FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION
(SECTION 10; RULE 13)
Title:
"ABUSE-PROOFED, EXTENDED RELEASE PHARMACEUTICAL
COMPOSITION COMPRISING TAPENTADOL OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PROCESSES FOR PREPARING THEREOF"
Applicant:
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRD3ES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
This invention relates to an abuse-proofed, extended release pharmaceutical composition comprising Tapentadol or a pharmaceutically acceptable salt thereof and process for preparing thereof.
BACKGROUND OF THE INVENTION
Tapentadol is both [muj-opioid receptor agonist and norephinephrine (NE) reuptake inhibitor. Chemically, tapentadol is 3-(3-dimethylamino-l-ethyl-2-methyl-propyl) phenol monohydrochloride.
The molecular weight of tapentadol HC1 is 257.80, and its molecular formula is C14H23NOHC1. The n-octanol:water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45. Tapentadol is a centrally-acting synthetic analgesic. Although its exact mechanism is unknown, analgesic efficacy is thought to be due to mu-opioid agonist activity and the inhibition of norepinephrine reuptake. It is 18 times less potent than morphine in binding to the human mu-opioid receptor and is 2-3 times less potent in producing analgesia in animal models. In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides.
Tapentadol hydrochloride is available in the United States of America as NUCYNTA® (tapentadol) immediate-release oral tablets and is indicated for the relief of moderate to severe acute pain in patients 18 years of age or older. It is available in various strengths i.e. 50mg, 75mg, lOOmg.
NUCYNTA® ER (tapentadol) extended-release oral tablets is indicated for the management
of:
• moderate to severe chronic pain in adults
• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time in various strengths i.e. 50mg,, 100mg,150mg,200mg and 250 mg.

Conventional compositions (i.e. immediate release compositions) for oral administration of tapentadol lead to rapid release of the active ingredient in the gastrointestinal tract resulting in quick onset of action, but at the same time, a subsequent rapid reduction in the action is observed due to short half life (4 hrs) of tapentadol. The immediate release tablets comprising tapentadol marketed by Ortho McNeil Janssen under the brand name of Nucynta® in various strengths i.e. 50mg, 75mg, lOOmg is thus required to be administered 4-6 times a day (i.e. at every 4-6 hours), to ensure an adequately high concentration of the active ingredient in vivo for perceptible pain relief. If adequate pain relief is not attained with the first dose, the second dose may be administered as soon as one hour after the first dose. The maximum recommended daily dose is 700 mg on the first day and 600 mg on subsequent days. Combinations of tapentadol with other active ingredients such as analgesics have also been prepared.
USRE39593 (the '593 patent) discloses a variety of l-phenyl-3-dimethylaminopropane compounds, processes for their preparation, pharmaceutical compositions comprising these compounds, and method of use thereof. These compounds have the stated activity as analgesic active ingredients in pharmaceutical compositions. Among them, tapentadol hydrochloride, 3-[(lR,2R)-3-(dimemylarnino)-l-ethyl-2-methylpropyl]phenol hydrochloride, is a centrally-acting analgesic with reported mode of action as an agonist at the [mu]-opioid receptor and as a norepinephrine reuptake inhibitor. The '593 patent discloses tapentadol as an analgesic composition which can be administered orally.
WO20003015531A2 discloses the methods and compositions for preventing abuse of dosage forms comprising an opioid analgesic and an aversive agent (e.g., a dye) in an effective amount to deter an abuser from administering a tampered form of the dosage form intravenously, intranasally, and/or orally.
US7776314 discloses a solid dosage form with reduced parenteral abuse containing, in addition to one or more active ingredients with potential for abuse, at least one viscosity-increasing agent in quantities such that, on extraction with the assistance of a necessary minimum quantity of aqueous liquid, a gel is formed which can still preferably pass through a needle, which gel, however, remains visually distinguishable even after being introduced into a further quantity of an aqueous liquid.

US 2005/0058706 discloses a slow-release pharmaceutical composition, containing tapentadol or a pharmaceutically acceptable salt thereof in a matrix wherein a peak serum level of the active ingredient is obtained in vivo within 2 to 10 hrs after administration of the composition. It also discloses simulation studies with repeated administration of the pharmaceutical composition at 12 hourly intervals, which apparently showed that, serum levels are achieved and do not fall below 20 μg/ml, so good analgesic efficacy might be obtained by twice daily administration.
US2005214223 discloses an abuse-proofed dosage form which, apart from one or more active ingredients with potential for abuse, comprises two or more of the following components (a) through (d):
(a) at least one substance which irritates the nasal passages and/or pharynx;
(b) at least one viscosity-increasing agent, which, with the assistance of a necessary rninimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel remains visually distinguishable when introduced into a further quantity of an aqueous liquid;
(c) at least one antagonist for the active ingredient or active ingredients with potential for abuse, and
(d) at least one emetic.
US20060039864A1 discloses an abuse-proofed oral dosage form with controlled release of the active ingredient (lR,2R)-3(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol for once daily administration, which dosage form comprises the active ingredient and/or one or more of the pharmaceutically acceptable salts thereof (A), at least one synthetic or natural polymer (C), delayed-release auxiliary substances, optionally physiologically acceptable auxiliary substances (B) and optionally a wax (D), component (C) or (D) in each case exhibiting a breaking strength of at least 500 Newtons (N), preferably of 1000 N.
US 2009/0099138 discloses a combination of tapentadol and one or more non-steroidal antiinflammatory drugs (NSAIDs).
WO 2009067703 discloses pharmaceutical compositions comprising slow release tapentadol hydrochloride in combination with a second analgesic

Despite the above mentioned prior arts on solid pharmaceutical formulations of Tapentadol, there still exists a need for an oral pharmaceutical composition of Tapentadol or pharmaceutically acceptable salts thereof, which is capable of complicating or preventing the abuse of the dosage form and accordingly there is a need to provide a dosage form for active ingredients with potential for abuse which ensures the desired therapeutic effect when correctly administered, without using of extrusion or hot melt extrusion technology and without using, any polymer or combination with wax which increase the hardness of the composition to about 500N. It has now been found, surprisingly, that abused proofed pharmaceutical composition, from which the active ingredients cannot be converted into a form suitable for abuse, is achieved by using an aversive agent and a nasal irritant with the process of preparation with simple granulation process, having the breaking strength less than 200 N.
OBJECT OF THE INVENTION
It is an object of the present invention to provide an abuse-proofed, extended release pharmaceutical composition comprising Tapentadol or a pharmaceutically acceptable salt thereof and process for preparing thereof.
It is another object of the present invention to provide an abuse-proofed, extended release pharmaceutical composition for oral administration comprising:
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) at least one Hydrogenated vegetable oil as an extended release agent;
c) at least one polyalkylene oxide polymer and;
d) at least one aversive agent, and nasal irritating agent, which complicate or prevent abuse;
wherein said pharmaceutical composition exhibits a breaking strength of less than 200N.
It is also an object of the present invention to provide a process to prepare a stable solid pharmaceutical composition of an abuse-proofed, extended release pharmaceutical composition prepared by granulation process, which exhibits a breaking strength of less than 200N, said composition comprising:
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient;
b) at least one Hydrogenated vegetable wax as an extended release agent;
c) at least one polyalkylene oxide polymer and;

d) at least one dye and nasal irritating agent, which complicate or prevent abuse.
It is yet another object of the present invention to provide a solid stable pharmaceutical composition of abuse-proofed, extended release pharmaceutical composition comprising Tapentadol or a pharmaceutically acceptable salt thereof, which uses a new and different beneficial formulation but is still bioequivalent to the commercially available compositions in the United States of America i.e. NUCYNTA ER ® tablets.
SUMMARY OF THE INVENTION
The present invention relates to an abuse-proofed, extended release pharmaceutical composition comprising Tapentadol or a pharmaceutically acceptable salt thereof and process for preparing thereof.
More particularly it relates to:
A. An abuse-proofed, extended release pharmaceutical composition for oral
administration comprising:
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient,
b) at least one Hydrogenated vegetable oil as an extended release agent;
c) at least one polyalkylene oxide polymer and,
d) at least one aversive agent, and nasal irritating agent, which complicates or prevents abuse;
Wherein said pharmaceutical composition is prepared by granulation process and exhibits a breaking strength of less than 200N.
B. The pharmaceutical composition as in A above, wherein the pharmaceutically
acceptable salt is the hydrochloride salt.
C. The pharmaceutical composition as in A above, wherein the extended release agent is
selected from the group comprising Hydrogenated Vegetable Oil, Xanthium Gum,
Bees Wax, Polymethacrylic Acid, Polyacrylic Acid, Pectins, Alginates and mixtures
thereof.
D. The pharmaceutical composition as in C above, wherein the Hydrogenated vegetable
oil is Hydrogenated Caster Oil.

E. The pharmaceutical composition as in A above, wherein the polyalkylene oxide is
selected from the group comprising polymethylene oxide, polyethylene oxide,
polypropylene oxide and mixtures thereof.
F. The pharmaceutical composition as in E above, wherein the polyalkylene oxide, is
polyethylene oxide having a molecular weight of about 1,00,000 or less than 1,00,000
g/mol.
G. The pharmaceutical composition as in A above, wherein the aversive agent is selected
from the group comprising FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow
No. 6, FD & C Blue No. 1, FD & C Blue No. 2, FD & C Green No. 1, FD & C Green
No. 3, FD & C Green No. 5, FD & C Red
No. 30, D & C Orange No. 5, D & C Red No. 8, D & C Red No. 33, caramel, and
ferric oxide, red, other FD & C dyes and lakes and natural coloring agents such as
grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika,
combinations and mixtures thereof.
H. The pharmaceutical composition as in G above, wherein the dye is FD & C Blue No. 1 which in aqueous solution imparts an intense colour.
I. The pharmaceutical composition as in A above, wherein the nasal irritant is selected from the group comprising Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (Black pepper) (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root) and mixtures thereof.
J. The pharmaceutical composition as in I above, wherein the nasal irritating agent is Piperis nigri fructus (Black pepper) (pepper).
K. The pharmaceutical composition as in A above, wherein the component(s) (b) and optionally (c) are present in such quantities that the dosage form exhibits a breaking strength of less than 200 N.
L. The pharmaceutical composition as in A above, wherein said pharmaceutical composition is prepared by wet granulation method.

M. A process to prepare a pharmaceutical composition of an abuse-proofed, extended release pharmaceutical composition with a breaking strength of less than 200N, said composition comprising;
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient,
b) at least one Hydrogenated vegetable wax as an extended release agent
c) at least one polyalkylene oxide polymer and,
d) at least one dye and nasal irritating agent, which complicates or prevents abuse;
Wherein the process comprises:
A. Mixing Tapentadol or a pharmaceutically acceptable salt thereof,
hydrogenated vegetable oil, polyalkylene oxide and diluents,
B. Granulating (A) with a suitable solvent and drying the granulates,
C. Milling the dried granules to a uniform size,
D. Adding and blending a diluents, Black pepper and Idacos FD&C Blue l with
the dried milled particles,
E. Lubricating (D) with suitable lubricating agent,
F. Compressing (E) to a force so that desired tablet form exhibits a breaking
hardness of less than 200N,
G. Coating the (F) with coating component.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes

one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed
The term "stable" as used herein refers to chemical stability of Tapentadol in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 1%, when the dosage form is kept at 40°C/75% RH for 3 months.
The term "extended release" is defined for purposes of the present invention as the release of the Tapentadol or pharmaceutical acceptable salt thereof, from the oral dosage form at such a rate that blood (e. g., plasma) concentrations (levels) are maintained within the therapeutic range but below toxic levels over an extended period of time as compared to an immediate release product, e. g., from about 12 to about 24 hours.
The term "aversive agent" is defined for purposes of the present invention to mean a dye, or combination of dyes, or equivalent thereof.

The term "parenterally" as used herein includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, infusion techniques, or other methods of injection known in the art.
The term "inhaled" as used herein includes trans-mucosal, trans-bronchial, and trans-nasal abuse.
The term "dye" as used herein includes a compound used to impart an indication of abuse to an abuser administering a tampered dosage form of the present invention.
According to this invention, and the teachings contained in this patent, the dosage form can be formulated as extended release oral formulation by any suitable granulation process, dry or wet in the form of tablet, coated tablet or multiparticulate formulation known to those skilled in the art.
This active ingredient also exhibits, apart from an excellent pain-relieving action, abuse potential, i.e. it may be used by an abuser to bring about an action which does not correspond to its intended purpose. This active ingredient may be used accordingly by abusers, for example, to induce a state of narcosis or euphoria.
These dosage forms containing active ingredient are frequently used for long-term treatment, for example for chronic pain or pain caused by tumours. However, because of the relatively large quantity of active ingredient, such dosage forms, which provide delayed release of the active ingredient, are particularly attractive to the abuser in order to induce the desired state of narcosis or euphoria as quickly as possible. Since, however, delayed-release dosage forms containing the stated active ingredient do not usually give rise to the kick desired by the abuser when taken orally even in abusively high quantities, these dosage forms for example in the form of tablets or capsules are also sometimes comminuted, e.g. ground, and sniffed by the abuser for the purpose of abuse or the active ingredients are preferably extracted from the powder obtained in this way by means of an aqueous liquid and the resultant solution is administered parenterally, in particular intravenously, optionally after filtration through cotton wool or cellulose wadding. This type of administration produces further accelerated increase in active ingredient level than with oral or nasal abuse, with the result desired by the abuser, namely the kick.

Since, however, as in the past, it is in most cases necessary for the purposes of abuse to pulverise dosage forms with controlled release of the active ingredient, it was the object of the present invention to complicate or prevent the pulverisation which precedes abuse of dosage forms with, controlled release of (lR,2R)-3-3-dimethylamino-lethyl-2-methyl-propyl)phenol with the means for potential abuse and in this manner to provide a dosage form for the active ingredient, which, when correctly administered, ensures the desired therapeutic action with once daily administration, but from which the active ingredient cannot be readily converted into a form suitable for abuse simply by pulverisation. The prior art achieved this by preparing the dosage form with thermoformed by extrusion or hot melt extrusion method by using the polymers having the stated minimum breaking strength (measured as stated in the application), preferably in quantities such that the dosage form also exhibits such a minimum breaking strength of at least 500 N, meaning that pulverisation of the dosage form is considerably more difficult using conventional means, so considerably complicating or preventing the subsequent abuse.
Extrusion or hot melt extrusion utilizes the heat and pressure for production; therefore, the degradation of materials should be optimized before used. In conclusion, hot melt extrusion is a potential technique for oral controlled drug release dosage form production. Solvent less and continuous process makes it superior to the conventional techniques. Since, the process involves the use of heat and high pressure therefore the materials must be stable at the processing condition. Hot melt extrusion utilizes the heat and pressure for production; therefore, the degradation of materials should be optimized before used and high pressure, results in the increasing the hardness of the final formulation. Extrusion or hot melt extrusion technology are often related to high energy input mainly related to shear forces and temperature the compound must be melted or dissolved in molten polymer at high temperatures. Thus, it is less applicable to compounds with higher melting temperatures or those that are thermally labile and a second disadvantage is that the formulation can be affected by process parameters such as temperature, high pressure, screw configuration, screw speed and feed rates; which have significant impact on product quality and degradation of drug and polymers this aspect, combined with the relatively large minimum batch size, results in cost and risk during early development.

In spite of the above mentioned the solid pharmaceutical formulations of Tapentadol, there still exists a need for an oral pharmaceutical composition of Tapentadol or pharmaceutically acceptable salts thereof, which is capable of complicating or preventing the abuse of the dosage form and without using of Extrusion or hot melt extrusion technology and without using, any polymer or combination with wax which increase the hardness at least 500N. It has now been found, surprisingly, that abused proofed pharmaceutical composition, from which the active ingredients cannot be converted into a form suitable for abuse, is achieved by using an aversive agent and a nasal irritant with the process of preparation with simple conventional granulation process, having the breaking strength less than 200 N.
In order to prevent possible abuse of the dosage forms according to the invention, the dosage forms according to the invention may contain abuse complicating or-preventing agents,
It was the object of the present invention to complicate or prevent the abuse of the dosage form by a potential abuser and accordingly to provide a dosage form for active ingredients with potential for abuse which ensures the desired therapeutic effect when correctly administered, but from which the active ingredients cannot be converted into a form suitable for abuse this is achieved by using, an aversive agent and nasal irritant.
An aversive agent such as a dye to discourage an abuser from tampering with the dosage form and thereafter inhaling, injecting, or swallowing the tampered dosage form is used in the composition of the present invention. Preferably, the dye is released when the dosage form is tampered with and provides a noticeable color which makes the act of abuse visible to the abuser and to others such that the abuser is less likely to inhale, inject and/or swallow the tampered dosage form. For example, the dye can stain the mucous membrane of the nose and/or mouth and make the act of abuse noticeable to e. g., teachers, parents, peers, etc., discourage abusing the drug due to the possible subsequent public scrutiny. Also, an abuser may be averse to injecting a solution containing extracted drug if the solution has a visible color. Various dyes can be employed as the aversive agent, including for example, and without limitation, FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 1, FD & C Blue No. 2, FD & C Green No. 1, FD & C Green No. 3, FD & C Green No. 5, FD &C Red No. 30, D & C Orange No. 5, D & C Red No. 8, D & C Red No. 33, caramel, and ferric oxide, red, other FD & C dyes and lakes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annate, carmine, turmeric, paprika,

combinations and mixtures thereof and other materials known to one of ordinary skill in the art. A full recitation of all FD & C dyes and their corresponding chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, at Volume 5, Pages 857-884, which is incorporated herein by reference. The amount of dye used will vary as desired, Preferably the composition is non-toxic, edible, color stable in light and air and free of potential hazards to human health. With the inclusion of a dye in the dosage form, when the dosage form is tampered with, the dye preferably imparts a color to the dosage form which makes the act of abuse visible to the abuser and others, such that the abuser is less likely to inhale, swallow, and/or inject the tampered dosage form. The dye may be added in an amount of from about 0. 01 % to about 99%, preferably in an amount of from about 0. 1 % to about 50% of the dosage form. The percentage of the dye depends on the particular dye or dyes included in the dosage form, as the amount present should be in a sufficient amount to stain the mucous membrane and/or skin when the dosage form is abused nasally or orally. The dye may also stain the point of injection if a solution containing the dye is sufficiently colored. It is preferred that the dye (as well as the other aversive agents) is at least partially dispersed in the opioid, rather than separate, e. g. in a film coat. This reduces the potential of the aversive agent from being separated from the opioid during the tampering process, making the aversive agent less or not effective. For safety reasons, the amount of the dye in the present invention should not be toxic to humans.
Nasal irritants as additional protection against abuse, are substances which irritate the nasal passages and/or pharynx and according to the invention are any substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the abuser that he/she does not wish to or cannot continue aa'ministration, for example burning, or physiologically counteracts taking of the active ingredient, for example due to increased nasal secretion or sneezing. These substances which conventionally irritate the nasal passages and/or pharynx may also bring about a very unpleasant sensation or even unbearable pain when administered parenterally, in particular intravenously, such that the abuser does not wish to or cannot continue taking the substance. Particularly suitable substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Appropriate substances and the quantities thereof may be derived by person skilled in the art based on the teachings of this invention. The substance which irritates the nasal passages and/or pharynx is preferably based on one or

more constituents or one or more plant parts of at least one hot substance drug. Corresponding hot substance drugs are known to the person skilled in the art and are described, for example, in "Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure. One or more constituents of at least one hot substance drug selected from the group comprising Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (Black pepper) (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root) may be used. The dosage form according to the invention may preferably also contain plant parts of the corresponding hot substance drugs in a quantity of 0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt. %, in each case relative to the total weight of the dosage unit. If one or more constituents of corresponding hot substance drugs are used, the quantity thereof in a dosage unit according to the invention preferably amounts to 0.001 to 0.005 wt. %, relative to the total weight of the dosage unit. A dosage unit is taken to mean a separate or separable administration unit, such as for example a tablet or a capsule.
The release extended agent is selected from the group comprising Hydrogenated Castor Oil, Hydrogenated Vegetable Oil, Xanthium Gum, Bees Wax, Polymethacrylic Acid, Polyethylene Oxide, Polyacrylic Acid, Pectins, Alginates and mixtures thereof. The polyalkylene oxide is selected from the group comprising polymethylene oxide, polyethylene oxide, polypropylene oxide and mixtures thereof.
Another object of the invention is the process of preparing the abused proofed dosage form without using of the thermoformed or holt melt extrusion technology, but instead using the simple granulation method to make a composition having breaking strength less than 200 N.
Thus, the abuse-proofed, extended release pharmaceutical composition for oral administration according to the invention may comprise:
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient,

b) at least one Hydrogenated vegetable oil as an extended release agent,
c) at least one polyalkylene oxide polymer and,
d) at least one dye and nasal irritating agent, which complicate or prevent abuse; Wherein said pharmaceutical composition is prepared by granulation method and exhibit a breaking strength of less than 200N.
The process to prepare a pharmaceutical composition of an abuse-proofed, extended release pharmaceutical composition with a breaking strength of less than 200N, said composition comprising;
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient,
b) at least one Hydrogenated vegetable oil as an extended release agent,
c) at least one polyalkylene oxide polymer and,
d) at least one dye and nasal irritating agent, which complicate or prevent abuse; wherein the process comprises:
A. Mixing Tapentadol or a pharmaceutically acceptable salt thereof, Hydrogenated
vegetable oil, polyalkylene oxide and diluents,
B. Granulating (A) with a suitable solvent and drying the granulates,
C. Milling the dried granules to a uniform size,
D. Adding and blending a diluents, Black pepper and Idacos FD&C Blue 1 with the dried
milled particles,
E. Lubricating (D) with suitable lubricating agent,
F. Compressing (E) to a force so that desired tablet form exhibits a breaking hardness of
less than 200N,
G. Coating the (F) with coating component.
It is yet another object of the present invention to provide a solid stable pharmaceutical composition of abuse-proofed, extended release pharmaceutical composition comprising Tapentadol or a pharmaceutically acceptable salt thereof, which is bioequivalent to the commercially available compositions in the United States of America i.e. NUCYNTA ER ® tablets.
The pharmaceutical composition of the present invention may further comprise conventional pharmaceutically acceptable excipients. Conventional pharmaceutical excipients include those which function in a dosage form, for example, as fillers or diluents, binders,

disintegrants, lubricants, glidants, and film forming material.
The diluents used in the composition of the present invention may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, lactose anhydrous, corn starch, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and the like and mixtures thereof, wherein lactose monohydrate and/or corn starch are preferred . The diluents may be present in an amount ranging from about 5 %w/w to about 60 %w/w of the composition.
The binders used in the composition of the present invention may be selected from hypromellose, Polyvinylpyrrolidone, cellulose derivatives (e.g., methylcellulose and sodium carboxymethylcellulose), gelatin, glucose, lactose, sucrose, polyethylene glycol, polyalkylen oxide,preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polymethacrylates, hydroxypropylcellulose, sugar alcohols (such as, e.g., sorbitol or xylitol), pregelatinized starch and sodium alginate, and the like and mixtures thereof. These may be helpful to form granules. The binders may be present in an amount ranging from about 1 %w/w to about 30 %w/w of the composition.
The disintegrants used in the composition of the present invention may be selected from pregelatinized starch, sodium starch glycolate, corn starch, cross-linked Polyvinylpyrrolidone, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na), cross-linked CMC-Na, polacrilin potassium, low-substituted hydroxypropylcellulose and the like and mixtures thereof, The presence of a disintegrant in compositions and formulations described herein is not necessary, but may desirable. The disintegrant may be present in an amount ranging from about 5 %w/w to about 40 %w/w of the composition.
The lubricants and/or glidants used in the composition of the present invention may be selected from metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and the like and mixtures thereof. The glidant used in the composition of the present invention may be selected from talc, colloidal silicon dioxide,

magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and the like and mixtures thereof.
Optionally, compositions and formulations described herein, including cores/tablets, can be coated with conventional materials used for film coating, e.g., as described in Pharmaceutical Coating Technology, 1995, edited by Graham Cole. Film coating compositions usually contain the following components: polymer(s), plasticizer(s), colorant{s)/opacifier(s), vehicle(s). Minor quantities of flavours, surfactants and waxes also can be used in the film coating solution or suspension. The majority of the polymers used in film coatings are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol and waxy materials.
Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film. The commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
Colorants/ opacifiers are classified into several groups; organic dyes and their lakes, inorganic colors, natural colors. Different materials from each group can also be combined in defined ratios.
One suitable composition of a coating suspension (calculated on dry material) comprises:
• (a) about 1 -99% by weight of polymer, preferably about 1 -95% of polymer,
• • (b) about 1-50% by weight of plasticizer, preferably about 1-40% of plasticizer,
• (c)about 0.1-20% of colorant/opacifier, preferably about 0.1-10% of
colorant/opacifier.

Film coats may be prepared from ready-to-make preparations which are available on the market. One preferred film-coat material is OPADRY®, particularly OPADRY®white, OPADRY® blue. A film coating dispersion or suspension can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), but water is preferred. The pharmaceutical compositions of the present invention may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression as known to those skilled in the art.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Example 1 The composition of the present invention was prepared as given in table 1.
Table: 1

Sr.No Ingredients % range in formulation
A. Intra granular
1 Tapentadol Hydrochloride 20-40
2 Hydrogenated castor oil 10.0-35.0
3 Lactose anhydrous 10.0-35
4 Polyethylene oxide 2.0-15.0
B. Granulation
6 Iso-Propyl alcohol Q.S.
C. Extra granular
7 Lactose anhydrous 5.0-15.0
8 Piperis nigri fructus (Black pepper) 0.2-2.0
9 FD&C Blue No. 1 0.05-1.0
D. Lubrication
10 Aerosil-200 1.0-3.0
11 Magnesium stearate 1.0-3.0
E Coating
12 Opadry 2.0-3.0
Manufacturing Procedure:
Hydrogenated Castor Oil, Tapentadol Hydrochloride, Anhydrous Lactose and Polyethylene oxide were shifted through required sieve and charged in RMG for dry mixing; followed by granulation with binder solution using Isopropyl alcohol. After granulation, granules were dried in FBD. This was followed by milling through required sieve. Co-Sifted equivalent quantity of Anhydrous Lactose with Black pepper and FD&C Blue 1 was added. Loaded

above granules in a blender followed by sifted extra-granular material and blended for sufficient time. Lubrication was done with Magnesium Stearate and Colloidal Silicon Dioxide. After lubrication, lubricated blend was compressed using suitable punch. This was followed by coating using opadry dispersion.
Example 2:
The composition of the present invention was prepared as given in table 2.
Table: 2

Sr.No Ingredients mg/Tab.
A. Intra granular
1 Tapentadol Hydrochloride 291.2
2 Hydrogenated castor oil 400.0
3 Lactose anhydrous 304.0
4 Polyethylene oxide 30.0
B. Granulation
6 Iso-Propyl alcohol Q.S.
C. Extragranular
7 Lactose anhydrous 135.8
8 Piperis nigri frucrus (Black pepper) 10.0
9 FD& C BlueNo. 1 2.0
D. Lubrication
10 Aerosil-200 18.0
11 Magnesium stearate 9.0
E Coating 1200.0
12 Opadry 36
Total Weight 1236
The composition of this example was prepared by the same process as given in example 1 above.
Drug Abuse Deterrence Test:
The drug abuse deterrence test of Tapentadol ER tablets prepared in example 2 was done to study the difference of the composition of the current invention with placebo for abuse potential by crushing and use through intranasal route.
A randomized , balanced, open label, placebo-controlled, single period, two sequence, two treatment, single dose, in ten divided doses, two way crossover assessing the difference for relative abuse potential of crushed & intranasally administered placebo of TAPENTADOL

250 mg ER tablets with of composition of example 2 in 24 healthy adult male human subjects was carried out.
Procedure:
Study was designed for accessing the difference for relative abuse potential of crushed & intranasally administered placebo in healthy adult male human subject. The single dose of Tapentadol 250 mg ER tablet placebo with or without black pepper was crushed and administered intranasally in a random sequence in ten divided dose to the 24 healthy subjects. Dosing was given in sitting position.
In each sequence, placebo of Tapentadol 250 mg ER with or without Black Pepper was administered to the subjects. Each sequence was separated by at least 5 hours. Total duration of the clinical phase was 01 days. Tl: Placebo of Tapentadol with black pepper
T2: Placebo of Tapentadol without black pepper.
Tapentadol ER Tablet (Example 2) The number of dosing observed mentioned in Table: 6
Table: 6

S.No. Randomization Subject No of dose in Tl No of dose in T2
1. T2T1 1 1 1
2. T1T2 2 1 5
3. T2T1 3 2 2
4. T1T2 4 3 5
5. T1T2 5 4 4
6. T2T1 6 2 9
7. T2T1 7 1 7
8. T1T2 8 2 6
9. T1T2 9 1 4

10. T2T1 10 2 5
11. T2T1 11 2 7
12. T1T2 12 2 5
13. T2T1 13 1 6
14. T1T2 14 1 5
15. T1T2 15 2 1
16. T2T1 16 2 4
17. T1T2 17 2 7
18. T2T1 18 1 4
19. T2T1 19 1 6
20. T1T2 20 2 5
21. T2T1 21 1 5
22. T1T2 22 2 7
23. T1T2 23 2 7
24. T2T1 24 2 6
As observed in data regarding number dosing of Subjects, it is seen that number of Dosing per subject is less in Tl as compared with T2. The results of this study indicated that test product (Tl) Placebo of Tapentadol with black pepper is more deterrent as compared to the test product (T2) placebo of Tapentadol without black pepper.
Bioequivalence Study:
The comparative study between the Tapentadol ER tablets of Example 2 of the present invention and NUCYNTA ER oral extended release tablet showed that the two formulations were bioequivalent (within 90% confidence interval for the ratios).The results are as shown in tables 7 and 8.

A. Tapentadol Hydrochloride 250 mg ER Tablet (Example 2): State: Fasting condition
Table: 7

Parameters Test Product Reference Product Ratio 90% CI

Lower Upper
Cmax (ng/mL) 86.6864 101.3636 85.52 81.20 90.07
AUC0-t(ng/mL).hr 1226.9259 1346.0619 91.15 85.35 97.34
AUCinf(ng/mL).hr 1243.682 1360.152 91.44 85.62 97.65
B. Tapentadol Hydrochloride 250 mg ER Tablet (Example 2): State: Fed condition
Table: 8

Parameters Test Product Reference Product Ratio 90% CI

Lower Upper
Cmax (ng/mL) 139.8736 155.3485 90.04 84.91 95.48
AUC0-t(ng/mL).hr 1924.7836 1982.8717 97.07 93.47 100.81
AUCinf(ng/mL).hr 1939.0121 1997.1572 97.09 93.50 100.81
From the above bioequivalent study, it can be seen that the composition of the present invention is bioequivalent to the innovator's product.
Method for Determining Breaking Strength:
The breaking strength of Tapentadol ER tablets exemplified in example 2 was determined with the Dr. Schleuniger tester.

Procedure:
The Dr.Schleuniger tester operated in a horizontal position. An electric motor drove an anvil to compress a tablet at a constant rate. The tablet was pushed against a stationary anvil until it fractured. A reading was taken from a scale indicator. The results are as shown in table 9.
Table: 9

Tapentadol Hydrochloride 250 mg ER Tablet of Example 2:
Sr. No. Weight (Mg) Thickness (mm) Hardness (N)
Average of 20 tablets 1232.88 6.7985 163.8
Min 1191.7 6.67 151
Max 1254.6 6.86 182
Example 3
The composition of the present invention was prepared as given in table 10.
Table: 10

Sr.No Ingredients mg/Tab.
A. Intra granular
1 Tapentadol Hydrochloride 291.2
2 Hydrogenated castor oil 200.0
3 Lactose anhydrous 370.0
4 Polyethylene oxide 150.0
B. Granulation
6 Iso-propyl alcohol Q.S.
C. Extra granular
7 Lactose anhydrous 149.8
8 Piperis nigri frucrus (Black pepper) 10.0
9 FD& C BlueNo. 1 2.0
D. Lubrication
10 Aerosil-200 18.0
11 Magnesium stearate 9.0
E Coating 1200.0
12 Opadry 36
Total Weight 1236

The composition of example 3 was prepared by the same process as given in example 1 above.
Example 4
The composition of the present invention was prepared as given in table 11.
Table: 11

Sr.No Ingredients mg/Tab.
A. Intra granular
1 Tapentadol Hydrochloride 291.2
2 Hydrogenated castor oil 420
3 Lactose anhydrous 120
4 Polyethylene oxide 180
B. Granulation
6 Iso-propyl alcohol QS
C. Extra granular
7 Lactose anhydrous 149.8
8 Piperis nigri fructus (Black pepper) 10
9 FD&C Blue No. 1 2
D. Lubrication
10 Aerosil-200 18
11 Magnesium stearate 9
E Coating
12 Opadry 36
Total Weight 1236
The composition of example 4 was prepared by the same process as given in example 1 above.
Example 5
The composition of the present invention as prepared as given in table 12.
Table: 12

Sr.No Ingredients mg/Tab.
A, Intra granular
1 Tapentadol Hydrochloride 291.2
2 Hydrogenated castor oil 120
3 Lactose anhydrous 400
4 Polyethylene oxide 40
B. Granulation
6 Iso-propyl alcohol QS

c.
Extra granular
7 Lactose anhydrous 168
8 Piperis nigri fructus (Black pepper) 22
9 FD&C BlueNo. 1 2
D. Lubrication
10 Aerosil-200 34
11 Magnesium stearate 33
E Coating
12 Opadry 33.0
Total Weight 1143.2
The composition of example 4 was prepared by the same process as given in example 1
above.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Claims:
1. An abuse-proofed, extended release pharmaceutical composition for oral
administration comprising:
a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient,
b) at least one hydrogenated vegetable oil as an extended release agent;
c) at least one polyalkylene oxide polymer and,
d) at least one aversive agent, and nasal irritating agent, which complicates or prevents abuse;
Wherein said pharmaceutical composition is prepared by granulation process and exhibits a breaking strength of less than 200N.
2. The pharmaceutical composition as in claim 1, wherein the pharmaceutically acceptable salt is the hydrochloride salt.
3. The pharmaceutical composition as in claim 1, wherein the extended release agent is selected from the group comprising Hydrogenated Vegetable Oil, Xanthium Gum, Bees Wax, Polymethacrylic Acid, Polyacrylic Acid, Pectins, Alginates and mixtures thereof.
4. The pharmaceutical composition as in claim 3, wherein the Hydrogenated vegetable oil is Hydrogenated Caster Oil.
5. The pharmaceutical composition as in claim 1, wherein the polyalkylene oxide is selected from the group comprising polymethylene oxide, polyethylene oxide, polypropylene oxide and mixtures thereof.
6. The pharmaceutical composition as in claim 5, wherein the polyalkylene oxide, is polyethylene oxide having a molecular weight of about 1,00,000 or less than 1,00,000 g/mol.
7. The pharmaceutical composition as in claim 1, wherein the aversive agent is selected from the group comprising FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 1, FD & C Blue No. 2, FD & C Green No. 1, FD & C Green No. 3, FD & C Green No. 5, FD & C Red

No. 30, D & C Orange No. 5, D & C Red No. 8, D & C Red No. 33, caramel, and ferric oxide, red, other FD & C dyes and lakes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, combinations and mixtures thereof.
8. The pharmaceutical composition as in claim 7, wherein the dye is FD & C Blue No. 1 which in aqueous solution imparts an intense colour.
9. The pharmaceutical composition as in claim l, wherein the nasal irritant is selected from the group comprising AUii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (Black pepper) (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root) and mixtures thereof.
. 10. The pharmaceutical composition as in claim 9, wherein the nasal irritating agent is Piperis nigri fructus (Black pepper) (pepper).
11. The pharmaceutical composition as in claim 1, wherein the component(s) (b) and optionally (c) are present in such quantities that the dosage form exhibits a breaking strength of less than 200 N.
12. The pharmaceutical composition as in claim 1, wherein said pharmaceutical composition is prepared by wet granulation method.
13. A process to prepare a pharmaceutical composition of an abuse-proofed, extended release pharmaceutical composition with a breaking strength of less than 200N, said composition comprising;

a) Tapentadol or a pharmaceutically acceptable salt thereof, as an active ingredient,
b) at least one hydrogenated vegetable wax as an extended release agent
c) at least one polyalkylene oxide polymer and,
d) at least one dye and nasal irritating agent, which complicates or prevents abuse;

Wherein the process comprises:
A. Mixing Tapentadol or a pharmaceutically acceptable salt thereof, Hydrogenated
vegetable oil, polyalkylene oxide and diluents,
B. Granulating (A) with a suitable solvent and drying the granulates,
C. Milling the dried granules to a uniform size,
D. Adding and blending a diluents, Black pepper and Idacos FD&C Blue lwith the
dried milled particles,
E. Lubricating (D) with suitable lubricating agent,
F. Compressing (E) to a force so that desired tablet form exhibits a breaking
hardness of less than 200N,
G. Coating the (F) with coating component.