CLIAMS:We Claim:

1. An orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof.

2. An orally disintegrating pharmaceutical composition of Tapentadol or salt thereof comprising taste masked Tapentadol or salt thereof and one or more pharmaceutically acceptable excipients.

3. The orally disintegrating pharmaceutical composition of claim 2, wherein said tapentadol or salt thereof is taste masked using an ion exchange resin.

4. The orally disintegrating pharmaceutical composition of claim 3, wherein said tapentadol or salt thereof is taste masked by complexation.

5. The orally disintegrating pharmaceutical composition of claim 3, wherein said ion exchange resin is a cationic exchange resin.

6. The orally disintegrating pharmaceutical composition of claim 5, wherein the cationic ion exchange resin is a cross-linked polymer of methacrylic acid.

7. The orally disintegrating pharmaceutical composition of claim 4, wherein the ratio of drug and ion exchange resin is about 1:1 to about 1:10.

8. The orally disintegrating pharmaceutical composition of claim 2, wherein said excipients is a diluents, binders, disintegrants, glidants, lubricants, flavor or others.

9. The orally disintegrating pharmaceutical composition comprising of tapentadol or salt thereof of claim 1, wherein said pharmaceutical composition is tablet or capsule.

10. Use of the orally disintegrating pharmaceutical composition according to claim 1, for the management of moderate to severe acute pain.

,TagSPECI:4. Description:

The present invention relates to orally disintegrating pharmaceutical compositions comprising Tapentadol or salt thereof. The present invention also relates to a process for the preparation of orally disintegrating pharmaceutical composition of Tapentadol or salt thereof along with taste masking agent and one or more pharmaceutically acceptable excipients to provide rapid onset of action and mask the bitter taste of Tapentadol or salt thereof.

Tapentadol hydrochloride is 3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methyl propyl] phenol hydrochloride and is represented by the following formula:

Tapentadol hydrochloride is approved in United States under the proprietary name Nucynta® as immediate release oral tablet and Nucynta ER® as extended release oral tablet by Janssen Pharms. Tapentadol is highly soluble drug having pH dependent solubility. Tapentadol is classified as BCS class I drug meaning high permeability and high solubility.

Tapentadol is an orally active ingredient used for the relief of moderate to severe acute pain. It falls under the category of centrally acting analgesic, as it gives rise to a pronounced inhibition of pain without the side effects known for other opioids. Tapentadol shows dual mode of action as an agonist at the µ-opioid receptor and as a nor-epinephrine reuptake inhibitor.

Tapentadol having mean absolute bioavailability after single-dose administration (fasting) is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of Tapentadol are typically observed at around 1.25 hours after dosing.

U.S. Patent No. 8,383,152 discloses the tamper-resistant dosage form of tapentadol.

U.S. Patent No. 6,248,737 discloses the tapentadol compound or its salts thereof.

U.S. Application No. 20130022670 discloses an aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof for oral administration.

U.S. Application No. 20130022654 discloses controlled release pharmaceutical compositions of tapentadol.

U.S. Application No. 20120225951 discloses an aqueous pharmaceutical composition for parenteral administration of tapentadol or a physiologically acceptable salt thereof having a pH value of at least 5.4.

U.S. Application No. 20120225950 discloses a semisolid aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof.

U.S. Application No. 20120034304 discloses a slow-release formulation comprising 3% to 70% of tapentadol in a matrix containing 1% to 80% by weight of one or more hydrophilic or hydrophobic polymers.

Thus attempts have been made to develop immediate as well as extended release formulations of Tapentadol hydrochloride for oral administration, the prior art does not disclose an orally disintegrating formulation of Tapentadol or its salt. Therefore, there is still enduring need exist to develop taste-masked, patient friendly dosage forms such as orally disintegrating tablet of tapentadol or its salt.

The inventors of present inventions have surprisingly found that orally disintegrating pharmaceutical composition of tapentadol or salts thereof along with taste masking agent and one or more pharmaceutically acceptable excipients, which provide a rapid onset of action, avoids first pass metabolism, improves bioavailability and increases the palatability to patients.

The present invention addresses this need and discloses after meticulous testing, orally disintegrating pharmaceutical composition of tapentadol or its salt having taste-masked property and disintegrates rapidly in the mouth to provide quick onset of action.

The present invention provides orally disintegrating pharmaceutical composition of taste masked tapentadol or salt thereof using one or more pharmaceutically acceptable excipients. The present invention further provides orally disintegrating pharmaceutical compositions of taste-masked tapentadol or its salt, which gives a quick onset of action.

The present invention provides orally disintegrating pharmaceutical composition of tapentadol or salt thereof having taste masked property and quick onset of action. The composition of the present invention comprises: a) tapentadol or salt b) a taste masking agent c) one or more pharmaceutically acceptable excipients.

The bitter taste of tapentadol or its salt of the composition of the present investigation is masked by complexation such as with ion exchange resins.

In one general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof wherein the composition comprises one or more pharmaceutical acceptable excipients.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol hydrochloride wherein the composition comprises taste masking agent and one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof wherein the pharmaceutical acceptable excipients comprising diluents, binders, disintegrants, glidants, lubricants, flavors and others.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof wherein taste masking of the composition is achieved by using complexation such as ion-exchange resins.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof wherein an ion-exchange resin selected from either cation exchange resin or anion exchange resin.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof wherein the ion exchange resin may be or may not be cross-linked polymers of acrylic acid.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof, cross-linked polymer of acrylic acid and one or more pharmaceutically acceptable excipients.

In another general aspect, the composition of the invention is in the form of powder, tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet, a trilayer tablet, or premixed powder filled in capsule.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof, wherein the composition comprises one or more pharmaceutical acceptable excipients and the amount of tapentadol or its salt ranges from about 5.0% w/w to about 95.0% w/w of the composition.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof, wherein the amount of cross linked polymer of acrylic acid in the composition ranges from 15% w/w to about 80% w/w of the composition.

In another general aspect, there is provided an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof, wherein the amount of tapentadol or salt and cross linked polymer of acrylic acid in the ratio of about 1:1 to about 1:10 w/w of the total weight of pharmaceutical composition.

The present invention provides an orally disintegrating pharmaceutical composition comprising tapentadol or salt thereof, cross linked polymer of acrylic acid and one or more pharmaceutically acceptable excipients. The composition of the invention is useful as analgesic in the treatment of moderate to severe acute pain which requires immediate drug release and it’s subsequent therapeutic action.

The term "tapentadol" as used herein is refers to mean at least one form of tapentadol chosen from tapentadol base, the individually optically active enantiomers of tapentadol, racemic mixtures thereof, active metabolites thereof, pharmaceutically acceptable salts thereof or polymorph thereof. Any of these said forms can be crystalline or amorphous.

The pharmaceutically acceptable salts of tapentadol according to the invention are acid addition salts wherein acid is selected from hydrochloric acid, hydrobromic acid, embonic acid, (2S.3S)- dibenzoyltartaric acid, dibenzoyltartaric acid, sebacic acid, 1 -hydroxys-naphthoic acid, phosphoric acid, L-(+)-tartaric acid, lysinic acid, L-lysinic acid, D-(+)-malic acid, 4-methylbenzenesulfonic acid, ethanesulfonic acid, benzoic acid, cinnamic acid, L-(+)-lactic acid, S-(+)-mandelic acid, (+)-camphor-10- sulfonic acid, gluconic acid, L-(+)-ascorbic acid, ascorbic acid, palmitic acid, naphthalene-1 ,5- disulfonic acid, hexanoic acid, oleic acid, stearic acid, gentisic acid, octanoic acid, decanoic acid, nitric acid, orotic acid, mucic acid, alginic acid and acesulfamic acid, nicotinic acid, hydrogen bromide, sulfuric acid, acetic acid, propionic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, hippuric acid, lactic acid, mandelic acid, malonic acid, malic acid, tartaric acid, methanesulfonic acid, citric acid, lactic acid. Preferably hydrochloric acid addition salt of tapentadol is used for the present invention and any embodiment thereof.

Orally disintegrating pharmaceutical composition includes the compositions which disintegrate/dissolve in the mouth rapidly, providing 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 who have difficulty in swallowing conventional tablets to adhere to daily medication regimens. Such tablets also serve useful where water may not be readily available to assist in swallowing the tablet in specific conditions like while traveling or patient is not in a condition to use water and swallow the conventional tablet.

“Ion exchange resins” are usually made from a polymer backbone with various displaceable functional groups ionically bonded to the polymer. The polymer chains are also typically cross-linked, leading to a gel-like insoluble composition formed in beads. Cationic ion exchange resins have negatively charged or anionic, binding sites. The anionic binding sites are bonded to displaceable cationic groups. Tapentadol hydrochloride is positively charged and displaces the cationic groups, typically becoming bonded to the resin by ionic bonds.

In an embodiment, the orally disintegrating pharmaceutical composition comprises tapentadol hydrochloride and one or more pharmaceutically acceptable excipients.

The pharmaceutical composition of the present invention may be developed in the form of a dosage form suitable of oral administration.

Dosage forms include solid dosage forms but not limited to tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs. The tablet can be coated or uncoated tablet.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.

For improving palatability and manufacturing process feasibility we are formulate two different strategy of taste masking methods in which two different drug: resin ratio suggest best formulation approach for Mouth dissolving of Tapentadol Hydrochloride.

Ion exchange resins for orally disintegrating pharmaceutical composition include, but are not limited to, Amberlite IR 400, Dowex 1, Indion 454, Duolite AP 143, Amberlite IR 4B, Dowex 2, Amberlite IR 120, Dowex 50, Indion 244, Purolite C 100 HMR, Kyron –T-154, Amberlite IRP 69, Indion 254, Tulsion-T-344, Amberlite IRC 50, Indion 204-234, Tulsion 335, 339, Purolite C 102DR, Kyron-T-104, Tulsion T 335, Doshion P544 (R), Amberlite IRP 88, Indion 234, Tulsion T 339, and Kyron-T-134.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate and starch.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

The sweeteners may be chosen from the following non-limiting list: glucose, dextrose, invert sugar, fructose, and combinations thereof, saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like.

The alkalizer is used to adjust the pH includes but not limited to potassium hydroxide, which increase the complex formation efficiency. The pH range of 3.5-7.0, Tapentadol shows better taste masking efficiency.

Further the addition of sweetener and povidone synergies the complex formation efficiency and taste masking efficiency of the Tapentadol formulation.

The addition of any acid will break the taste masked complex and leads to increase the bitterness of the formulation.

For better formulation parameters placebo granules: taste masked granules ratio should be in the range of about 1:2.5 to 1:4.5.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

Example 1: Tapentadol Hydrochloride Tablet

Sr. No. Ingredients Quantity (% w/w)
Taste Masking by complexation with Kyron
1 Tapentadol HCl 18.95
2 Kyron T-114 56.87
3 Purified Water (1:1.75 of drymix weight) -
Extragranular Material
4 Pearlitol Flash 14.16
5 Crosspovidone XL 10 2.90
6 Avicel PH102 3.22
7 Aspartame 1.93
8 Aerosil 200 0.64
9 Peppermint Flavour permeseal 76175-51 0.80
10 Magnesium Stearate 0.48
Total wt. 100.0

Process for preparing tablet:
The required quantity of purified water was taken and kept for stirring. Cross- linked polymer was added to above purified water under stirring and stirring was continued for the period of 15 minutes. Tapentadol hydrochloride was added to above solution under stirring and stirring was continued for some minutes. The pH of the solution was checked and the observed pH 4.0 to 4.5. The obtained weight complex was then dried in tray dryer till LOD reaches below 5.0% w/w. Again the wet complex further dried in fluidized bed drier at 60°C, till LOD reaches below 3.0% w/w. The obtained dried complex was passed through # 40 mesh. Dried complex was mixed with pearlitol flash in blender for 10 minutes. To this crosspovidone, aerosol 200, aspartame and peppermint flavor were mixed in blender for 10 minutes. Magnesium stearate was added to above blended granules and lubricate for 3 minutes. The above lubricated blend was then compressed.

Example 2: Tapentadol Hydrochloride Tablet

Sr. No. Ingredients % w/w
Taste Masking by complexation with Kyron
1 Tapentadol HCl 18.08
2 Cross-linked polymer of methacrylic acid 54.24
3 Purified Water(1:1.75 of drymix weight) -
Placebo granulation
4 Mannitol 14.28
5 Microcrystalline Cellulose 6.153
6 Crosspovidone 1.53
Binder
7 Polyvinyl pyrrolidone 0.769
8 P.water
Extragranular Material
9 Crosspovidone 1.23
10 Aspartame 1.84
11 Aerosil 200 0.61
12 Peppermint Flavour 0.769
13 Magnesium Stearate 0.461
Total wt 100%

Process for preparing tablet:

Taste Masking:
The required quantity of purified water was taken and keeping for stirring. Cross-linked polymer was added to above purified water with continuous stirring. Tapentadol hydrochloride was added to above solution under stirring and stirring was continued for some minutes. The pH of the solution was checked and the observed pH 4.0 to 4.5. The obtained wet complex was then dried in tray dryer till LOD reaches below 5.0% w/w. Again the weight complex further dried in fluidized bed drier at 60°C, till LOD reaches below 3.0% w/w. The obtained dried complex was passed through # 40 mesh.

Placebo granulation:

Mannitol, Microcrystalline cellulose and Crosspovidone were sifted through respective sieve and then loaded into RMG in that mixing was done for 10 mins at slow impeller speed. PVP was added in sufficient quantity of water and allowed for dissolving in it. This binder solution was added into the RMG for drying at slow impeller speed. The weight mass was then dried by using FBD and the obtained dried granules was sieved through 20#. The sized granules were further mixed in blender for 5 minutes.

To this crosspovidone, colloidal silicon dioxide, aspartame and peppermint flavor were mixed in blender for 10 minutes. Magnesium stearate was added to above blended granules and lubricate for 3 minutes. The above lubricated blend was then compressed.

Example 3: Tapentadol Hydrochloride Tablet

Sr. No. Ingredients % w/w
Taste Masking by complexation
1 Tapentadol Hydrochloride 17.33
2 Aspartame 0.73
3 Povidone 0.73
4 Cross-linked polymer of methacrylic acid (Kyron T-114) 51.98
5 Purified water
KOH required for pH adjustment to 4.3 2.65
Taste masked granules 73.45
Placebo granulation
6 Mannitol 12.24
7 Microcrystalline cellulose 7.37
8 Crospovidone 1.47
9 Povidone 0.73
10 Purified water
Placebo granules 21.82
Prelubrication material
11 Crospovidone 1.17
12 Aspartame 1.76
13 Colloidal Silicon Dioxide 0.58
14 Peppermint Flavour 0.73
Lubrication
13 Magnesium Stearate 0.44
Total wt 100%

Process for preparing tablet:
The weighed amount of Tapentadol hydrochloride, aspartame and povidone were dissolve in purified water under continuous stirring. Kyron T-114 approximately in 1:3 (Drug: Resin) proportion to the above bulk under stirring was added. pH of the solution was adjusted using potassium hydroxide solution. The obtained wet complex was then dried in tray dryer till LOD reaches below 2-3% w/w.

Placebo granules preparation:
Mannitol, microcrystalline cellulose and crospovidone was mixed. Povidone was dissolved in purified water and used to granulate the mannitol, MCC and crospovidone mixture to form dough mass. These obtained granules were dried in fluidized bed dryer till LOD is achieved to 2-3%w/w and sized through #30 mesh.

Preparation of Lubricated blends:
Prelubrication material, taste masked granules and Placebo granules were mixed in Octagonal blender for 20 minutes at slow speed. Magnesium Stearate was added in above prelubricated blend and Lubricated for 5 minutes. The above Lubricated blend was then compressed on rotary compression machine

Example 4: Tapentadol Hydrochloride Tablet

Sr. No. Ingredients Quantity in Mg/Tablet
Taste masking by complexation
1 Tapentadol Hydrochloride 117.54
2 Kyron T-114 122.46
3 Povidone 5.00
4 Sucralose 10.00
5 Purified water q.s
KOH required for pH adjustment to 4.3 15.00
Taste masked granules 270.00
Prelubrication material
6 Crospovidone 15.00
7 Mannitol 109.00
8 Microcrystalline Cellulose 180.00
9 Povidone 5.00
10 Sucralose 10.00
11 Colloidal Silicon Dioxide 4.00
12 Peppermint flavor 4.00
Lubrication
13 Magnesium Stearate 3.00
Total 600.00

Process for preparing tablet:
Tapentadol Hydrochloride in Purified water was dissolved under stirring at 1500 rpm. Sucralose and Povidone were added in above solution under stirring at 1500 rpm. Kyron T-114 approximately in 1:3 (Drug: Resin) proportion to the above bulk was added under stirring at 2200 rpm. pH of bulk was checked and adjusted to 4.3 ± 0.2 using 50% w/w Potassium Hydroxide solution. After Complete stirring, the wet complex was dried in Tray dryer till LOD of dried mass comes within limit of 2-3%w/w. and the dried mass passed through #30 mesh.

Preparation of Lubricated blends:
Prelubrication material and Taste masked granules mixed in Octagonal blender for 20 minutes at slow speed. Magnesium Stearate was added in above prelubricated blend and Lubricated for 5 minutes. The above Lubricated blend was then compressed on rotary compression machine.