FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10)
TITLE OF THE INVENTION
Orally Disintegrating Tablets


APPLICANTS
Rubicon Research Private Limited, an Indian Company
having its registered office at 221, Annexe Building,
Goregaon-Mulund Link Road, Opposite Indira Container Yard,
Off L.B.S Marg, Bhandup (W), Mumbai 400 078, Maharashtra, India
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention and the manner in which it is to be performed.



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ORALLY DISINTEGRATING TABLETS
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. 5
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.
10 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 15 used techniques arc 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.
20 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. Patent 5298261 discloses freeze- drying a slurry or paste comprising an
25 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
30 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

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and, therefore, require special moisture-and impact-resistant packaging and require careful handling.
US Patent 5464632 claims use of high levels of disintegrants such as 16% starch 1500 5 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.
US Patent 5178878 discloses a rapidly dissolving oral formulation that requires an extragranular microparticulate active in conjunction with an effervescent agent
10 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. US Patent 5178878 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
15 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.
20 Another orally disintegrating technique is spray drying technology as explained in US patent 5958471 and 6165511, 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
25 directly compressible and highly compactible composition by co-spray drying of mannitol and sorbitol solution resulting in nonfilamentous micro structure. Both these patents describe use of highly concentrated aqueous solutions, which are to be maintained and sprayed at high temperature thus demanding special equipment.
30 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

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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). 5 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.
10 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
15 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.
20
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
25 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.
30 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

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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 5 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. 10
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 15 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 20 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%
25 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. 30
It is yet another object of the present invention to develop an orally disintegrating tablet with a lag time of less than 10 seconds.

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It is yet another object of the present invention to develop an orally disintegrating tablet with hardness of at least t ON.
5 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 10 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 15 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
20 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
25 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
30 such tablets would be useful is where water may not be readily available to assist in swallowing the tablet in specific conditions.

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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. 5
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 10
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 15 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. 20
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 25 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. 30

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Composites
Composites are blend of excipients obtained by co-processing of at least one water
soluble excipient and at least one water insoluble excipient.
5 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,
10 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
15 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.
20
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 tricJinic forms thereof, magnesium trisilicate-ortho and meta forms thereof or light anhydrous silicic acid, mica, 25 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 30 aspect ratio of about 1:1 to about 2.5:1 and an oil absorption of from about 20 ml/lOOgm to 220 ml/100 gm. It is a unique physical form of Calcium Silicate, which reduces the disintegration time of a dosage form.

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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.

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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. 5 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%.
10 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
15 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.
20
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
25 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*
30 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,

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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 5 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 simvastatin, atrovastatin, and pravastatin; anti-ulcer agents, including, but not limited to cimietidine, ranitidine, famotidine, omeprazole, esomeprazole, rabeprazole and lansoprazol; anti emetics, 10 including, but not limited to meclizine hydrochoride, ondansetron, granisetron, ramosetron, and tropisetron; anticoagulants such as ticlopidine hydrochloride, dicumarol, or warfarin potassium; antiepileptics such as phenytoin sodium, and lamotrigine, anti¬asthmatic agents, including, but not limited to aminophylline, theophylline, terbuttaline, fenoterol, formoterol, and ketotifen; brain metabolism altering drugs such as 15 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 20 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 25 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 30 hydrochloride, mephenesin, chlorozoxazone, phenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, or dantrolene sodium; oral antidiabetic agents such as glibenclamide, tolbutamide, or glymidine sodium; circulatory

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agents such as ubidecarenone or ATP-2Na; iron preparations such as ferrous sulfate or dried ferrous sulfate; vitamins such as vitamin Bl, 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 5 4-diethylamino-l,I-dimethyl-2-butynyI (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 10 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, 15 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
20 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.
25
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 30 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.

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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 5 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.
10 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, raicrocrystalline cellulose and the like.
15 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,
20 sodium chloride or precipitated micronsied 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,
25 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
30 chosen based on the age of the patient consuming the solid dosage form.

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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 5 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. 10
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.
15 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.
20
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.
25 The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations.

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EXAMPLES
Example 1: Orally disintegrating tablets produced by physical mixing
Table 1: Composition of orally disintegrating tablets

All excipients except lubricant were blended in a blender to get a unifonn 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
10 Tablets with desired friability and disintegration time were obtained.
v

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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 5 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 Outlet Temperature Nozzle diameter Feed rate Atomisation pressure

180-200°C 80-120°C I mm
150-200 ml/Hr 0.7-1.2 Kg/cm2

The composites obtained were free flowing with bulk density in the range of 0.3-0.5 10 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.
15 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 Outlet Temperature
Nozzle diameter Feed rate Atomisation pressure

180-200°C
70-100°C
1 mm
150-200 mi/Hr
3-4 Kg/cm2

20

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10

The composites obtained were free flowing with bulk density of 0.4-0.5 gm/cc
Example 4; Co-processing of mannitol, microcrystailine 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 microcrystailine 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:

15

Inlet Temperature Outlet Temperature Nozzle diameter
Feed rate Atomisation pressure

200-220°C 80-120?C 2.0 mm 70-90 ml/min
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 20 63%.
Example 6: Co-processing of mannitol and calcium silicate by spray drying
600.0g Mannitol was dissolved in 3.0 liter water at room temperature. In this solution 600.0g of calcium silicate was added and stirred to get a uniform mass. The mass was 25 sprayed in the spray dryer under following conditions;

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Inlet Temperature Outlet Temperature Nozzle diameter Feed rate Atomisation pressure

200-205°C 105-125°C 2.0 mm 70-90 ml/min 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 mannitoi, calcium silicate and Polyethylene glycol by spray drying
340.0g Mannitoi and 20.0g 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:
10

Inlet Temperature Outlet Temperature Nozzle diameter Feed rate Atomisation pressure

200-205°C 105-I25°C 2.0 mm 70-90 ml/Hr 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%.
15 Example 8: Co-processing of mannitoi and calcium silicate by spray drying using a rotary disc
900.0g Mannitoi 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:
20 . .

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Inlet Temperature Outlet Temperature Rotary disc radius Rotary disc speed Feed rate

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.
5 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

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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-\ 0
Disintegration time in oral cavity (sec) 40-50 25-40
5 Robust tablets were obtained with low friability and desired disintegration time.
Example 10: Tablet formulation using composite of mannitol, micro crystal line cellulose and calcium silicate
Table 3: Compositions of orally disintegrating tablets using composite of example 4

All excipients except lubricant were blended in a blender to get a unifonn mass. The mass was lubricated and compressed into tablets having following parameters:

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Hardness (N)
Friability (%)
In vitro Disintegration time (sec)
Disintegration time in oral cavity (sec)

10-20 0.8-0.9
8-12 30-40

Robust tablets were obtained with low friability and desired disintegration time.

10
15

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

20

Wicking time suggest that the spray dried composites exhibits lesser wicking rime indicating rapid disintegration of these tablets. Between spray dried mannitol and the composite of the present invention, the composite gives much reduced wicking time.

25

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Example 12: Orally disintegrating tablets of drugs having no bitter taste
Table 4 Compositions of orally disintegrating tablets

The drug and the composite was mixed to get a premix. This premix was further mixed 5 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 tramadol hydrochloride 108.0
Composite of example 3 57.0
Starch 18.0
Microcrystalline cellulose 14.0
Croscarmellose sodium 4.5

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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.
5 All the tablets had good mouth feel and disintegrated in mouth within 60 sec.
Example 14: Orally disintegrating tablets of taste masked donepczil


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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.
5 Example 15: Orally disintegrating tablets of high dose bitter drug paracetamol .

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 10 desired wicking time of about 55 sec and a good mouth feel.
15

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Example 16: Taste-masked Aripiprazole incorporated in Tablets along with spray-dried ODT Excipient prepared in Example 5.

5 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 330mg tablets of the following properties:
10 Hardness (N) 15-22
Friability (%) : 0.75
Disintegration time (sec) 15
Disintegration time in oral cavity (sec) 30-40
15 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

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Example 17: Taste-masked ropinirole incorporated in Tablets comprising physical mix of spray-dried Mannitol and Calcium silicate in the ratio 9:1

5 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 lOOmg tablets of the following properties:
10 Hardness (N) 20-25
Friability (%) : 0.5
Wicking time (sec) : 30
Disintegration time in oral cavity (sec) : 30
15

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Example 18: Orally disintegrating tablets of enteric coated esomeprazoie

Process:
5 The ingredients were sieved through 40# sieve along and was blended to homogenize, lubricated and compressed to obtain 250mg tablets of the following properties:
Hardness (N) 40
Friability (%) : OS
10 Wicking time (sec) : 45
Disintegration time in oral cavity (sec) : 50
15

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Example 19: Orally disintegrating tablets of memantine

Process:
5 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:


10

Hardness (N)
Friability (%)
Wicking time (sec)
Disintegration time in oral cavity (sec)

45
0.3
48
40-50

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CLAIMS
1. A directly compressible composite for an orally disintegrating tablet comprising at least one water-soluble excipient and calcium silicate prepared by co-processing. 5 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. 10 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
15 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.
20 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/lOOgm to 220 ml/100 gm. 25 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 1:5Q. 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. 30 13. A directly compressible composite as claimed in claim 1 wherein the composite has
not less than 40% of particles less than 150 microns.

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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 atleast about 50%.
5 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, lyophil ization, microencapsulation, spray congealing, hot melt, gas antisolvent or rapid evaporation of supercritical solvent methods employed with supercritical fluid processing. 10 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.
15 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
20 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,
25 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
30 and calcium silicate.
c. At least one other excipient.

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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
5 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
10 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 ftirocemide and spironolactone; anti-hypertensive agents, including, but
not limited to propranolol, amlodipine, felodipine, nifedipine, captoprile, ramiprile,
15 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 hydrochoride, ondansetron, granisetron, ramosetron, and tropisetron; anticoagulants
20 such as ticlopidine hydrochloride, dicumarol, or warfarin potassium; antiepileptics
such as phenytoin 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, clonazepam,
25 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
30 and aripiprazole; oral antibacterial and antifungal agents such as penicillin,
ampicillin, amoxicillin, cephalexin, erythromycin ethylsuccinate, acampicillin hydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline,

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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,
5 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
10 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 Bl, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K or folic acid; poilakiuria remedies such as flavoxate hydrochloride, oxybutynin hydrochloride, terodiline
15 hydrochloride, or 4-diethylamino-1,1 -dimethyI-2-butynyI (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,
20 lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir or stavudine and
combinations thereof.
22. An orally disintegrating tablet as claimed in claim 20, wherein nutraceurical
ingredients include agents that have a beneficial effect on human health such as
coenzyme Q-10, chondroitoin, echinacea, ephedra, glucosamine, garlic, ginkgo
25 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
30 agents, suitable taste masking agents, viscosity builders, glidants or lubricants,
solubilizers, and stabilizers.

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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. 5 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 hydroxypropylmethyi cellulose
(HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and
10 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
15 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
20 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
25 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
30 35. An orally disintegrating tablet formulation having optimal mechanical strength comprising a. at least one pharmaceutically active ingredient or a nutraceutical agent

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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,

A
Dated this 30thday of September 2008

karuna Goleria of DePENNING & DePENNING Agent for Applicants