants, including, but not limited to fluoxetine, mirtazepine, escitalopram and sertraline; drugs for treatment of parkinson's disease or restless leg syndrome such as ropinirole hydrochloride; drug for alzheimer's disease such as memantine; drugs for schizophrenia such as risperidone, olanzepine and aripiprazole; oral antibacterial and antifungal agents such as penicillin, ampicillin, amoxicillin, cephalexin, erythromycin ethylsuccinate, acampicillin hydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline, erythromycin, fluconazole, itraconazole, ketoconazole, miconazole or terbinafine; synthetic antibacterial agents such as nalidixic acid, piromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, or sulfamethoxazole trimethoprim; antipasmodics such as propantheline bromide, atropine sulfate, oxapium bromide, timepidium bromide, antitussive, anti-asthmatic agents; muscle relaxants such as chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorozoxazone, phenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, or dantrolene sodium; oral antidiabetic agents such as glibenclamide, tolbutamide, or glymidine sodium; circulatory agents such as ubidecarenone or ATP-2Na; iron preparations such as ferrous sulfate or dried ferrous sulfate; vitamins such as vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K or folic acid; pollakiuria remedies such as flavoxate hydrochloride, oxybutynin hydrochloride, terodiline hydrochloride, or 4-diethylamino-1,1-dimethyl-2-butynyl (I)-a-cyclohexyl-oc-phenylglycolate hydrochloride; angiotensin-converting enzyme inhibitors such as enalapril maleate, anti-viral agents such as trisodium phosphonoformate, didanosine, dideoxycytidine, azido-deoxythymidine, didehydro-deoxythymidine, adefovir dipivoxil, abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir or stavudine and combinations thereof.
22. An orally disintegrating tablet as claimed in claim 20, wherein nutraceutical ingredients include agents that have a beneficial effect on human health such as coenzyme Q-10, chondroitoin, echinacea, ephedra, glucosamine, garlic, ginkgo biloba, ginseng, grape seed extract, guarana, hawthorn, herbs, kava, kola nut, lutein, St. John's wort, vinpocetine, and yohimbe and combinations thereof.
23. An orally disintegrating tablet as claimed in claim 20, wherein excipient is selected from a group of one or more binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, suitable taste masking agents, viscosity builders, glidants or lubricants, solubilizers, and stabilizers.
24. An orally disintegrating tablet as claimed in claim 23, wherein the super disintegrant is natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems.
25. An orally disintegrating tablet as claimed in claim 24, wherein the preferred super disintegrants are crospovidone and starch.
26. An orally disintegrating tablet as claimed in claim 23, wherein the binder is starch, pregelatinized starch, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.
27. An orally disintegrating tablet as claimed in claim 23, wherein the diluent is starch, dicalcium phosphate, microcrystalline cellulose and the like.
28. An orally disintegrating tablet as claimed in claim 23, wherein the lubricant is magnesium stearate, calcium stearate, stearic acid, talc, and sodium fumarate stearate.
29. An orally disintegrating tablet as claimed in claim 23, wherein the glidant is selected from colloidal silica, silica gel, precipitated silica and combinations thereof.
30. An orally disintegrating tablet as claimed in claim 23, wherein the salivating agent is micronised polyethylene glycol, sodium chloride and precipitated micronised silica.
31. An orally disintegrating tablet as claimed in claim 23, wherein the sweetener is aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate.
32. An orally disintegrating tablet of claim 20 wherein the wicking time of the tablets is less than 60 seconds
33. An orally disintegrating tablet of claim 20 wherein the lag time for mouth disintegration is less than 10 seconds
34. An orally disintegrating tablet of claim 20 wherein the disintegration time is less than 60 seconds in the oral cavity
35. An orally disintegrating tablet formulation having optimal mechanical strength comprising
a. at least one pharmaceutically active ingredient or a nutraceutical agent
b. composites produced by co-processing of mannitol and calcium silicate.
c. At least one other excipient.
such that the tablet has optimal mechanical strength and a disintegration time of about 60 seconds in the oral cavity,
US12/293,857 2006-03-31 2007-03-30 Orally Disintegrating Tablets Abandoned US20090208576A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN498/MUM/2006 2006-03-31
IN498MU2006 2006-03-31
PCT/IN2007/000138 WO2007113856A2 (en) 2006-03-31 2007-03-30 Directly compressible composite for orally disintegrating tablets

Publications (1)

Publication Number Publication Date
US20090208576A1 true US20090208576A1 (en) 2009-08-20

Family

ID=38562805

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/293,857 Abandoned US20090208576A1 (en) 2006-03-31 2007-03-30 Orally Disintegrating Tablets
US12/270,905 Expired - Fee Related US8545890B2 (en) 2006-03-31 2008-11-14 Orally disintegrating tablets

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/270,905 Expired - Fee Related US8545890B2 (en) 2006-03-31 2008-11-14 Orally disintegrating tablets

Country Status (13)

Country Link
US (2) US20090208576A1 (en)
EP (1) EP2001450B1 (en)
JP (1) JP5535616B2 (en)
KR (1) KR101324898B1 (en)
CN (1) CN101460150B (en)
AU (1) AU2007232098A1 (en)
BR (1) BRPI0709909A2 (en)
CA (1) CA2650498A1 (en)
IL (1) IL194355A0 (en)
MX (1) MX2008012299A (en)
NO (1) NO20084612L (en)
NZ (1) NZ572106A (en)
WO (1) WO2007113856A2 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110053942A1 (en) * 2008-02-13 2011-03-03 Dainippon Sumitomo Pharma Co., Ltd. Orally disintegrating tablets
WO2011152875A1 (en) * 2010-06-03 2011-12-08 Bayer Healthcare Llc Chewable, swallowable and effervescent solid dosge form for oral delivery of pharmaeutical actives
US8501816B2 (en) 2010-10-12 2013-08-06 Cerecor, Inc. Antitussive compositions comprising memantine
WO2013155054A1 (en) * 2012-04-12 2013-10-17 Cerecor Inc. Compositions and methods for treating cough
EP2666464A1 (en) 2012-05-24 2013-11-27 Substipharm Developpement Stable pharmaceutical composition comprising aripirazole
US8637540B2 (en) 2003-11-26 2014-01-28 Acura Pharmaceuticals Compositions for deterring abuse of opioid containing dosage forms
WO2014173515A1 (en) * 2013-04-22 2014-10-30 Pharmathen S.A. Pharmaceutical composition comprising an atypical antipsychotic agent and method for the preparation thereof
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US8920839B2 (en) 2009-05-20 2014-12-30 Sumitomo Dainippon Pharma Co., Ltd. Dry-coated orally-disintegrating tablet
US20150104512A1 (en) * 2012-04-27 2015-04-16 Merck Patent Gmbh Coated tablets and the production thereof
US20150157660A1 (en) * 2013-12-10 2015-06-11 Lifewave, Inc. Nutritional product composition for energy
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US20160095818A1 (en) * 2013-06-03 2016-04-07 Mcneil Ab Solid pharmaceutical dosage form for release of at least one active pharmaceutical ingredient in the oral cavity
US9616029B2 (en) 2014-03-26 2017-04-11 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
US10226413B2 (en) 2013-11-15 2019-03-12 Damy Chemical Co., Ltd. Solution solubilization composition of insoluble material and method for solubilizing insoluble material using same
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US20220211668A1 (en) * 2013-03-15 2022-07-07 Aprecia Pharmaceuticals LLC Rapid disperse dosage form
WO2023088885A1 (en) * 2021-11-16 2023-05-25 Dsm Ip Assets B.V. Granules obtainable by continuous melt granulation
WO2025012877A1 (en) * 2023-07-13 2025-01-16 Posi Visionary Solutions Llp Orodispersible clonazepam pharmaceutical composition

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9198862B2 (en) * 2005-07-22 2015-12-01 Rubicon Research Private Limited Dispersible tablet composition
US8497258B2 (en) 2005-11-12 2013-07-30 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
CN101460150B (en) 2006-03-31 2014-02-12 鲁比康研究私人有限公司 Directly compressible compounds for orally disintegrating tablets
US20100092564A1 (en) * 2006-12-21 2010-04-15 Jae Han Park Composition of and Method for Preparing Orally Disintegrating Tablets
HUP0700485A3 (en) * 2007-07-23 2010-01-28 Richter Gedeon Nyrt Pharmaceutical composition with controlled release containing tolperisone
CA2703501C (en) 2007-10-01 2017-06-13 Laboratorios Lesvi, S.L. Orodispersible tablets
WO2009084017A2 (en) * 2007-10-10 2009-07-09 Rubicon Research Private Limited Taste-masked orally disintegrating tablets of memantine hydrochloride
WO2009078034A2 (en) * 2007-11-26 2009-06-25 Rubicon Research Private Limited Oral disintegrating tablets of ropinirole hydrochloride
KR101075556B1 (en) * 2008-11-21 2011-10-20 씨제이제일제당 (주) Orally fast-disintegrating tablets and processes for the preparation thereof
EP2198857A1 (en) 2008-12-19 2010-06-23 Ratiopharm GmbH Oral dispersible tablet
US20100179202A1 (en) * 2009-01-14 2010-07-15 Ajanta Pharma Limited. Orally disintegrating composition of zolmitriptan
WO2010094471A1 (en) 2009-02-17 2010-08-26 Krka, D. D., Novo Mesto Pharmaceutical compositions comprising prasugrel base or its pharmaceutically acceptable acid addition salts and processes for their preparation
CN102355890A (en) * 2009-03-16 2012-02-15 尼普洛株式会社 Orally disintegrating tablet
US20120178822A1 (en) * 2009-04-28 2012-07-12 Isp Investments Inc. Co-Processed Excipient Compositions
WO2010144865A2 (en) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
WO2011001214A1 (en) * 2009-06-30 2011-01-06 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Surface amorphization of phenprobamate
EP2451446B1 (en) * 2009-07-10 2014-03-05 Merck Patent GmbH Composition for the production of tablets, and method for the production of said composition
WO2011030351A2 (en) 2009-09-03 2011-03-17 Rubicon Research Private Limited Taste - masked pharmaceutical compositions
EP2477609A1 (en) * 2009-09-15 2012-07-25 Ratiopharm GmbH Orally disintegrating pharmaceutical dosage form containing aripiprazole
EP2316434A1 (en) * 2009-10-22 2011-05-04 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Orally disintegrating tablets of memantine
CN103284968B (en) * 2010-04-13 2015-11-18 齐鲁制药有限公司 Oral cavity disintegration tablet of a kind of aripiprazole composition microcrystalline and preparation method thereof
EP2384742A1 (en) 2010-05-03 2011-11-09 The Jordanian Pharmaceutical Manufacturing Co. Pharmaceutical excipient, method for its preparation and use thereof
JP5665372B2 (en) * 2010-06-02 2015-02-04 旭化成ケミカルズ株式会社 Fast disintegrating solid preparation
JP5785548B2 (en) * 2010-08-04 2015-09-30 武田薬品工業株式会社 Fused heterocyclic compounds
EP2468254A1 (en) * 2010-12-15 2012-06-27 Hexal AG Orally disintegrating tablet having a taste masking effect
WO2013019056A1 (en) * 2011-08-01 2013-02-07 Sam-A Pharm. Co., Ltd. Novel granule formulation containing sildenafil or pharmaceutically acceptable salts thereof as an active ingredient
US10806685B2 (en) * 2011-09-30 2020-10-20 Rubicon Research Private Limited Oral care compositions
WO2013058721A1 (en) * 2011-10-13 2013-04-25 Mahmut Bilgic Pharmaceutical granules and production method
CN102525978B (en) * 2012-02-07 2013-08-07 海南卫康制药(潜山)有限公司 Children amoxicillin-potassium clavulanate composition
WO2013125617A1 (en) * 2012-02-22 2013-08-29 富山化学工業株式会社 Solid pharmaceutical composition containing 1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or salt thereof
CN102631331A (en) * 2012-04-26 2012-08-15 北京哈三联科技股份有限公司 Olanzapine oral disintegration tablet and preparation method thereof
CN103385859A (en) * 2012-05-08 2013-11-13 中国人民解放军成都军区总医院 Propranolol hydrochloride oral disintegrating tablet used for treating post-traumatic stress disorder, and preparation method thereof
WO2014007775A1 (en) * 2012-07-02 2014-01-09 Mahmut Bilgic A novel formulation having fast dissolution
FR2999432B1 (en) * 2012-12-17 2014-12-12 Ethypharm Sa ORODISPERSIBLE COMPRESSES OBTAINED BY COMPRESSION MOLDING
CN103127024B (en) * 2013-03-12 2014-10-15 成都天台山制药有限公司 Stable disodium adenosine triphosphate tablet
JP5713421B1 (en) 2013-07-19 2015-05-07 株式会社三和化学研究所 Orally disintegrating tablets
KR101428018B1 (en) * 2013-10-18 2014-08-12 주식회사 한독 Orally disintegrating tablet containing aripiprazole and manufacturing method thereof
CN104027319A (en) * 2014-06-25 2014-09-10 万特制药(海南)有限公司 Celecoxib dispersible tablet and preparation method thereof
BR112017006141A2 (en) * 2014-09-24 2018-02-06 Wellesley Pharmaceuticals Llc pharmaceutical compositions and their uses and methods for reducing patient bladder spasms
CN104490832A (en) * 2014-12-05 2015-04-08 海南卫康制药(潜山)有限公司 Lyophilized tablet prepared from warfarin composition and preparation method thereof
DE202016008304U1 (en) 2015-01-22 2017-07-05 Pfeifer & Langen GmbH & Co. KG Cellobiose in compositions for consumption or ingestion
CN105935445B (en) * 2016-03-28 2019-02-01 赤峰赛林泰药业有限公司 Pharmaceutical composition and preparation method thereof containing 2- (- 4- isobutyl phenenyl) propionic acid dextrogyre
TR201617675A2 (en) 2016-12-02 2018-06-21 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi DISTRIBUTED TABLET FORM OF ARIPIPRAZOLE MONOHYDRATE FORMULATIONS
JP6838474B2 (en) * 2017-04-14 2021-03-03 大正製薬株式会社 Solid composition
US10350171B2 (en) 2017-07-06 2019-07-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same
CN107334744B (en) * 2017-07-24 2020-09-04 湖南洞庭药业股份有限公司 Memantine hydrochloride medicine composition and preparation method thereof
CN109806232A (en) * 2017-11-20 2019-05-28 四川科瑞德制药股份有限公司 Tizanidine oral disintegrating tablet and preparation method thereof
CN110613691A (en) * 2018-06-19 2019-12-27 北京万全德众医药生物技术有限公司 Orally disintegrating tablet containing PEG-DSPE-memantine hydrochloride compound
JP2019069991A (en) * 2018-12-27 2019-05-09 ウェルズリー ファーマスーティカルズ、エルエルシー Pharmaceutical formulations for reducing bladder spasms and use methods thereof
EP4248955A3 (en) * 2019-01-15 2023-11-22 Dr. Willmar Schwabe GmbH & Co. KG Method for the preparation of easily consumable tablets containing ginkgo biloba leaf extract
CN109975461B (en) * 2019-04-10 2022-03-22 中生北控生物科技股份有限公司 Calibration material and quality control material for mass spectrometry detection of vitamin D and metabolites thereof, and preparation method and application thereof
CN111419816A (en) * 2020-04-28 2020-07-17 广东润源中天生物科技有限公司 Vitamin B tablets and production method thereof
RS63725B1 (en) 2020-05-18 2022-12-30 Orexo Ab NEW PHARMACEUTICAL COMPOSITION FOR DRUG ADMINISTRATION
CN111838663A (en) * 2020-08-05 2020-10-30 田井文 A Chinese medicinal composition for tonifying yang and invigorating kidney, and its preparation method
CN113712926A (en) * 2021-08-31 2021-11-30 南京恒正药物研究院有限公司 Sildenafil orally disintegrating tablet
GB202117016D0 (en) 2021-11-25 2022-01-12 Orexo Ab New pharmaceutical device
IL313016A (en) 2021-11-25 2024-07-01 Orexo Ab Pharmaceutical composition comprising adrenaline
CN115089552B (en) * 2022-06-10 2024-03-29 南京瑞捷医药科技有限公司 Ibuprofen orally disintegrating tablet
US20240408042A1 (en) * 2023-06-08 2024-12-12 Clinical Research Associates LLC Orally disintegrating baclofen compositions and methods of making same

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060276473A1 (en) * 2004-03-17 2006-12-07 Keith Bostion Use and administration of bacterial efflux pump inhibitors
US20070048374A1 (en) * 2005-08-24 2007-03-01 Wyeth Bazedoxifene acetate formulations
US20070077301A1 (en) * 2002-12-23 2007-04-05 Meyer Glenn A Venlafaxine osmotic device formulation
US20070104785A1 (en) * 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
US20070110808A1 (en) * 2003-06-05 2007-05-17 Alembic Limited Extended release osmo-microsealed formulation
US20070196475A1 (en) * 2004-04-30 2007-08-23 Withiam Michael C Rapidly disintegrating low friability tablets comprising silica materials
US20070269510A1 (en) * 2004-09-29 2007-11-22 Sudarshan Nimbalkar Solid Unit Dosage Forms of 5-Ht1 Agonist
US20070275059A1 (en) * 2000-04-12 2007-11-29 Sanjeev Kothari Flashmelt oral dosage formulation
US20070275058A1 (en) * 2003-10-15 2007-11-29 Fuji Chemical Industry Co., Ltd. Tablet Quickly Disintegrating in Oral Cavity
US20070298107A1 (en) * 2003-11-25 2007-12-27 Aurobindo Pharma Ltd. Pharmaceutical Compositions of Mirtazapine

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4293539A (en) * 1979-09-12 1981-10-06 Eli Lilly And Company Controlled release formulations and method of treatment
US4480068A (en) * 1981-09-14 1984-10-30 Fiberglas Canada Inc. High temperature resistant binders
US4719181A (en) * 1985-12-20 1988-01-12 Warner-Lambert Company Free flowing granular indicator material for peroxidase-like activity
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US5178878A (en) * 1989-10-02 1993-01-12 Cima Labs, Inc. Effervescent dosage form with microparticles
AU646232B2 (en) 1989-10-02 1994-02-17 Cima Labs, Inc. Effervescent dosage form and method of administering same
DK546289D0 (en) * 1989-11-02 1989-11-02 Danochemo As carotenoid
US5464632C1 (en) * 1991-07-22 2001-02-20 Prographarm Lab Rapidly disintegratable multiparticular tablet
US5298261A (en) * 1992-04-20 1994-03-29 Oregon Freeze Dry, Inc. Rapidly distintegrating tablet
US5576014A (en) * 1994-01-31 1996-11-19 Yamanouchi Pharmaceutical Co., Ltd Intrabuccally dissolving compressed moldings and production process thereof
DE4439858A1 (en) * 1994-11-08 1996-05-09 Merck Patent Gmbh By co-spray drying available polyol composition
JP2000507587A (en) 1996-04-03 2000-06-20 メルク エンド カンパニー インコーポレーテッド Farnesyl protein transferase inhibitor
DE19615418A1 (en) * 1996-04-22 1997-10-23 Merck Patent Gmbh Polyol composition
ATE477793T1 (en) * 1996-06-14 2010-09-15 Kyowa Hakko Kirin Co Ltd A TABLET THAT DISAPPOINTS QUICKLY IN THE MOUTH
US20030203036A1 (en) * 2000-03-17 2003-10-30 Gordon Marc S. Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
JP4494539B2 (en) * 1997-02-28 2010-06-30 ディーエスエム アイピー アセッツ ビー．ブイ． Free-flowing dry particles
US6696484B2 (en) * 1997-10-31 2004-02-24 University Of Chicago Office Of Technology And Intellectual Property Method and compositions for regulation of 5-alpha reductase activity
JPH11302157A (en) 1998-04-17 1999-11-02 Eisai Co Ltd Tablet quickly disintegrating in oral cavity
ES2559766T3 (en) * 1998-05-18 2016-02-15 Takeda Pharmaceutical Company Limited Disintegrable tablets in the mouth
KR100421264B1 (en) * 1998-07-15 2004-03-18 아사히 가세이 가부시키가이샤 Excipient
WO2000006126A1 (en) * 1998-07-28 2000-02-10 Takeda Chemical Industries, Ltd. Rapidly disintegrable solid preparation
JP2000086537A (en) 1998-09-11 2000-03-28 Fuji Chem Ind Co Ltd Inorganic compound saccharide composition, vehicle, rapidly disintegrating compression molded product, and their production
AU3574500A (en) * 1999-03-25 2000-10-16 Yuhan Corporation Rapidly disintegrable tablet for oral administration
CA2374760A1 (en) * 1999-06-18 2000-12-28 Takeda Chemical Industries, Ltd. Quickly disintegrating solid preparations
US20020076437A1 (en) * 2000-04-12 2002-06-20 Sanjeev Kothari Flashmelt oral dosage formulation
CA2311734C (en) * 2000-04-12 2011-03-08 Bristol-Myers Squibb Company Flash-melt oral dosage formulation
DK1294383T3 (en) * 2000-06-30 2008-11-10 Procter & Gamble Oral compositions comprising antimicrobial agents to prevent systemic diseases
US20020098999A1 (en) * 2000-10-06 2002-07-25 Gallop Mark A. Compounds for sustained release of orally delivered drugs
CA2440361A1 (en) * 2001-03-06 2002-09-12 Kyowa Hakko Kogyo Co. Ltd. Intraorally rapidly disintegrable preparation
US6872405B2 (en) * 2001-05-10 2005-03-29 Yamanouchi Pharmaceutical Co., Ltd. Quick-disintegrating tablet in buccal cavity and manufacturing method thereof
US6610266B2 (en) * 2001-11-28 2003-08-26 Michael C. Withiam Calcium metasilicates and methods for making
DE10161402A1 (en) * 2001-12-13 2003-06-18 Merck Patent Gmbh Process for the production of directly tablettable beta-mannitol
US7118765B2 (en) * 2001-12-17 2006-10-10 Spi Pharma, Inc. Co-processed carbohydrate system as a quick-dissolve matrix for solid dosage forms
EP1488811A1 (en) * 2002-03-06 2004-12-22 Kyowa Hakko Kogyo Co., Ltd. Tablets quickly disintegrating in oral cavity
US6738873B2 (en) * 2002-05-24 2004-05-18 Sun Microsystems, Inc. Memory management system supporting deletion of transient objects
US20060163534A1 (en) * 2002-10-08 2006-07-27 Ken Sugimoto Oxygen scavenger composition
EP1595533B1 (en) * 2003-01-21 2010-01-06 Nippon Shinyaku Co., Ltd. Tablet quickly melting in oral cavity
FR2851734B1 (en) * 2003-02-28 2006-06-09 Galenix Innovations PROCESS FOR THE PRODUCTION OF A PHARMACEUTICAL COMPOSITION IN THE FORM OF TABLETS CONTAINING A FIBRATE AND COMPRESSES OBTAINED BY THE PROCESS
WO2004082664A1 (en) 2003-03-21 2004-09-30 Ranbaxy Laboratories Limited Water-soluble tablets of metformin
KR100503949B1 (en) 2003-04-28 2005-07-26 주식회사유한양행 A composition of fast dissolving tablets effectively masked bitter taste of ondansetron hydrochloride
JP3841804B2 (en) * 2003-10-15 2006-11-08 富士化学工業株式会社 Composition for intraorally rapidly disintegrating tablets
JP2006052167A (en) * 2004-08-11 2006-02-23 Rohto Pharmaceut Co Ltd Tablet composition
EP1681048A1 (en) * 2005-01-14 2006-07-19 Krka Tovarna Zdravil, D.D., Novo Mesto Orally disintegrating composition of olanzapine or donepezil
CA2600533A1 (en) 2005-03-24 2006-09-28 Daiichi Sankyo Company, Limited Pharmaceutical composition
EP1990062A1 (en) 2006-02-20 2008-11-12 ASAHI BREWERIES, Ltd. Granules, tablets and method of producing the same
CN101460150B (en) 2006-03-31 2014-02-12 鲁比康研究私人有限公司 Directly compressible compounds for orally disintegrating tablets
US20070243248A1 (en) * 2006-04-14 2007-10-18 Cherukuri S Rao Rapidly disintegrating solid oral dosage form of liquid dispersions
AU2007338751A1 (en) 2006-12-21 2008-07-03 Mallinckrodt Inc. Composition of and method for preparing orally disintegrating tablets containing a high dose of pharmaceutically active ingredients

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070275059A1 (en) * 2000-04-12 2007-11-29 Sanjeev Kothari Flashmelt oral dosage formulation
US20070077301A1 (en) * 2002-12-23 2007-04-05 Meyer Glenn A Venlafaxine osmotic device formulation
US20070110808A1 (en) * 2003-06-05 2007-05-17 Alembic Limited Extended release osmo-microsealed formulation
US20070275058A1 (en) * 2003-10-15 2007-11-29 Fuji Chemical Industry Co., Ltd. Tablet Quickly Disintegrating in Oral Cavity
US20070298107A1 (en) * 2003-11-25 2007-12-27 Aurobindo Pharma Ltd. Pharmaceutical Compositions of Mirtazapine
US20060276473A1 (en) * 2004-03-17 2006-12-07 Keith Bostion Use and administration of bacterial efflux pump inhibitors
US20070196475A1 (en) * 2004-04-30 2007-08-23 Withiam Michael C Rapidly disintegrating low friability tablets comprising silica materials
US20070269510A1 (en) * 2004-09-29 2007-11-22 Sudarshan Nimbalkar Solid Unit Dosage Forms of 5-Ht1 Agonist
US20070104785A1 (en) * 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
US20070048374A1 (en) * 2005-08-24 2007-03-01 Wyeth Bazedoxifene acetate formulations

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492443B2 (en) 2003-11-26 2016-11-15 Acura Pharmaceuticals, Inc. Abuse deterrent compositions and methods of making same
US8637540B2 (en) 2003-11-26 2014-01-28 Acura Pharmaceuticals Compositions for deterring abuse of opioid containing dosage forms
US8822489B2 (en) 2003-11-26 2014-09-02 Acura Pharmaceuticals Abuse deterrent compositions and methods of making same
US20110053942A1 (en) * 2008-02-13 2011-03-03 Dainippon Sumitomo Pharma Co., Ltd. Orally disintegrating tablets
US8920839B2 (en) 2009-05-20 2014-12-30 Sumitomo Dainippon Pharma Co., Ltd. Dry-coated orally-disintegrating tablet
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US10155044B2 (en) 2009-09-30 2018-12-18 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
WO2011152875A1 (en) * 2010-06-03 2011-12-08 Bayer Healthcare Llc Chewable, swallowable and effervescent solid dosge form for oral delivery of pharmaeutical actives
US8501816B2 (en) 2010-10-12 2013-08-06 Cerecor, Inc. Antitussive compositions comprising memantine
WO2013155054A1 (en) * 2012-04-12 2013-10-17 Cerecor Inc. Compositions and methods for treating cough
US20150104512A1 (en) * 2012-04-27 2015-04-16 Merck Patent Gmbh Coated tablets and the production thereof
EP2666464A1 (en) 2012-05-24 2013-11-27 Substipharm Developpement Stable pharmaceutical composition comprising aripirazole
US10688184B2 (en) 2012-11-30 2020-06-23 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10441657B2 (en) 2012-11-30 2019-10-15 Abuse Deterrent Pharmaceuticals, Llc Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9320796B2 (en) 2012-11-30 2016-04-26 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US11857629B2 (en) 2012-11-30 2024-01-02 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US12396979B2 (en) 2013-03-15 2025-08-26 Aprecia Pharmaceuticals LLC Rapid disperse dosage form
US20220211668A1 (en) * 2013-03-15 2022-07-07 Aprecia Pharmaceuticals LLC Rapid disperse dosage form
WO2014173515A1 (en) * 2013-04-22 2014-10-30 Pharmathen S.A. Pharmaceutical composition comprising an atypical antipsychotic agent and method for the preparation thereof
US20160095818A1 (en) * 2013-06-03 2016-04-07 Mcneil Ab Solid pharmaceutical dosage form for release of at least one active pharmaceutical ingredient in the oral cavity
US10226413B2 (en) 2013-11-15 2019-03-12 Damy Chemical Co., Ltd. Solution solubilization composition of insoluble material and method for solubilizing insoluble material using same
US20150157660A1 (en) * 2013-12-10 2015-06-11 Lifewave, Inc. Nutritional product composition for energy
US9980917B2 (en) 2014-03-26 2018-05-29 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
US9616029B2 (en) 2014-03-26 2017-04-11 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11986554B2 (en) 2015-04-29 2024-05-21 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
WO2023088885A1 (en) * 2021-11-16 2023-05-25 Dsm Ip Assets B.V. Granules obtainable by continuous melt granulation
WO2025012877A1 (en) * 2023-07-13 2025-01-16 Posi Visionary Solutions Llp Orodispersible clonazepam pharmaceutical composition

Also Published As

Publication number Publication date
KR20090008307A (en) 2009-01-21
CN101460150A (en) 2009-06-17
CN101460150B (en) 2014-02-12
WO2007113856A3 (en) 2008-06-05
WO2007113856A2 (en) 2007-10-11
EP2001450A2 (en) 2008-12-17
MX2008012299A (en) 2008-11-18
JP2009532343A (en) 2009-09-10
BRPI0709909A2 (en) 2011-07-26
US8545890B2 (en) 2013-10-01
NZ572106A (en) 2010-12-24
JP5535616B2 (en) 2014-07-02
IL194355A0 (en) 2009-08-03
US20090087485A1 (en) 2009-04-02
AU2007232098A1 (en) 2007-10-11
EP2001450B1 (en) 2019-01-30
CA2650498A1 (en) 2007-10-11
KR101324898B1 (en) 2013-11-04
NO20084612L (en) 2008-10-31

Similar Documents

Publication Publication Date Title
US8545890B2 (en) Orally disintegrating tablets
US20230255891A1 (en) Highly Compactable and Durable Direct Compression Excipients and Excipient Systems
CN108136032A (en) Composite granulate comprising sugar or sugar alcohol, swelling binder, disintegrant and high-absorbency excipient and its production method
KR20030094272A (en) Tablets quickly disintegrating in oral cavity
JP5859664B2 (en) Oral pharmaceutical composition with masked taste of drug and method for producing the same
JP2009114113A (en) Orally disintegrating tablet and method for producing the same
JP2013544849A (en) Rapidly dispersible granules, orally disintegrating tablets, and methods
EP2745848B1 (en) Orally disintegrating tablet containing hydroxyalkyl cellulose fine particles
JP5572321B2 (en) Orally disintegrating tablets containing coated fine particles
JP5433295B2 (en) Xanthan gum-coated water-soluble saccharide and compression-molded preparation
WO2015050209A1 (en) Method for producing tablets
JP5080856B2 (en) Tablets for oral administration
TW201113051A (en) Oral disintegrating tablet and manufacturing method thereof
JP5801266B2 (en) Method for producing tablets containing hydrophobic drugs
WO2016098459A1 (en) Delayed disintegrating particulate composition
WO2013185789A1 (en) Pharmaceutical composition containing phosphate binding polymer
Thabassum DEVELOPMENT AND EVALUATION OF FAST DISSOLVING TABLETS OF ANGIOTENSIN–II RECEPTOR ANTAGONIST BY SUBLIMATION METHOD.
HK1146387A (en) Oral dispersable tablet
HK1166024B (en) Highly compactable and durable direct compression excipients and excipient systems

Legal Events

Date Code Title Description
AS Assignment

Owner name: RUBICON RESEARCH PRIVATE LIMITED, INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PILGAONKAR, PRATIBHA, MRS.;RUSTOMJEE, MAHARUKH, MRS.;GANDHI, ANILKUMAR, DR.;AND OTHERS;REEL/FRAME:021580/0361

Effective date: 20060706

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION