Oral dispersable tablet

The present invention is directed to an oral disintegratable tablet which exhibits oral disintegratability of not more than 60 seconds. The tablet for oral administration, comprises an effective amount of at least one active agent, an amount of at least 50% (w/w) of a water insoluble parts, a surfactant and a disintegrant, such that said tablet is orally disintegretable or dispersable.

Oral dispersable tablets are in principle not different from common immediate release (IR) tablets. They should be mechanically stable, to allow handling during technical operations and handling by the patient or customer. Their disintegration time in aqueous environment should be fast and complete. A softening under the conditions of release, so that weak mechanical stress is sufficient for complete dispersion, is also acceptable.

To improve disintegration properties, several principles are common. For example tablets containing gas-developing mixtures of at least one acid component (like e.g. citric acid) and at least one basic component in form of a carbonate or hydrogen-carbonate. Such a tablet for oral dispersibility is described e.g. in US 2002/01 10578. Another common method is the use of rapidly soluble tablet excipients like e.g. sugar alcohols (Mannitol, Sorbitol, Xylitol, Erythritol etc.), sugars or specialized forms of these like Pharmaburst™ or F-Melt™. Rapid disintegration is a result of the dissolution of these excipients.

For tablets, used for disintegration in the oral cavity, some additional properties are desirable. The resulting solution or dispersion after tablet disintegration should be easy to swallow, acceptable in its taste and mouth-feel. Hence often additional measurements for the taste-masking of the active component or components (like micro-encapsulation, coating, salt-formation, ester-formation etc.) are necessary. Furthermore aroma and/or sweeteners are used to improve the taste and the patient acceptance. Sometimes the used excipients also have a pleasant taste (sugars, sugar-alcohols) and by this property improve patient acceptance.

Another difficulty in the rapid disintegration in the oral cavity is the limited amount of liquid that is present. In comparison to water, the liquid inside the oral cavity is of higher viscosity. The amount of liquid and its viscosity is not constant. There is a variation between different subjects and even within one subject depending on the time of the day, the amount of liquid consumed (drinking-status), the consumed food etc. Highly porous tablet structures, into which liquid can easily penetrate are therefore also common in the field of oral dispersable tablets. Several specialized manufacturing technologies ensure highly porous tablet structures. The geometry of the

tablet can also influence the disintegration time. Short ways for liquid penetration are preferred. This prerequisite also influences the tablet shape and geometry. The desired optimal geometry also has to consider mechanical stability, as described already.

In the manufacturing of all tablets, and also for oral dispersable tablets, the costs are important. The manufacturing cost should be as low as possible. This can best be achieved by using established standard technologies and keeping the manufacturing process as lean as possible. Any additional manufacturing step would increase cost and has to be avoided. Also the use of specialized excipients tends to increase the costs, as these are more expensive than standard excipients.

The target group for the application of oral dispersable tablets can be found in patients with difficulties in swallowing tablets or in groups were water for the intake of normal tablets is not readily available. In some markets the convenience of taking tablets without water has a high preference. In all cases, the disintegration time of the tablet should be short and the patient/costumer should get the impression of something happening with the tablet inside his mouth. This perception of disintegrating action helps the patients/costumers expectation of a positive influence of the active principle(s) on his/her state or health.

JP 9071523 describes the formulation of oral dispersable tablet. The use of microcrystalline cellulose (MCC) in combination with low substituted hydroxyl-propyl Cellulose (L-HPC) is described. A certain ratio of the two excipients is found to yield the desired tablet properties.

WO 2004091585 describes the use of Prosolv (silicified microcrystalline Cellulose) for the formulation of oral dispersable tablets. Prosolv is a trademark excipient and further described in the US 6471994 as a new tablet excipient also for the use with oral dispersable tablets.

In the development of a new formulation approach to oral dispersable tablets, the use of surfactants was studied. Surfactants and hydrophilic, wetting polymers, like Poloxamer, are used to aid the wettability of active ingredients (drug substance(s)) or increase their bioavailibilty by enhancing their dissolution. In the field of oral dispersable tablets surfactants can be used to reduce the viscosity of the aqueous media inside the oral cavity, independent of the wettability of the active. This effect can be promoted by the use of one or more sweet tasting substances inside the formulation. Salt (NaCl), acid components or intensive flavour can have a similar effect and would also reduce the viscosity of the aqueous media inside the oral cavity. Combinations of these can be used to increase the effect.

Rapid tablet disintegration was found to by promoted by less hydrophobic lubricant at minimized amount, as the most commonly used Magnesium-stearate tends to slow down tablet disintegration A potent tablet disintegrant is also advantages in combination with other insoluble substances within the formulation

The present invention is directed to a non-effervescent tablet for oral administration, comprising an effective amount of at least one active agent, an amount of at least 50% (w/w) of a water insoluble parts, a surfactant and a disintegrant, such that said tablet is orally disintegretable or dispersable The said tablet exhibits oral disintegratabihty in not more than 60 seconds Preferably the tablet exhibits oral disintegratabihty in not more than 30 seconds More preferably the tablet exhibits oral disintegratabihty in not less than 5 seconds Most preferred the tablet exhibits oral disintegratabihty in not less than 2 seconds

The water insoluble carrier in the tablet is selected from the group Cellulose, microcrystalline Cellulose or sihcified microcrystalline Cellulose or mixtures thereof The sihcified microcrystalline cellulose is contained in an amount within the range of 20% to 90% preferably within the range of 25% to 60%

The said sihcified microcrystalline cellulose contains 1 -5% silicon dioxide The tablet sihcified microcrystalline cellulose in the tablet has an average particle size within the range of 20-300 μm

The desintegrant in the tablet is selected from the group consisting of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, crosscarmelose sodium, crosspovidone (crosslinked Polyvinylpyrohdone), sodium starch glycolate, starch, and combinations thereof Preferrabihty the disintegrant is low substituted hydroxypropyl cellulose or crosspovidone (crosslinked Polyvinylpyrohdone) or combinations thereof The disintegrant is contained in the tablet in an amount of 0 5% to 50%

The surfactant in the tablet is selected from the group Sodium dodecylsulfate, Polyoxyethylen Sorbitan fatty acid esters (Tweens), Polyoxyethylene Stearates, Sorbitan fatty acid esters (Spans)

The tablet according to the invention is one which has a tensile strength of 300 to 2000 kN/m ² (calculated as Tensile strength =2*Breakingload / (diameter * thickness *π, observed tensile failure of the measured tablet)

The tablet according to the invention has a friability of less than 1 % The tablet according to the invention does not contain a water soluble binder

The tablet according to to the invention may further comprises at least one additional excipient selected from the group consisting of taste masking agents, sweeteners, lubricants, stabilizers, preservatives, and pH-adjustors The active agent in the tablet according to the invention is selected from the group consisting of pharmaceutical active agents, nutrients, nutπceuticals, and cosmetics The active agent can be one or more vitamins The active agent can also be one or more pharmaceutically active agent(s)

The said pharmaceutically active agent can be present in the form of coated particles containing said pharmaceutically active agent The coating can be an extended release or an enteric coating

The tablet according to the invention is a tablet, wherein said pharmaceutically active agent is selected from the group consisting of antiinflammatories, antirheumatics, antiemetics, analgetics, antiepileptics, antipsychotics, antidepressants, hypnotics, antiulceπcs, prokinetic, antiasthmatics, antiparkinsonics, cardiovasculars, vasodilators, urologies, hypolipidemics, antidiabetics, and antihistamines

The said pharmaceutically active agent can be selected from the group consisting of lbuprofen, acetominophen, piroxicam, leflunomide, ondansetron, granisetron, paracetamol, carbamazepin, lamotπgine, clozapine, olanzapine, risperidone, citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, zopiclon, Zolpidem, cimetidine, ranitidine, omeprazole, metoclopramide, cisapride, dompeπdon, zafirlukast, montelukast, prarnipexol, selegiline, Zolpidem, zopiclon, doxazosin, terazosin, atenolol, bisoprolol, amlodipme, nifedipine, diltiazem, enalapπl, captopπl, ramipπl, losartan, glyceroltπnitrate, alfuzosin, finasteride, pravastatin, atorvastatin, simvastatin, gemfibrozil, metformin, terfenadine, loratadine, celecoxib, πfecoxib, and πvastigmine, as well as a pharmaceutically acceptable salt, ester, hydrate or solvate of the active agent

According to the invention the pharmaceutical orally disintegratable non-effervescent tablet is one which consists essentially of 20% to 90% sihcified microcrystalline cellulose or cellulose or microcrystalline cellulose, 0% to 20% of low substituted hydroxypropyl cellulose, 0% to 20% crosslinked Polyvinylpyrohdone, a lubricant, a surfactant and an effective amount of a pharmaceutically active agent, wherein said tablet exhibits disintegration within 1 to 15 seconds when tested in an in vitro disintegration test

The tablet can further comprise flavorants, colorants, or both

The invention is further directed to the use of a surfactant for making an orally disintegratable non- effervescent pharmaceutical tablet

The present invention provides also a process of rapidly releasing an active agent from a solid tablet, which comprises disintegrating a tablet as described above, by placing the tablet in a water environment The said water environment is an oral cavity or is a waterfilled container

The percentage of insoluble parts of the tablet mixture should be above 30% by weight Insoluble excipients can be either of inorganic origin (like salts e g Calcium Phosphate, Calcium sulfate,

Magnesium carbonate, Calcium Carbonate, Sihcate(s), Oxides like Titanium dioxide, Aluminium oxide, Magnesium oxid or their respective hydrates and/or polymorphic forms) or of organic nature (like natural polymers e g Cellulose, Cellulose esters or ethers, Chitin, Chitosan, Starch,

Starch esters or ethers, Alginates, synthetic polymers e g Polyethylen, Polypropylen, Polyvinylchloπde, Polymethacrylate) If the active pπnciple(s) are insoluble or their solubility is low, they would also act as insoluble parts

Suitable disintegrants in this respect are e g swellable polymers, crosslinked swellable polymers, hydrophilic polymers or other substances which take up water and with that increasing their volume Pharmaceutically common are Crosscarmellose, crosslinked Polyvinylpyrohdone, L-HPC or Sodium starch glycolate Other soluble excipients, such as sugars (Lactose, Saccarose, Glusose, Fructose, Maltose) sugar alcohols (Mannitol, Sorbitol, Xyhtol, Erythπtol) or soluble actives can be used, as long as their proportion is not to high and their mean particle size remains above 50μm The use of this soluble excipients is also common in the field of oral dispersable tablets

For the incorporation of soluble actives it was found, that their particle size has an influence on tablet disintegration It is advantageous to have the particles not to small in this case A particle size of greater than 50μm (mean value of the distribution) was found to yield the desired tablet properties If solubility of the active(s) is high, or time for dissolution is short, greater mean particle sizes are preferred The way in which the particle size is increased is not important Larger crystals work as good as agglomerates made by granulation (wet- or dry-granulation methods can be used)

For the manufacturing of the described formulation, a direct compression manufacturing workflow can be used Thus manufacturing costs are low and standard technology can be used, which keeps investments low

Desired tablet properties are sufficient mechanical stability (expressed as tensile strength and friability), rapid disintegration (expressed as disintegration time using the method described in the European Pharmacopia (European Pharmacopia 5 ^lh edition 2007 (5 8) Method 2 9 1 , using water at 37°C and the disk), acceptable mouth feeling and taste

With the described formulation principle pharmaceutically active substances (drug substances) of different solubility can be formulated. Drug substances can either be soluble (like e g the oral Antidiabetics Acarbose or Miglitol) up to insoluble (like e g Nifedipine) In the case of soluble drug substances a special definition (fraction) of the particle size can be advantageous with respect to disintegration time, content uniformity and tablet hardness The particles of the pharmaceutically active substances could be crystals or agglomerates The particle size of the pharmaceutically active substances can be 50μm-1000μm, preferably 100μm-800μm, more preferably 125μm-630μm, and most preferably 125μm-800μm In particular useful in this particle size are the pharmaceutically active substances acarbose, miglitol and voghbose

Examples

The tablets can be obtained by mixing the given components (except for the lubricant Na-stearyl- fumerat) in a suitable mixing device (e g Turbula mixer or tumble blender) for 10 minutes Then add the lubricant and mix for another 5 minutes

This mixture is then compressed into tablets using a 9mm flat-faced beveled edged set of punches to give tablets of the given mass For double dose tablets use 13mm flat-faced beveled edged punches and compress to the double of the given mass Tablets should match the given tensile strength range (Breakingloads between 20 to 60 N)

In case of Acarbose as active, the Acarbose is premixed with 0,5% (w/w) Na-stearyl-fumerat and compacted The compacts are broken and sieved (Dry-granulation or roller-compaction) After sieving the fraction 125μm-800μm is used

The tablets disintegrate within 5-10 seconds using the described European Pharmacopia Method

Example 1

Substance Amount [mg/Tabl.] Mass [%]

Active *) 50,25 30,15%

Prosoiv (SMMC 90) ^{" ~} io Cob 60,6 i%

L-HPC Type Bl 13,30 7,98%

Natrium 0,42 0,25%

Dodecylsulfat

NaCl 0,50 0,30%

Saccharin-Natrium 0,17 0,10%

Na-Stearyl-Fumarat ϊ.oδ 0,60%

Tablet 166,64 ^" 100,00%

") used as 99.5% (m/m) Acarbose and 0.5% (m/m) Sodium stearyl fumerat or Miglitol

Example 2

Substance , Amount [mg/Tabl.] Mass [%]

^■ Active ^" *) ^{"" " " " ■} 50,25 ^" 30 ^~ 15%

Prosolv (SMMC 90) ^" 75,00 45,01 %

Avicel PH200 26,08 15,65%

L-HPC Type Bl ^{" " """"} 13,30 7,98%

Natrium ^" 0,42 O ^' ,25% ^"

Dodecylsulfat N _a ^,-, ; ^~ ό,50 0,30%

Saccharin-Natrium ^' . 0,09 ^{" " '} 0,05%

Na-Stearyl-Fumarat ^' 1 ,00 ^] 0,60%

Tablet ^{" :} 166,64 ^" 100,00%

*) used as 99.5% (m/m) Acarbose and 0.5% (m/m) Sodium stearyl fumerat or Miglitol

Example 3

Substance ; Amount [mg/Tabl.] Mass [%]

Active *) ; 50,25 30,21 % ^"

Prosolv (SMMC 90) ^■ 45,00 27, ^" θ5% ^{" "}

Avicel PH200 ^' ^ 26,08 15,68%

Arbocel P290 ! 25,00 15,03% ^"

L-HPC Type Bl : i 8,oo 15,82% ^"

Natrium : 0,42 0,25% ^"

Dodecylsulfat

NaCl ^{" ■} 0,50 0,30%

Saccharin-Natrium ! 0,09 0,05%

Na-Stearyl-Fumarat ' 1 ,00 0,60%

Tablet ; 166,34 100,00%

*) used as 99.5% (m/m) Acarbose and 0.5% (m/m) Sodium stearyl fumerat or Miglitol

Example 4

Substance ^' ' Amount [mg/Tabl.] Mass [%]

Active *) ^' 50,25 30,21 %

Prosolv (SMMC 90) 45,00 27,05% ^"

Arbocel 290 , 20,00 12,02%

Kollidon CL 749,08 29,51 %

Natrium ^; 0,42 0,25%

Dodecylsulfat •

NaCl ^" 0,50 ^" 0,30%

Saccharin-Natrium ^' 0,09 0,05%

Na-Stearyl-Fumarat . 1 ,00 ^" θ,6O% ^"

Tablet ^■ 166,34 100,00% ^"

*) used as 99.5% (m/m) Acarbose and 0.5% (m/m) Sodium stearyl fumerat or Miglitol

Example 5

Substance Amount [mg/Tabl.] Mass [%]

Active *) 50,25 30,21 %

^" Prosόϊv (SMMC 90) ^{~ "} 45,00 27,05%

Arbocel 290 ^" ib.oό ^{" "} ϊ8 ^" ,04%

Kollid ^' on CL ^{' "} 39,08 ^" 23,49%

Natrium 0,42 0,25%

Dodecylsulfat

NaCl ^" 0,50 ^{' "} 0,30% ^"

Saccharin-Natrium 0,09 0,05%

Na-Stearyl-Fumarat 1 ,00 0,60%

Tablet 166,34 100,00%

*) used as 99.5% (m/m) Acarbose and 0.5% (m/m) Sodium stearyl fumerat or Miglitol

Example 6

Substance Amount [mg/Tabl.] Mass [%]

Active *) ! 50,25 ^' 30,21 %

Prosolv (SMMC 90) ^' 45,00 ^' 27,05%

Aqualon EC TIO ^' 3 ^~ 8,6θ ^{" "} 22,84%

Kolϊidon CL . 15,08 9,07%

L-HPC Type Bl ^' 16,00 ^' 9,62%

Natrium ^" θ,42 ^{" " "} 6,25% ^"

Dodecylsulfat

NaCl 1 0,50 ^' 0,30% ^"

Saccharin-Natrium ₁ 0,09 ' 0,05% ^"

Na-Stearyl-Fumarat ] 1 ,00 ^' 0,60%

Tablet i 166J4 ^"' 100,00% ^"

") used as 99.5% (m/m) Acarbose and 0.5% (m/m) Sodium stearyl fumerat or Miglitol