PHARMACEUTICAL INVENTION OF TAPENTADOL
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions for nasal administration,
their preparation and their use in the treatment of pain. In particular, the present
invention relates to a pharmaceutical composition of tapentadol for nasal administration
for the management of pain.
BACKGROUND OF THE INVENTION
Tapentadol is 3-[(1 R,2R)-3-(dimethylamino)-1 -ethyl-2-methylpropyl]phenol. A
particularly preferred form is the hydrochloride salt, 3-[(1 R,2R)-3-(dimethylamino)-1-
ethyl-2-methylpropyl]phenol monohydrochloride. Tapentadol is highly soluble drug and
its solubility is pH dependent. It is considered as BCS class - 1drug.
Tapentadol is a centrally acting analgesic having both -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, cancer related 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 equi-analgesic pure -opioid receptor agonist results in
improved tolerability and adherence to therapy.
US patent 6248737 discloses tapentadol and its hydrochloride salt. Tapentadol is
available commercially as a brand name NUCYNTA® as 50mg, 75mg and 100mg oral
tablet, indicated for the relief of moderate to severe acute pain.
When tapentadol is given orally, it undergoes extensive first pass metabolism, which
leads to achieve low bioavailability (32%). About 97% of the parent compound is
metabolized. None of the metabolites contributes to the analgesic activity. Lipid
solubility of tapentadol is approximately 2.8, which is comparatively low. 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 and 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. The bitter taste of tapentadol is not
patient friendly, which eventually leads to non adherence to the drug therapy.
Generally, opioids are known to show higher inter-subject variability (Clinical
pharmacology and therapeutics; 2007; 81; 429-444). Exact reasons for such variability
are not yet characterized completely but genetic polymorphism of opioid receptors,
species effect, metabolic effect or placebo related phenomenon can be possible
reasons. It has been observed that the route of administration also have great impact on
inter-subject variability. It has been observed that variation of absorption after intranasal
route may be a greater than intramuscular or sc route {Acta Anaesthesiol Scand 2002;
46; 759-770). Like other opioids, tapentadol also has high inter-subject variability, when
given orally, as given in Tapentadol clinical study report synopsis R331333-PAI-30003
(KF 5503/32). High clearance of the tapentadol may be one of the reasons of this high
inter-subject variability.
Thus, there exists need for an alternative dosage form of tapentadol which overcomes
the above problems such as bitter taste, adverse effects etc and moreover provides
quick onset of action with reduction of inter-subject variability and improved patient
compliance.
WO2005020906 discloses intranasal opioid composition for pain management with
improved bioavailability and improved patient compliance.
US20061 10333 discloses a composition for nasal absorption of opioid comprises
calcium carbonate and/or calcium phosphate having particle size of up to 500, with
lower risk of developing side effects as compared to oral route.
US562901 1 discloses a composition for nasal administration comprises polar metabolite
of opioid analgesic consists of glucoronides and ethereal sulphates of opioid analgesics.
US201 000227921 discloses that tapentadol is associated with high inter-patient
variability and therefore a uniform patient response may be lacking. Therefore, to
overcome the problems, amino acids and peptide carbamate pro-drugs of tapentadol
are prepared.
The prior art does not provide a suitable dosage form of tapentadol which masks the
bitter taste thereby being more palatable to patients whilst at the same time providing a
quick onset of action.
Inventors of present inventions have discovered intranasal formulation of tapentadol,
which surprisingly overcome many problems associated with oral formulation, which
provides comparative bioavailability to oral formulation and also reduces intersubject
variability.
OBJECTS OF THE INVENTION
It is an object of the present invention to overcome the drawbacks of the prior arts.
It is another object of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier.
It is yet another object of the present invention to provide a pharmaceutical product
comprising a nasal composition and a dispensing device wherein the device is adapted
for administering the composition to the nasal mucosa.
It is another object of the present invention to provide a process for the preparation of a
composition comprising the step of mixing tapentadol or its pharmaceutically acceptable
salt(s) with at least one nasal carrier.
SUMMARY OF THE INVENTION
The present invention relates to a nasal composition comprising tapentadol or its
pharmaceutically acceptable salt (s) and at least one nasal carrier.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt and at least one nasal carrier, in
combination with instructions for use by nasal administration.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) wherein inter-subject variability in
Tmax is less than 50%, preferably less than 40%, more preferably less than 30%, most
preferably less than 20%, when administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) wherein inter-subject variability in
Cmax is less than 50%, preferably less than 40%, more preferably less than 30%, most
preferably less than 20%, when administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) wherein inter-subject variability in
AUC is less than 50%, preferably less than 40%, more preferably less than 30%, most
preferably less than 25%, when administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprises
tapentadol or its pharmaceutically acceptable salt(s) formulated as liquid, wherein Tmax
is characterized as having inter-subject variability of less than 50%, preferably less than
40%, more preferably less than 30%, most preferably less than 20%, when
administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprises
tapentadol or its pharmaceutically acceptable salt(s) formulated as liquid, wherein Cmax
is characterized as having inter-subject variability of less than 50%, preferably less than
40%, more preferably less than 30%, most preferably less than 20%, when
administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprises
tapentadol or its pharmaceutically acceptable salt(s) formulated as liquid, wherein AUC
is characterized as having inter-subject variability of less than 50%, preferably less than
40%, more preferably less than 30%, most preferably less than 25%, when
administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt and at least one nasal carrier wherein
Cmax is achieved in less than 45 minutes when administered to mammal.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt and at least one nasal carrier,
wherein the pH of the nasal composition is from 3.0 to 9.0, preferably from 3.0 to 8.0,
more preferably from 3.0-7.0 and most preferably from 4.0 - 6.0.
It is another aspect of the present invention to provide a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt and at least one nasal carrier wherein
a unit dose of the composition has a volume of from 25 to 150 , preferably 100 to
130 .
It is yet another aspect of the present invention to provide a pharmaceutical product
comprising a nasal composition and a dispensing device wherein the device is adapted
for administering the composition to the nasal mucosa.
It is another aspect of the present invention to provide a process for the preparation of a
composition comprising the step of mixing tapentadol or its pharmaceutically acceptable
salt(s) with at least one nasal carrier.
Fig 1: Comparative pharmacokinetic profile of nasal formulations vs oral formulation in
rabbits
DETAILED DESCRIPTION OF THE INVENTION
The following paragraphs detail various embodiments of the invention. For the
avoidance of doubt, it is specifically intended that any particular feature(s) described
individually in any one of these paragraphs (or part thereof) may be combined with one
or more other features described in one or more of the remaining paragraphs (or part
thereof). In other words, it is explicitly intended that the features described below
individually in each paragraph (or part thereof) represent important aspects of the
invention that may be taken in isolation and combined with other important aspects of
the invention described elsewhere within this specification as a whole, and including the
examples and figures. The skilled person will appreciate that the invention extends to
such combinations of features and that these have not been recited in detail here in the
interests of brevity.
The term "tapentadol" as used herein is defined 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.
The term "liquid composition" as used herein is defined as a solution, suspension or
dispersion.
The term "Crystal growth inhibitor" as used herein is defined as an agent which
facilitates in formation of homogenous nasal composition of tapentadol.
The term "inter-subject variability" as used herein is defined as the variability in
response which occurs between subjects in an experiment or in patient population or in
a group of people, administered with a drug or a composition. The inter subject
variability is represented in the form of coefficient of variation.
The term "Mammal" as used herein is defined as a human or an animal such as
monkeys, primates, dogs, cats, horses, cows, rabbit and the like.
The use of the terms "a" and "an" and "the" and similar references 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.
It is well known to the skilled person that apart from many factors, lipid solubility play
crucial role in the absorption of drug through nasal mucosa. Drugs with high lipophilicity
have higher tendency to get absorbed through nasal mucosa compared to almost
negligible absorption of low lipophilicity drugs. It has been tested that, intranasal
formulations of low lipophilicity drugs like morphine gives less bioavailability as
compared to intravenous administration, when given in solution form. Therefore they are
required to be given with agent like chitosan which provides longer time for drug
transport across the nasal membrane, before the formulation is cleared by the
mucociliary clearance mechanism.
Surprisingly, it has been found that nasal composition of tapentadol can be prepared
according to present invention having good absorption and comparative bioavailability
to oral composition in spite of its low lipid solubility.
The nasal composition of tapentadol of the present invention provides a quick onset of
action as compared to the oral route. The Cmax can be achieved in a shorter period of
time as compared to the oral route.
Tapentadol is a high clearance drug (C1 =1468.+-. 122 mL/min) and consequently
exhibits low oral bioavailability (Eur. J. Drug Met and Pharmacokinetics; 2007; 32; 163-
169). This high clearance results in wide inter-patient variability in plasma drug
concentrations (relative standard deviation in Cmax is 46%) Surprisingly, inter-subject
variability is found lower with intranasal formulation of tapentadol compared to oral
formulation.
Therapeutic administration of tapentadol requires a high drug dose for nasal
administration. It is difficult to formulate a nasal composition of tapentadol as each
single dose must have a volume limitation (maximum volume limitation is /ί )
so that the target dose delivery can be achieved without causing irritation. Volume
limitation is an important factor when considering nasal administration; if the volume
exceeds the maximum volume limitation, the formulation will drain from the pharynx or
may run out from the nostrils; conversely, if the formulation is significantly less than the
maximum volume limitation, a high concentration of tapentadol will be required to
achieve the target dose, which eventually leads to high osmolality and causes irritation
to the nasal cavity. Present invention provides a nasal composition wherein a unit dose
of the composition has a volume of from 25 to 150 , preferably 100 to 130 .
It is observed that increase in concentration of the tapentadol in the solution leads to
formation of crystals, when stored for extended duration (for more than 3 days). This
makes the formulation non-homogeneous and therefore non-suitable for nasal
administration. This crystal growth may further leads to altered therapeutic effect of the
drug. Present invention overcomes this problem by providing a composition, wherein no
such crystal growth is observed in the composition comprising high concentration of
drug, when stored for longer duration.
The present invention is to provide a nasal composition comprising tapentadol or its
pharmaceutically acceptable salt(s) and at least one nasal carrier.
The present invention is to provide a nasal composition comprising tapentadol
hydrochloride and at least one nasal carrier.
A nasal carrier according to present invention may be selected from the group
consisting of buffering agent, isotonicity agent, preservative, permeation enhancer,
stabilizer, solubilizer, chelating agent, antioxidant, mucoadhesive agent, viscosity
modifying agent, humectants, sweetener, taste masking agent, solvents, co-solvents, insitu
gelling agent, surfactant, polymer, thickening agent, lubricant, bulking agent,
colorant, oil, phospholipids and flavoring agent.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier,
wherein the composition is formulated as a liquid composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol hydrochloride and at least one nasal carrier, wherein the composition is
formulated as a liquid composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier,
wherein the composition is formulated as a liquid composition, and wherein the liquid
composition is in the form of aqueous solution.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol hydrochloride and at least one nasal carrier, wherein the composition is
formulated as a liquid composition, and wherein the liquid composition is in the form of
aqueous solution.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier
selected from the group consisting of buffering agent, isotonicity agent, preservative,
permeation enhancer, stabilizer, chelating agent, antioxidant, mucoadhesive agent,
viscosity modifying agent, humectants, sweetener, taste masking agent, solvents, cosolvents,
thickening agent, solubilizer, flavoring agent, and surfactant, wherein the
composition is formulated as a liquid composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier
formulated as a liquid composition, and wherein the said composition forms a gel in-situ
after nasal administration.
Another embodiment the of present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier
selected from the group consisting of in-situ gelling agent, mucoadhesive agent,
polymer, humectant, buffering agent, stabilizer, surfactant, preservative, thickening
agent, solvents, co-solvents, permeation enhancer, chelating agent, viscosity modifying
agent, sweetener, taste masking agent, solubilizer, flavoring agent, and isotonicity agent
formulated as a liquid composition, and wherein the said composition forms gel in-situ
after nasal administration.
Another embodiment of the present invention provides a nasal composition comprises
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier,
wherein the composition is formulated as a gel composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), polymer and at least one nasal
carrier selected from the group consisting of mucoadhesive agent, viscosity modifying
agent, humectant, chelating agent, buffering agent, solvents, co-solvents, permeation
enhancer, sweetener, taste-masking agent, solubilizer, flavoring agent, surfactant,
preservative and stabilizer, wherein the composition is formulated as gel composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier,
wherein the composition is formulated as powder composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier
selected from the group consisting of mucoadhesive agent, lubricant, preservative,
permeation enhancer, sweetener, taste-masking agent, flavoring agent, bulking agent
and colorant, wherein the composition is formulated as powder composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier,
wherein the composition is formulated as micro/nanoemulsion composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), oil and at least one nasal carrier
selected from the group consisting of polar solvent, co-solvent, surfactant,
mucoadhesive agent, buffering agent, isotonicity agent, permeation enhancer, chelating
agent, viscosity modifying agent, taste masking agent, solubilizer, preservative,
flavoring agent, stabilizer and sweetener, wherein the composition is formulated as
micro/nanoemulsion composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one nasal carrier,
wherein the composition is formulated as a liposome composition.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), phospholipids and optionally at
least one nasal carrier selected from the group consisting of antioxidant, chelating
agent, buffering agent, preservative, mucoadhesive agent, taste-masking agent,
viscosity modifying agent, isotonicity agent, flavoring agent and sweetener, wherein the
composition is formulated as a liposome composition.
The present invention is to provide a nasal composition comprising tapentadol or its
pharmaceutically acceptable salt(s) and at least one nasal carrier, and wherein the pH
of the nasal composition is from 3.0 to 9.0, preferably from 3.0 to 8.0, more preferably
from 3.0-7.0 and most preferably from 4.0-6.0.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol hydrochloride and at least one nasal carrier formulated as a liquid
composition, and wherein the pH of the said composition is from 3.0 to 9.0, preferably
from 3.0 to 8.0, more preferably from 3.0-7.0 and most preferably from 4.0-6.0.
Another embodiment of present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one crystal growth
inhibitor.
Another embodiment of present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and at least one viscosity
modifying agent wherein the viscosity of the said formulation is equal to or less than 100
cps, preferably equal to or less than 50 cps, most preferably equal to or less than 30
cps.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) and a preservative. Preferably the
preservative is benzalkonium chloride. The invention also provides a nasal composition
comprising tapentadol or its pharmaceutically acceptable salt(s), benzalkonium chloride
and sodium chloride.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), a preservative, at least one nasal
carrier and a sweetener. Preferably, the preservative is benzalkonium chloride.
Preferably, the sweetener is sucralose or neotame. Preferably, nasal carrier is
hydroxypropylmethyl cellulose or sodium carboxymethylcellulose or mixture thereof.
The invention also provides a nasal composition comprising tapentadol hydrochloride,
benzalkonium chloride, sodium chloride and sucralose or neotame. The composition
may further comprise a humectant (for example sorbitol), and/or a further nasal carrier
selected from a polymer, a mucoadhesive agent and a viscosity modifying agent. The
composition may further comprise a surfactant such as polyoxyethylenepolyoxypropylene
copolymer. The invention further provides a nasal composition
comprising tapentadol or its pharmaceutically acceptable salt(s), sorbitolhydroxy
propylmethyl cellulose, sucralose, polyoxyethylene-polyoxypropylene copolymer and
benzalkonium chloride.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), a preservative and a humectant.
Preferably, the preservative is benzalkonium chloride. Preferably the humectant is
sorbitol or polyethylene glycol. The composition may comprise a further nasal carrier
selected from an in-situ gelling agent, a thickening agent and a mucoadhesive agent,
such as genu pectin and/or sodium alginate. The invention also provides a nasal
composition comprising tapentadol or its pharmaceutically acceptable salt(s), genu
pectin, sodium alginate, sorbitol and benzalkonium chloride.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), a preservative, a humectant and a
solvent. The composition may also comprise a sweetener, such as sucralose or
neotame. Preferably, the preservative is benzalkonium chloride. Preferably the
humectant is sorbitol or polyethylene glycol. Preferably, the solvent is propylene glycol.
The composition may comprise a further nasal carrier selected from an anti-oxidant and
a stabiliser, such as butylate hydroxyl toluene. The invention also provides a nasal
composition comprising tapentadol or its pharmaceutically acceptable salt(s),
polyethylene glycol, propylene glycol, butylate hydroxyl toluene and sucralose.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s), at least one nasal carrier and a
crystal growth inhibitor. Preferably, the crystal growth inhibitor is polyoxyethylenepolyoxypropylene
copolymer. Preferably, nasal carrier is hydroxypropylmethyl cellulose
or sodium carboxymethylcellulose or mixture thereof.
The nasal composition comprising tapentadol, or its pharmaceutically acceptable salt(s),
according to present invention, provides comparative bioavailability as oral composition
of tapentadol. Being a drug with low lipophilicity, tapentadol is expected to have poor
absorption across the mucous membrane and hence low bioavailability. Surprisingly, it
has been found that a nasal composition according to present invention provides
bioavailability equivalent to its oral composition.
The invention also provides a pharmaceutical product comprising a nasal composition
as described herein and a dispensing device wherein the device is adapted for
administering the composition to the nasal mucosa. For example, the device may
comprise a nasal pump so that the product is in the form of a nasal spray. Alternatively
the device may comprise another suitable nasal applicator. The pharmaceutical product
may further comprise instruction for use, for example in the form of an insert or label.
Another embodiment of the present invention provides a nasal composition comprising
tapentadol or its pharmaceutically acceptable salt(s) for the treatment of pain and in
particular acute pain. The nasal composition is according to any one of the
compositions described herein.
Also provided does the use of a nasal composition comprise tapentadol or its
pharmaceutically acceptable salt(s) in the treatment of acute pain. The nasal
composition is according to any one of the compositions described herein.
Further provided is a method of treating pain, and particularly acute pain, comprising
administering to a subject in need thereof, a nasal composition comprising tapentadol or
its pharmaceutically acceptable salt(s). The nasal composition is according to any one
of the compositions described herein.
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.
Another embodiment of the present invention provides a process for the preparation of
a nasal composition comprising tapentadol or its pharmaceutically acceptable salt(s)
and at least one nasal carrier. The process comprises the step of mixing tapentadol or
its pharmaceutically acceptable salt(s) with at least one nasal carrier.
In another embodiment, the present invention provides a nasal composition comprising
1 to 50% w/w of tapentadol or its pharmaceutically acceptable sat(s), Preferably 5 to
50% of tapentadol or its pharmaceutically acceptable sat(s), more preferably 5 to 40%
of tapentadol or its pharmaceutically acceptable sat(s), most preferably 5 to 30 % of
tapentadol or its pharmaceutically acceptable salt(s).
In another embodiment, the present invention provides a nasal composition comprising
tapentadol, wherein the said composition achieves the Cmax in a period ranging from 5
to 45 minutes, preferably from 7 to 30 minutes, more preferably from 7 to 20 minutes
when administered to mammal.
The nasal composition according to present invention provides less inter-subject
variability as compared to oral formulation, when administered to mammal. The intersubject
variability in Tmax, AUC and Cmax is preferably less than about 50%,
preferably less than 40%, more preferably less than 30%, most preferably less than
25%. The inter-subject variability in Tmax and Cmax is preferably lower than 20%.
Liquid composition
Nasal composition of the present invention can be formulated as a liquid composition
which can be of aqueous or non aqueous solution, preferably aqueous solution. The pH
of the nasal liquid composition is within a range of 3.0 to 9.0, preferably from 3.0 to 8.0,
more preferably from 3.0 to 7.0 and most preferably from 4.0-6.0. The nasal
composition also comprises at least one nasal carrier.
Nasal carrier used in the liquid composition is selected from buffering agent, isotonicity
agent, preservative, permeation enhancer, stabilizer, solubilizer, chelating agent,
antioxidant, mucoadhesive agent, viscosity modifying agents, humectants, sweeteners,
taste masking agents, solvents, co-solvents, thickening agent, flavoring agent, or
surfactant. The said composition of the present invention also includes diluents.
Suitable diluent includes aqueous or non-aqueous diluents or combination thereof.
Gel composition
Nasal composition of the present invention can be formulated as gel composition of
tapentadol for nasal administration to increase the residence time of the drug in the
nasal mucosa so as to bring about complete absorption of drug.
A nasal carrier used in the gel composition is selected from mucoadhesive agent,
viscosity modifying agent, flavoring agent, permeation enhancer, sweetener, tastemasking
agent, solubilizer, humectant, chelating agent, buffering agent, solvents, cosolvents,
surfactant, preservative, stabilizer and polymer. The pH of the nasal gel
composition is within a range of 3.0 to 9.0, preferably from 3.0 to 8.0, more preferably
from 3.0 to 7.0 and most preferably from 4.0-6.0.
In-situ gel composition
Nasal formulation of the present invention can be formulated as liquid composition
which forms a gel after nasal administration, can be hydrogel or organogel, preferably
hydrogel which increase the residence time of drug to provide better absorption of the
drug over a prolong period of time, thus may reduce dosing frequency. Theses
composition will be in the form of solution under ambient conditions, which will form gel
upon contact with the nasal mucosa. The composition consists of tapentadol or its
pharmaceutically acceptable salt(s) solubilised in aqueous/non aqueous medium
containing mucoadhesive agent(s). Composition may contain humectants to have a
soothing effect on mucosa.
The pH of the nasal in-situ gel composition is in the range of 3.0 to 9.0, preferably from
3.0 to 8.0, more preferably from 3.0 to 7.0 and most preferably from 4.0-6.0. The
preferred composition is nasally applied as a cytoadhesive or mucoadhesive
composition which will have either thermoresponsive, ionotropic gelation, water
triggered gelation / lyotropic systems or pH responsive bioadhesive properties or any
combination of these.
A nasal carrier used in the in-situ gel composition is selected from in-situ gelling agent,
mucoadhesive agent, humectants, thickening agents, permeation enhancer, chelating
agent, flavoring agent, viscosity modifying agent, sweetener, taste masking agent,
solubilizer, preservative, chelating agent, stabilizer, surfactant, solvents, co-solvents
and buffering agent.
Powder composition
Nasal composition of the present invention can be formulated as a powder composition
having improved drug absorbability via nasal mucosa. More specifically, the present
invention relates to powder composition for nasal administration that exhibit high
maximum blood concentration by using tapentadol having a specific particle size. The
composition may contains only tapentadol or along with nasal carrier.
Nasal carrier used in the powder composition is selected from mucoadhesive agent,
lubricants, permeation enhancer, flavoring agent, sweetener, taste-masking agent,
diluents or bulking agents and/or preservative.
According to present invention, average particle size of the formulated drug in powdered
form is less than 300 micron, preferably less than 200 micron, most preferably in the
range of 0.5 to 150 microns.
Micro/Nanoemulsion composition
Nasal composition of the present invention can be formulated as micro/nanoemulsion
composition of tapentadol for nasal administration having improved drug absorbability
via nasal mucosa. The emulsion comprises of an aqueous phase, an oily phase and
surfactant to stabilize the emulsion. The oily phase comprises of fatty acid esters and
surfactant is primarily hydrophilic.
The micro/nanoemulsion composition is not limited to any particular pH. However,
generally for nasal administration a mildly acid pH will be preferred. The pH ranges from
about 3.0 to 9.0 are preferred. More preferably pH ranges from 3.0 to 8.0, most
preferably from 3.0 to 7.0 and most preferably from 4.0-6.0.
Nasal carrier used in the micro/nanoemulsion composition is selected from solvents,
surfactant, mucoadhesive agent, isotonicity agent, permeation enhancer, chelating
agent, flavoring agent, viscosity modifying agent, taste masking agent, solubilizer,
buffering agent, sweetener and oil.
Liposome composition
Nasal composition of the present invention can be formulated as liposomal composition
of tapentadol for nasal administration includes phospholipids, the composition may
contain other excipients to enhance the shelf life of liposomal composition.
The liposome composition is not limited to any particular pH. However, generally for
nasal administration a mildly acid pH will be preferred. The pH ranges from about 3.0 to
9.0 are preferred. More preferably pH ranges from 3.0 to 8.0, most preferably from 3.0
to 7.0 and most preferably from 4.0-6.0.
Nasal carrier used in the liposome composition is selected from antioxidants, buffering
agent, chelating agents, preservative, viscosity modifying agent, isotonicity agent,
flavoring agent, sweetener and phospholipids.
In some embodiments of the present invention, the composition contains a diluent(s).
Examples of aqueous diluent include, but are not limited to, saline, water, dextrose or
combinations thereof. Non-aqueous diluents include, but are not limited to, alcohols,
particularly polyhydroxy alcohols such as propylene glycol, polyethylene glycol, glycerol,
and vegetable and mineral oils. These aqueous and/or non-aqueous diluents can be
added in various concentrations and combinations to form solutions, suspensions, oil in
water emulsions or water in oil emulsions.
In some embodiments of the present invention, the composition comprises solvent(s)
which can be aqueous or non-aqueous, polar or non-polar. Examples of solvent include,
but are not limited to purified water, water for injection, aliphatic alcohols, polyhydric
alcohols, butanol, glycols, such as propylene glycol, or medium chain alcohols, amines,
or acids, saline solution, polyglycols, disodium lauryl B-iminodipropionate, (Monateric™
1188M), alkyl polyglucosides (Atlox AL-2575), deceth-4 phosphate (Monafax™ 1214),
Non-volatile benzoate ester (Prifer™ 681 3), glycerine and the like or mixtures thereof.
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. A
preferred preservative is benzalkonium chloride.
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 adjusts pH changes. Preferred buffering agents for
use in the present invention include, but are not limited to, salts of citrate, acetate, or
phosphate. More preferred buffering agents are selected from 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 some embodiments of the present invention, the composition contains a thickening
agent(s). Examples of thickening agent include, but are not limited to CMC, HPMC,
sodium alginate, collagen, gelatin, and hyaluronic acid, polyacrylic polymers like
Carbopol, gellan gum (Gelrite), and xyloglucan alone or in combination.
In some embodiments of the present invention, the composition contains oil. Examples
of oil include, but are not limited to cod liver oil, lanolin oil, mink oil, orange roughy oil,
and shark liver oil, almond oil, apricot kernel oil, avocado oil, castor oil, coconut oil, corn
oil, evening primrose oil, jojoba oil, olive oil, safflower oil, sesame oil, soybean oil, and
wheat germ oil, oleoyl macrogol-6 glycerides (Labrafil® M 1944 CS), linoleoyl macrogol6
glycerides (Labrafil® M 2125 CS), lauroyl macrogol-6 glycerides (Labrafil® M 2130
CS), propylene glycol dicaprylocaprate (Labrafac™), medium-chain triglycerides
(Lipophile WL 1349), propylene glycol dicaprylocaprate (Labrafac™ PG),
polyoxyethylene (6) caprylic/capric glycerides (Acconon CC-6), polyglycerol esters of
oleic acid (Caprol MPGO), glyceryl monocaprylate (Capmul MCM) and some silicone
oils, alone or in combination.
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.
In some embodiments of the present invention, the composition contains a cosolvents).
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
mucoadhesive agent(s). Examples of mucoadhesive agent include, but are not limited
to such as polyacrylic polymers like carbopols, polycarbophil, carboxymethylcellulose,
MCC, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
methylcellulose, poloxamers, pectin, xanthan gums, alginates, gelatin alone or in any
combination thereof.
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
(NaCI), potassium chloride, sugars and sugar alcohols like glucose, dextrose, sucrose,
mannitol, glycerol and any component from the group of amino acids, alone or in any
combination thereof.
In some embodiments of the present invention, the composition contains a permeation
enhancer(s). Examples of permeation enhancer include, but are not limited to fatty acid,
medium chain glyceride, surfactant, steroidal detergent, acyl carnitine, alkanoyl choline,
d-alpha tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), macrogol
( 15)-hydroxystearate (Solutol HS 15), N-acetylated amino acid, esters, salts and
derivatives thereof alone or in any combination thereof.
In some embodiments of the present invention, the composition contains a viscosity
modifying agent(s). Examples of viscosity modifying agent include, but are not limited to
methyl cellulose, carboxymethylcellulose sodium, ethyl cellulose, carrageenen,
polyacrylic polymers like carbopol, polyethyleneglycol, or cross linked
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, sodium alginate, collagen, gelatin,
and hyaluronic acid, alone or in any combination thereof.
In some embodiments of the present invention, the composition contains a polymer(s).
Examples of polymers include, but are not limited to hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose, and carboxymethyl cellulose sodium
crystalline cellulose, a-cellulose, PVP, cross-linked carboxymethyl cellulose sodium,
cross-linked starch, gelatin, casein, gum tragacanth, xanthan gum, chitin, carbopol,
poloxamer (Pluronics), PEO-PLLA diblock copolymer, PEG-PLGA-PEG triblock
copolymer, membrane matrix (Matrigel), cellulose acetophalate latex, pectins, sodium
alginate, gellan gum alone or in any combination thereof.
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, alphatocopherol,
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.
In some embodiments of the present invention, the composition contains a chelating
agent(s). Examples of chelating agent include, but are not limited to EDTA,
polycarboxylic acids and salts thereof such as tartaric acid, citric acid, gluconic acid,
malic acid and the like; polyphosphates and salts thereof, such as polyphosphates with
n=2 or more; copolymers of carboxylic polymers such as PVM/MA copolymer (Gantrez);
copolymers of phosphate polymers and salts thereof, alone or in any combination
thereof.
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 sweetener.
The sweetener is selected from the group comprising of aspartame, saccharin sodium,
acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose,
levulose, maltose, neotame, sucralose, neotame and mixture thereof. Preferred
sweetener is sucralose. Another preferred sweetener is neotame.
In some embodiments of the present invention, the composition contains an antioxidant.
Examples of antioxidant(s) include, but are not limited to 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 or
vitamin E, alone or in any combination thereof.
In some embodiments of the present invention, the composition contains a tastemasking
agent. Examples of taste-masking agent(s) include, but are not limited to
sucralose, dimethylaminoethyl methacrylate polymer, hydroxypropylmethylcellulose,
hydroxypropyl cellulose, gelatin, sodium carboxymethylcellulose, aspartame, saccharin
sodium, acesulfame potassium, neotame, methylcellulose, polyethylene glycol alone or
in any combination thereof.
In some embodiments of the present invention, the nasal composition contains a
lubricant. Examples of lubricant(s) include, but are not limited to aluminium stearate,
sodium stearate, sodium stearyl fumarate, polyethylene glycol alone or in any
combination thereof.
In some embodiments of the present invention, the nasal composition contains a
bulking agent. Examples of bulking agent(s) include, but are not limited to mannitol,
sorbitol, lactose, maltose, dextrose, sucrose, maltodextrin, corn starch,
hyroxypropylmethylcellulose, hydroxypropyl cellulose, microcrystalline cellulose,
hydroxyethyl cellulose, hydroxymethylcellulose, sodium carboxymethylcellulose alone or
in any combination thereof.
In some embodiments of the present invention, the composition contains a colorant.
Examples of colorant(s) include, but are not limited to Red no. , D&C BLUE NO. 1,2,6,
D&C YELLOW NO. 10, 5,6, D&C YELLOW NO. 6 LAKE, FD&C yellow NO. 5 alone or
in any combination thereof.
In some embodiments of the present invention, the composition contains a
phospholipid. Examples of phospolipid(s) include, but are not limited to
phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI),
phosphatidic acid (PA), phosphatidylserine (PS), or mixtures, Stearylamine (SA),
Cholesterol, dilaurylphosphatidylcholine (DLPC), dimyristolphosphatidylcholine (DMPC),
dipalmitoylphosphatidylcholine (DPPC), dilaurylphosphatidylglycerol (DLPG),
dimyristolphosphatidylglycerol (DMPG), dioleoylphosphatidylcholine (DOPC),
dioleoylphosphatidylglycerol (DOPG), dioleoylphosphatidylethanolamine (DOPE),
cholesteryl sulphate and the like, alone or in any combination thereof.
In some embodiments of the present invention, the composition contains a flavoring
agent. Examples of flavoring agent(s) include, but are not limited to flavor anise, flavor
apple, flavor apricot, flavor Banana, flavor bitter mask, flavor buttermint, flavor citrus,
flavor orange, flavor menthol mint, flavor mint, flavor peppermint alone or in any
combination thereof.
In some embodiments of the present invention, the composition contains solubilizer.
Examples of solubilizer include, but are not limited to d-alpha tocopheryl polyethylene
glycol 1000 succinate (Vitamin E TPGS), macrogol (15 )-hydroxystearate (Solutol HS
15), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), PEO-PLLA
diblock copolymer, PEG-PLGA-PEG triblock,copolymer, cyclodextrins, hydroxypropyl
betadex, polyoxyethylene castor oil derivatives, povidone,, sulfobutylether-bcyclodextrin,
tricaprylin, triolein, glyceryl monostearate, sorbitan esters (sorbitan fatty
acid esters), polyoxyethylene fatty acid esters alone or in combination thereof.
In some embodiments of the present invention, the composition contains crystal growth
inhibitor. Examples of crystal growth inhibitor include, but are not limited to polysorbate
80, polysorbate 20 or macrogol-1 5-hydroxysterate, most preferably polyoxyethylenepolyoxypropylene
copolymer or in combination thereof.
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.
This specification also makes use of the following abbreviations:
CMC carboxymethylcellulose
HPMC hydroxypropylmethyl cellulose
MCC microcrystalline cellulose
PVP polyvinylpyrrolidone
PEO poly(ethylene oxide)
PLLA poly-l-lactide
PEG polyethylene glycol
PLGA poly(lactic-co-glycolic acid)
EDTA ethylenediaminetetraacetic acid
The invention will be further illustrated by the following examples, however, without
restricting its scope to these embodiments.
Example 1
S.No. Ingredients Concentration Range (w/w)
1 Tapentadol Hydrochloride 5-50%
2 Sodium chloride 0.5-2%
3 Benzalkonium chloride 0.01-1%
4 Purified water q.s.
Procedure:
1. Sodium chloride is dissolved in purified water.
2. Weighed quantity of tapentadol hydrochloride is added to the solution
obtained in step 1, followed by addition of benzalkonium chloride.
3. Make up the volume with purified water.
Example 2
procedure:
1. Sodium chloride and sucralose is dissolved in purified water.
2. Weighed quantity of tapentadol hydrochloride is dissolved in the solution
obtained in step 1, followed by benzalkonium chloride.
3. Make up the volume with purified water.
Example 3
Procedure:
1. Pectin and sodium alginate are dissolved in appropriate ratio in purified water.
2. Sodium chloride, sorbitol and benzalkonium chloride are dissolved separately in
purified water then weighed quantity of tapentadol hydrochloride is added and
dissolved.
3. Drug solution is then added in pectin alginate solution
4. Make up the volume with purified water.
Example 4
Procedure:
1. Weighed quantity of tapentadol is dissolved in PEG 400 and the solution is diluted
with propylene glycol
2. Sucralose, Benzalkonium chloride and butylate hydroxy toluene are then added with
stirring to composition of step 1.
3. Make up the volume with propylene glycol.
Example 5
Procedure:
1. Dissolve sorbitol in purified water.
2. Dissolve hydroxypropyl methyl cellulose in solution of step 1.
3. Dissolve sucralose followed by tapentadol hydrochloride to solution of step 2.
4. Add Benzalkonium chloride to solution of step 3.
5. Make up the volume with purified water.
Example 6
Procedure:
1.Hydroxypropylmethylcellulose was dissolved in purified water to prepare a solution.
2. Neotame was added in the solution of step 1.
3. Tapentadol Hydrochloride was dissolved in solution of step 2.
4. Benzalkonium chloride was added to the solution of step 3 followed by addition of
spearmint supreme.
6. Volume was made up with purified water.
pH=5.23
Example 7
Procedure:
Procedure of Example 6 was followed replacing hydroxypropylmethylcellulose with
Sodium Carboxymethylcellulose to prepare solution.
pH- 5.15
Example 8
Procedure:
Procedure of Example 6 was followed replacing hydroxypropylmethylcellulose with
Sodium Carboxymethylcellulose to prepare solution.
pH= 5.34
Example 9
Procedure:
Hydroxypropylmethylcellulose was dissolved purified water. Poloxamer 188 was added
into the obtained solution and stirred to form homogenous solution. In the obtained
solution, neotame was added. Tapentadol hydrochloride was dissolved in obtained
solution, followed by addition of benzalkonium chloride and spearmint supreme. Volume
of the solution was made up with purified water.
DH =4.69
Example 10
Procedure:
Procedure of Example 9 was followed by using 25% of tapentadol concentration.
pH =4.72
Example 1 1
ln-vivo characterization:
Animals (NZW Rabbit) were kept on fasting overnight. Next day Tapentadol
Hydrochloride (solution of tapentadol hydrochloride and 1% NaCI) was administered by
oral route using an oral gavage and graduated syringe at the dose of 5 mg/kg (dosage
volume of 2 ml/kg body weight and 2.5 mg/ml concentration). For intranasal study 25 
of formulation obtained in example 6, 7 and 8 were instilled into each nostril using
metered dose pump VP-7 at the dose of 5 mg/kg (each 25 delivers 6.25 mg
Tapentadol Hydrochloride) administering 12.5 mg dose. Results are summarized in
Table 1 and Fig 1.
Table 1:
Example 12
Droplet size distribution:
Droplet size distribution was checked by spraying composition according to example 9
and 10 with two different nasal pumps ( 100 and 130 ) at a distance of 3 cm and 6
cm by using Spraytec® system with innova systems automated velocity based actuator
and computed with NSS spray view® software system. Droplet size distribution was
found out to ascertain the effective droplet size pattern. Results are summarized in
Table 2.
Table 2
CLAIMS
1) A nasal composition comprising tapentadol or its pharmaceutically acceptable
salt(s) and at least one nasal carrier.
2) The composition according to claim 1 wherein tapentadol or its pharmaceutically
acceptable salt(s) is tapentadol hydrochloride.
3) The composition according to any of the preceding claims wherein the
composition is formulated as liquid, gel, in-situ gel, emulsion or liposome
composition.
4) The composition according to any of the preceding claims wherein Cmax is
achieved in less than 45 minutes, when administered to mammal.
5) The composition according to any of the preceding claims wherein inter-subject
variability in Tmax is less than 50%, preferably less than 40%, more preferably
less than 30%, most preferably less than 20%, when administered to mammal.
6) The composition according to any of the preceding claims wherein inter-subject
variability in Cmax is less than 50%, preferably less than 40%, more preferably
less than 30%, most preferably less than 20%, when administered to mammal.
7) The composition according to any of the preceding claims wherein inter-subject
variability in AUC is less than 50%, preferably less than 40%, more preferably
less than 30%, most preferably less than 25%, when administered to mammal.
8) The composition according to any one of the preceding claims having a pH in the
range of 3.0 to 9.0, preferably from 3.0 to 8.0, more preferably from 3.0 to 7.0
and most preferably 4.0-6.0.
9) The composition according to any of the preceding claims wherein tapentadol or
its pharmaceutically acceptable salt(s) is present at a concentration of from 5% to
50 % by weight.
10) The composition according to claim 9 wherein a unit dose of the composition
has a volume of from 25 to 150 , preferably 100 .-1 30 .
11) The composition according to claim 10 wherein a unit dose of the composition
has droplet size distribution Dv(90) preferably less than 200 , more preferably
less than 180 .
12) The composition according to any of the preceding claims wherein the viscosity
of the composition is equal to or less than 100 cps, preferably equal to or less
than 50 cps, more preferably equal to or less than 30 cps.
13) The composition according to claim any of the preceding claims wherein the
composition is formulated as liquid composition.
14) The composition according to claim 9 wherein the liquid composition is in the
form of aqueous solution.
15) The composition according to claim 1 to claim 13, wherein nasal carrier is
selected from the group consisting of buffering agent, isotonicity agent,
preservative, permeation enhancer, stabilizer, solubilizer chelating agent,
antioxidant, mucoadhesive agent, viscosity modifying agent, humectants,
sweetener, taste masking agent, solvents, co-solvents, in-situ gelling agent,
surfactant, polymer, thickening agent, lubricant, bulking agent, colorant, oil,
phospholipids and flavoring agent.
16) A pharmaceutical product comprising a nasal composition according to any one
of the preceding claims and a dispensing device wherein the device is adapted
for administering the composition to the nasal mucosa.
17) A process for the preparation of a composition as defined in any one of the
preceding claims comprising the step of mixing tapentadol or its pharmaceutically
acceptable salt(s) with at least one nasal carrier.
18) A nasal composition comprising tapentadol or its pharmaceutically acceptable
salts as substantially described and exemplified herein.