Claims:1. Solid lipid nanoparticles of tapentadol.

2. Solid lipid nanoparticles according to claims 1, wherein average particle size of nanoparticles is less than 1000 nm, preferably 50-600 nm, more preferably 200- 500 nm.

3. Solid lipid nanoparticles according to any of the preceding claims, comprises at least one lipid and at least one emulsifier.

4. Solid lipid nanoparticles according to claim 3, wherein lipid is selected from glycerides, fatty acids, steroids and waxes.

5. Solid lipid nanoparticles according to claim 4, wherein glyceride is glyceryl behenate.

6. Solid lipid nanoparticles according to claim 3, wherein lipid is present in the range of 1-60% w/w, more preferably 5-50% w/w of the total weight of solid lipid nanoparticles.

7. Solid lipid nanoparticles according to claim 3, wherein emulsifier is selected from polyoxyethylene sorbitan monolaurate, poloxamer and mixture thereof.

8. Solid lipid nanoparticles according to claims 3, wherein emulsifier is present range of 10-40%w/w, more preferably 15-25% w/w of total weight of solid lipid nanoparticles.

9. A pharmaceutical composition comprising solid lipid nanoparticles according to any of the preceding claims.

10. The pharmaceutical composition according to claim 8, wherein composition is suitable for nasal administration.
, Description:FIELD OF INVENTION
The present invention relates to solid lipid nanoparticles of tapentadol, pharmaceutical composition comprising said solid lipid nanoparticles and process of preparation thereof. Particularly present invention relates to in-situ gel composition comprising solid lipid nanoparticles of tapentadol for nasal administration.

BACKGROUND
Tapentadol is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol, which is available commercially as hydrochloride salt having a brand name NUCYNTA® as an oral tablet, indicated for the relief of moderate to severe acute pain.

Tapentadol is a centrally acting analgesic having both µ-opioid receptor agonist and noradrenalin (Norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition. This dual mode of action makes tapentadol particularly useful in the treatment of both nociceptive pain and neuropathic pain. Clinical trial evidence in acute and chronic non-cancer pain and neuropathic pain supports an opioid-sparing effect that reduces some of the typical opioid-related adverse effects. Specifically, the reduction in treatment-emergent gastrointestinal adverse effects for tapentadol compared with equianalgesic pure µ-opioid receptor agonist results in improved tolerability and adherence to therapy. US patent 6248737 discloses tapentadol and its hydrochloride salt.

When tapentadol is given orally, it undergoes extensive first pass metabolism, which leads to achieve 32% bioavailability. About 97% of the parent compound is metabolized. None of the metabolites contributes to the analgesic activity. Being an opioid analgesic, tapentadol is useful for the treatment of severe pain such as post operative pain, cancer pain etc. In such cases nausea & vomiting is a frequently associated problem and hence poor patient compliance is seen with oral administration. Moreover, for the treatment of breakthrough pain oral formulations are inadequate as it needs at least 45 minutes to absorb after administration, which is not suitable in the treatment of breakthrough pain, as this delay in absorption is typically longer than the episode of breakthrough pain. The maximum serum concentration of tapentadol is typically observed at around 1.25 hours after oral dosing. Bitter taste of tapentadol is not patient friendly, which eventually leads to non adherence to the drug therapy.

Additionally, Tapentadol has short duration of action which compel patient to take frequent administration of tapentadol and like other opioids, tapentadol is also known to have abuse potential. To combat this problem, US8075872 provides abuse proof controlled release formulation of tapentadol for oral administration.

Thus, there exist needs for an alternative dosage form, which mask the bitter taste, provides quick onset of action of the tapentadol and at the same time provides extended release of tapentadol thereby reduces the frequency of administration and chances of abuse.

To overcome the problem associated with available dosage form of Tapentadol, inventors of present invention have developed new dosage form comprising solid lipid nanoparticles which provides quick onset of action as well as extended plasma exposure.

SUMMARY OF THE INVENTION
The first aspect of the present invention is to provide solid lipid nanoparticles of tapentadol.

Another aspect of present invention is to provide pharmaceutical composition comprising solid lipid nanoparticles of tapentadol.

Another aspect of present invention is to provide pharmaceutical composition comprising solid lipid nanoparticles of tapentadol, wherein composition is suitable for nasal administration.

Another aspect of present invention is to provide a nasal composition comprising solid lipid nanoparticles of tapentadol, wherein composition form in-situ gel.
Another aspect of present invention is to provide pharmaceutical composition comprising solid lipid nanoparticles of tapentadol, wherein average particle size of solid lipid nanoparticles is less than 1000 nm, preferably 50-600, more preferably 200- 500nm.

Another embodiment of the present invention provides a process for the preparation of pharmaceutical composition comprises solid lipid nanoparticles of tapentadol.

DETAIL DESCRIPTION OF THE INVENTION
The term “Tapentadol” as used herein is defined to mean at least one form of tapentadol chosen from tapentadol, the individually optically active enantiomers of tapentadol, racemic mixtures thereof, active metabolites thereof, pharmaceutically acceptable salts thereof, polymorph thereof, any of the said form can be crystalline or amorphous. Preferably tapentadol is in base form as “3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2¬ methylpropyl]phenol”.

The term “solid lipid nanoparticles” as used herein means, a colloidal carrier comprising drug entrapped or embedded in lipid and optionally one or more pharmaceutical acceptable excipient(s), having particle size as defined in present invention.

The term “Average particle size” or “particle size” as used herein means Z average diameter of particles in the specified range when measured by a suitable method for example dynamic light scattering instrument.

The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term “w/w” as used herein means weight of component by total weight of composition, calculated by its solid part, unless specified otherwise. The term “w/v” as used herein means weight of component by total volume of composition.

First embodiment of the present invention provides solid lipid nanoparticles of tapentadol.
Another embodiment of present invention provides a pharmaceutical composition comprising solid lipid nanoparticles of tapentadol.

Particle size of said solid lipid nanoparticles may vary from 1 nm to 1000 nm. Preferably it is 50-600 nm, more preferably 200- 500nm. Particle size is average particle size, Z average diameter, as measured through light scattering instrument.

Solid lipid nanoparticles can be in the form of a matrix of lipid comprising tapentadol dispersed therein or tapentadol can be encapsulated in lipid component.

In an embodiment, solid lipid nanoparticles of tapentadol comprises at least one lipid and at least one emulsifier.

“Lipid” as used according to present invention for the preparation of solid lipid nanoparticles of tapentadol includes but not limited to glycerides, fatty acids, steroids and waxes.
Particularly, the glyceride of the present invention is selected from the group consisting of mono-glycerides, di-glycerides and tri-glycerides.
In accordance with one of the embodiments of the present invention, the glyceride is selected from the group consisting of glyceryl behenate (Docosanoate), tricaprin, trilaurin, trimyristin, tripalmitin, tristearin, 1 ,2-dioctanoyl-sn-glycerol, 1 ,2-didecanoyl-sn-glycerol, 1 ,2-dilauroyl-sn-glycerol, 1 ,2-dimyristoyl-sn-glycerol, 1 ,2-dipalmitoyl-sn-glycerol, 1 - palmitoyl-2-oleoyl-sn-glycerol, 1 -stearoyl-2-linoleoyl-sn-glycerol, 1 -stearoyl-2- arachidonoyl-sn-glycerol, 1 -stearoyl-2-docosahexaenoyl-sn-glycerol, 1 -oleoyl-2-acetyl- sn-glycerol, 1 ,2-di-O-phytanyl-sn-glycerol, 1 ,2-dipalmitoyl ethylene glycol, 1 -2-dioleoyl ethylene glycol, glyceryl monostearate, behenoyl polyoxyl-8 glycerides, glyceryl palmitostearate, 1 -O-hexadecyl-sn-glycerol, 1 -O-hexadecyl-2-acetyl-sn-glycerol, 1 -O- hexadecyl-2-O-methyl-sn-glycerol, 1 ,2-diacyl-3-O-(a-D-glucopyranosyl)-sn-glycerol, stearoyl macrogol-32 glycerides, stearoyl polyoxyl-32 glycerides, lauroyl macrogol-32 glycerides, lauroyl polyoxyl-32 glycerides, lauroyl macrogol-6 glycerides, lauroyl polyoxyl-6 glycerides, oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6 glycerides, linoleoyl macrogol-6 glycerides, polyglyceryl-3 dioleate, glycerol monolinoleate, glyceryl monolinoleate, glycerol monooleates, diethylene glycol monoethyl ether, glyceryl dibehenate, glycerol distearate, glyceryl distearate, glyceryl dipalmitostearate and linoleoyl polyoxyl-6 glyceride. Preferably, the glyceride is Glyceryl dibehenate or Glyceryl behenate i.e. Compritol 888ATO ®.
The fatty acid used according to present invention is selected from the group consisting of saturated C4-C28 fatty acids and unsaturated C4-C28 fatty acids. Preferably, the fatty acid is stearic acid.
Lipid can be present in range of 1-60% w/w more preferably 5-50% w/w of the total weight of solid lipid nanoparticles and in the range of 0.01-20% w/v more preferably 0.01-10% w/v of the total composition comprising solid lipid nanoparticles.
Emulsifier used according to present invention can be selected from the group consisting of anionic emulsifiers, cationic emulsifiers, non ionic emulsifiers or zwitterionic emulsifiers. In accordance with one of the embodiment of the present invention the emulsifier is at least one selected from the group consisting of soy lecithin, egg lecithin, phosphatidylcholine; ethylene oxide copolymers, propylene oxide copolymers, poloxamers, sorbitan ethylene oxide/propylene oxide copolymers, polysorbate (polyoxyethylene sorbitan monolaurate) such as polysorbate 20, polysorbate 60, polysorbate 80; sorbitan esters, alkyllaryl polyether alcohol polymers, tyloxapol, bile salts, cholate, glycocholate, taurocholate, taurodeoxycholate. Preferably, emulsifier is selected from polysorbate, poloxamer or mixture thereof; more preferably, emulsifier is polysorbate 80. Emulsifier can be present in the range of 10-40%w/w, more preferably 18-25% w/w of total weight of solid lipid nanoparticles; and in the range of 0.001-10% w/v, more preferably 0.01-5% w/v of the total composition comprising solid lipid nanoparticles. It was observed that concentration of emulsifier affects the stability, gelation time and morphology of solid lipid nanoparticles of tapentadol. Preferably, amount of polysorbate or poloxamer is more than or equal to 18% w/w by total weight of solid lipid nanoparticles.
Tapentadol can be present in the range of 2-10 % w/w of solid lipid nanoparticles, preferably it is 4-6% w/w of solid lipid nanoparticles. Solid nanoparticles prepared according to present invention may further comprises one or more excipients selected from stabilizer and cryoprotectant.

Suitable stabilizer which can be used to stabilize the solid lipid nanoparticles of tapentadol includes but not limited to polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, Stabilizer can be present in the range of 1-10% w/w more preferably 2-7.5% w/w of total weight of solid lipid nanoparticles.

Suitable cryoprotectant used according to present invention includes sucrose, mannitol, trehaloseand the like or mixture thereof. Preferably cryoprotectant is sucrose. Cryoprotectant can be present in the range of 15-60% w/w, preferably 25-55% w/w of total weight of solid lipid nanoparticles.

It was observed that amount of cryoprotectant affects the reconstitution time of solid lipid nanoparticles of tapentadol. Preferably concentration of sucrose is equal to more than 30%.

Solid lipid nanoparticles of tapentadol can be prepared by any suitable method. Preferably, solid lipid nanoparticles of tapentadol are prepared using hot homogenization method. Method comprises mixing of hot lipid phase and hot aqueous or non-aqueous phase comprising emulsifier. Any of the said phase can comprise tapentadol. Lipid phase is heated upto the melting point of tapentadol, preferably 90 to 100 degree centigrade. Though temperature of lipid phase and second phase comprising emulsifier may vary, but it is preferred that temperature of both phases remain same. Mixing of both the phase is followed by continuous homogenization at suitable RPM and simultaneously ultrasonication at suitable amplitude. Preferably, RPM is more than 10000, more preferably it is between 10000 to 20000 RPM and ultrasonication preferably probe sonication with 100% amplitude with 2 sec stop/start cycle for 20-30 minutes.

Solid nanoparticles obtained according to above process can remain in dispersed or suspended form in the aqueous solution or can be dried as powder/particles by suitable drying process, preferably lyophilization. Preferably, solid lipid nanoparticles are present in the form of lyophilized particles/powder.

Optional excipients such as cryoprotectant and/or stabilizer can be added in any of the above mentioned phase or after homogenization. It is preferred that cryoprotectant is added after homogenization, particularly, when solid lipid nanoparticles are prepared using lyophilization process.

Another embodiment of present invention provides pharmaceutical composition comprising solid lipid nanoparticles of tapentadol, wherein composition is suitable for nasal administration.

Nasal composition can be prepared by using suitable nasal carrier. Nasal composition can be in the form of dry powder for inhalation or in liquid form comprising solid lipid nanoparticles. Liquid composition can be aqueous or non-aqueous suspension or dispersion.

Preferably liquid formulation is used for in-situ gel formulation. Suitable nasal carrier which can be used for preparation of in-situ gel formulation of solid lipid nanoparticles of tapentadol include in-situ gelling agent, mucoadhesive agent, humectant, buffering agent, stabilizer, surfactant, preservative, thickening agent, solvents, co-solvents and isotonicity agent.

In some embodiments of the present invention, the composition comprises solvent(s) which can be aqueous or non-aqueous. Examples of solvent include, but are not limited to purified water, water for injection, aliphatic alcohols, polyhydric alcohols and the like or mixtures thereof. Solvent can be present in the range of 30-97% w/v of total composition.

In some embodiments of the present invention, the composition contains a co-solvent(s). Example of co-solvent includes, but is not limited to benzyl alcohol, butanol, glycols, C3-C9 chain alcohols, amines, acids, saline solution and polyglycols.

In some embodiments of the present invention, the composition contains a preservative that is chosen in quantities that preserve the composition, but do not cause irritation of the nasal mucosa. Suitable preservative for use in some embodiments of the present invention include, but are not limited to, benzalkonium chloride, sodium benzoate, methyl, ethyl, propyl or butyl paraben, benzyl alcohol, phenylethyl alcohol, benzethonium chloride, chlorobutanol, potassium sorbate or combination thereof.

In some embodiments of the present invention, the composition is preservative - free. As used herein, preservative-free includes composition that does not contain any preservative.

In some embodiments of the present invention, the composition contains a buffering agent, it is chosen in quantities that preferably do not irritate the nasal mucosa. Buffering agent includes agent that reduces pH changes. Preferred buffering agents for use in the present invention include, but are not limited to, salts of citrate, acetate, or phosphate. The most preferred buffers include sodium citrate, sodium acetate, sodium phosphate, and/or combinations thereof.

In some embodiments of the present invention, the composition contains an in-situ gelling agent(s). Examples of in-situ gelling agent(s) include, but are not limited to polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), PEO-PLLA diblock copolymer, PEG-PLGA-PEG triblock copolymer, Membrane Matrix (Matrigel), cellulose acetophalate latex, pectins, sodium alginate, polyacrylic polymers like carbopols, gellan gum and the like, either alone or in any combination thereof. In-situ gelling agent, preferably gellan gum, can be present in the range of 0.1-30% w/v of total composition.

In some embodiments of the present invention, the composition contains a thickening agent(s). Examples of thickening agent include, but are not limited to carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), sodium alginate, collagen, gelatin, and hyaluronic acid, Carbopol, chitosan, and xyloglucan alone or in combination. Thickening agent, preferably hydroxypropyl methyl cellulose, can be present in the range of 0.1-30% w/v of total composition.

In some embodiments of the present invention, the composition contains a mucoadhesive agent(s). Examples of mucoadhesive agent include, but are not limited to such as carbopols, polycarbophil, carboxymethylcellulose, chitosan or its derivatives, MCC, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, poloxamers, pectin, xanthan gums, alginates, gelatin, alone or in combination.

In some embodiments of the present invention, the composition contains a humectant(s), preferably aqueous humectant(s). Examples of aqueous humectants include, but are not limited to PEG, glycerol, sorbitol, sucrose, mannitol, xylitol, maltitol, polymeric polyols like polydextrose, or natural extracts like quillaia, lactic acid or urea, alone or in any combination thereof.

In some embodiments of the present invention, the composition contains a surfactant. Examples of surfactant include, but are not limited to polyoxyethylen-sorbitan fatty acid esters (Tween), polyethylene-polypropylene glycols, polyoxyethylene-stearates, polyoxyethylene alkyl ethers, e.g. polyoxyethylene monolauryl ether, alkylphenylpolyoxy-ethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), and sodium dodecyl sulphate (SDS), alone or in combination. When one or more surfactants is employed, the amount surfactant present in the compositions of the invention will vary depending on the particular surfactant chosen, the particular mode of administration (e. g. drop or spray) and the effect desired. Preferably, surfactant is polyoxyethylen-sorbitan fatty acid esters, which can be present in the range of 1-20% w/v of total composition.

In some embodiments of the present invention, the composition contains isotonicity agent(s). Examples of isotonicity agent include, but are not limited to sodium chloride (NaCl), potassium chloride, sugars and sugar alcohols and any component from the group of amino acids, alone or in combinations.

In some embodiments of the present invention, the composition contains a stabilizer(s). Examples of stabilizers include, but are not limited to amino acids such as lysine, phenylalanine, leucine and the like, sugars including raffinose, inulin and the like, alpha-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium sulfite, tartaric acid and vitamin E.
The pharmaceutical composition of the present invention can be filled in suitable container such as vial. In one embodiment, composition comprises a lyophilized particles of solid lipid nanoparticles prepared according to present invention and other vial comprises vehicle for reconstitution. In an alternate embodiment composition comprises ready-to-use composition, specifically for nasal administration, wherein solid lipid nanoparticles of tapentadol and vehicle are reconstituted. Amount or concentration of Tapentadol per vial ranges from 15 mg to 30 mg, more preferably tapentadol concentration is 25 mg per vial.

The pharmaceutical composition of the present invention can be administered through a nasal spray or any suitable nasal applicator. Nasal composition can be of multi dose container or unit dose container, preferably in multi dose container.

In another embodiment, the present invention provides the use of nasal composition comprises tapentadol or its pharmaceutically acceptable salt(s) in the treatment of acute pain.

The acute pain according to present invention is selected from but not limited to breakthrough cancer pain, dental pain or pain associated with the medical conditions which include day care surgeries, appendicectomy, cholecystectomy, nailing, plating, fixation of fractured bone, burns dressing, jejunostomy dressing and wound dressing.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

A. Preparation of solid lipid nanoparticles (SLN)

Example 1-4:
Excipients Example 1
Example 2
Example 3
Example 4

% of excipients before drying
Glyceryl Behenate 10% 10% 10% 10%
Tapentadol base 1% 1% 1% 1%
Polysorbate 80 2% 2% 4%
poloxamer 188 0.6% - 0.6% -
PVP K12 0.5% (polyvinyl pyrrolidone) _ _ _ 0.5%
Sucrose _ _ _ 2%
Mili Q water Q. S(100%) Q. S(100%) Q. S(100%) Q. S(100%)
Morphology
spherical in shape with not uniformity in size spherical in shape with not uniformity in size spherical in shape with not uniformity in size spherical in shape with uniformity in size
Particle size (nm)*(by zetasizer) 897.2 _ _ 297.8
Polydispersibility Index (by zetasizer) 0.478 _ _ 0.371
*after diluting with purified water (1:4)
Q. S. - Quantum satis (required to make 100%)

Tapentadol and glyceryl behenate were taken in one beaker and 10gm of freshly prepared solution of polysorbate 80 (Example 2 and 4), poloxamer (Example 1) or mixture of polysorbate 80 and poloxamer (Example 3) were taken in another beaker. Simultaneously both the beakers were heated to the temperature more than 100°C. Hot solution of polysorbate 80/poloxamer or its mixture was added to the mixture of Tapentadol and glyceryl behenate, instantaneously followed by sonication using probe sonicator at 100% amplitude 0.5s cycle under constant homogenization at 20,000 RPM at temperature more than 100°C. The sonication was continued for the next 20 min. Obtained suspension was cooled to room temperature. 2% Sucrose solution (in water) was prepared in another beaker and transfer to the obtained suspension in Example 4. Suspension was stirred and then filled in 10 ml vials (5 gm).

Example 5-7
Excipients Example 5
Example 6
Example 7

% of excipients before drying
Glyceryl Behenate 10% 10% 10%
Tapentadol base 1% 1% 1%
Polysorbate 80 4% 4% 4%
Sucrose 5% ( hot solution in water) - -
Mannitol 5% ( hot solution in water 10%( hot solution in water)
Mili Q water Q. S(100%) Q. S(100%) Q. S(100%)
Morphology
spherical in shape with uniformity in size spherical in shape with uniformity in size spherical in shape with uniformity in size
Particle size (nm) 238.2 232.4 290.4
PDI 0.238 0.251 0.279

Composition of example 5-7 were prepared according to the procedure of example 1-4 and then lyophilized as per cycle given below.

Lyophilization cycle:
Step Shelf set point (°C) Ramp rate (°C/min) Time (min) Pressure (mTorr)
Freezing
1 5.0 1.0 30 0
2 -5.0 1.0 30 0
3 -40.0 1.0 180 0
4 -20.0 1.0 10 0
5 -40.0 1.0 180 0
Primary/secondary drying
6 -37.0 0.50 300 75
7 -26.60 0.50 540 75
8 -23.70 0.50 1200 75
9 0.0 0.30 960 75
10 20.0 0.30 480 75

Example 8:
Composition of example 8 was prepared according to the procedure of example 1-4.
Excipient Example 8
% of excipients before drying
Glyceryl Behenate 10%
Tapentadol 1%
Polysorbate 80 4%
Sucrose 7.5%
Mili Q water Q. S(100%)
Morphology
spherical in shape with uniformity in size
Particle size (nm)(Before Lyo.) 245.5

Particle size (nm)(After Lyo.) 367.9
PDI (Before Lyo.) 0.305
PDI (After Lyo.) 0.390
Zeta potential (mV)(Before Lyo. -43.5
Zeta potential (mV)( After Lyo.) -34.3

B. Preparation of in-situ gel nasal composition

Example 9
Lyophilized vial of Tapentadol SLN
S.No. Ingredients mg/vial %w/w
1 Tapentadol 25.0 3.2
2 Lipid (Glyceryl behenate) 250 32.3
3 Surfactant (Polysorbate 80) 100 12.9
4 Sucrose 400 51.9

Vehicle for SLN
S.No. Ingredients mg/gm % w/w
1 Gellan gum 3.0 0.3
2 Polysorbate 80 4.0 0.4
3 Hydroxypropyl methyl cellulose (6cps) 20.0 2.0
4 WFI q.s. to 1 gm QS to 100 %

After reconstitution of Lyophilized vial of Tapentadol SLN
S.No. Ingredients mg/gm %w/w
1 Tapentadol 6.6 0.662
2 Lipid (Glyceryl behenate) 66.2 6.623
3 Surfactant (Polysorbate 80) 26.4 2.649
4 Sucrose 105.9 10.596
5 Gellan gum 2.38 0.238
6 Polysorbate 80 3.18 0.318
7 Hydroxypropyl methyl cellulose (6cps) 15.89 1.589
8 WFI q.s. to 1 gm Q.s. to 100%

Solid lipid nanoparticles of example 9 was prepared according to examples 1-4.
Vehicle for SLN was prepared by mixing gellan gum, hydroxypropyl methyl cellulose, polysorbate 80 in water.
Tapentadol SLN was reconstituted with 3 ml of vehicle, each ml contains 0.662 mg of Tapentadol base.
For administration in rabbits Tapentadol base was added into SLN suspension to compensate the Total dose (6.43 mg).

Example 10
Formulation according to example 9 was administered (0.050ml- 6.43 mg) to each nostril of 8 Newzealand Rabbits using metered dose pump. Pharmacokinetic (PK) parameters were calculated from concentration versus time data of tapentadol using non-compartmental PK methods with the PK analysis software Phoenix WinNonlin software (version 6.3, Pharsight Corporation, USA). Result is present in table 1.

Table 1
Units Example 9
Mean SD
Kel 1/hr 0.14 0.14
T1/2 hr 11.58 10.05
Tmax hr 0.19 0.07
Cmax ng/mL 73.86 32.39
Tlast hr 21.00 6.00
Clast ng/mL 1.02 0.51
AUClast hr*ng/mL 124.08 48.42
AUCINF_obs hr*ng/mL 139.87 59.05

Observation: It was observed from given values that composition prepared according to present invention provided high plasma concentration in very less time which retained for long duration.