FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
2. APPLICANT (S)
(a) NAME: WOCKHARDT LIMITED (b)NATIONALITY:
(d) ADDRESS: Wockhardt Towers,
Bandra-Kurla Complex, Bandra East, Mumbai -400051.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.
ATTACHED HEREWITH.

WCK 2006/06/22
5 PHARMACEUTICAL COMPOSITIONS FOR ANALGESIA.
Field of the Invention
[0001] This invention relates to a pharmaceutical composition for treatment of pain
10 and that provides a superior analgesic effect. In particular, the composition is useful to treat painful conditions. The combination composition includes two drugs, the first belongs to a class of centrally acting analgesics and the second belongs to the class of anti-inflammatory agents. The centrally acting analgesic agent is preferably released at a controlled rate whereas the anti-inflammatory agent can be an NSAID and is meloxicam.
15 The present invention provides once a day pharmaceutical composition including meloxicam in an immediate release form and tramadol in an extended release form with pharmaceutically acceptable carrier
Background of the Invention
20
[0002] U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-
substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1R, 2R or IS, 2S)-2-[(dimethylamino) methyl]-l-(3-methoxyphenyl)-cyclohexanol, commonly known as tramadol, is specifically disclosed therein. A series of
25 articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim, Forsch. (Drug Res.), 28(1), 114 (1978). Driessen et al., Arch. Pharmacol., 341, R104 (1990) disclose that tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like. The Abstracts of the Vlth World Congress on Pain, Apr. 1-6 (1990), disclose that tramadol
30 hydrochloride is an orally active pure agonist opioid analgesic. However, clinical experience indicates that tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim Forsch. (Drug Res.), 28(1), 183 (1978)), constipation (I. Arend et al., Arzneim. Forsch. (Drug Res.), 28(1), 199 (1978)), tolerance (L. Flohe et, al., Arzneim. Forsch. (Drug Res.), 28(1), 213 (1978)), and
35 abuse liability ( T. Yanagita, Arzneim. Forsch. (Drug Res.), 28(1), 158 (1978)). When given at a dose of 50 mg by rapid i.v. injection, tramadol may produce certain side effects unique to tramadol including hot flushes and sweating. Despite these side effects, tramadol's combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently being marketed by Grunenthal GMBH as an analgesic.
1

WCK 2006/06/22
5 [0003] Opioids have for many years been used as analgesics to treat severe pain.
They, however, produce undesirable side effects and as a result cannot always be given
repeatedly or at high doses. The side effect problems are well documented in the
literature. See, for example, J. Jaffe in "Goodman and Gilman's, The Pharmacological
Basis of Therapeutics", 8th edition; Gilman et al.; Pergamon Press, New York, 1990;
10 Chapter 22; pages 522-573 wherein it is disclosed that morphine and its congeners, e.g.,
codeine, hydrocodone and oxycodone, are opioid agonist analgesics that exhibit side
effects such as respiratory depression, constipation, tolerance and their use may cause
addiction and withdrawal symptoms.
[0004] Non-opioids such as aspirin and ibuprofen are used as analgesics, because
15 ibuprofen, like aspirin, is not subject to the tolerance, addiction and toxicity of the opioid analgesics. However, ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs (commonly referred to as NSAIDs) are only useful in relieving pain of moderate intensity, whereas the opioid analgesics are useful in relieving more intense pain; See Woodbury, D. and Fingl, E. in "The Pharmacological Basis of Therapeutics", 5th Ed.;
20 Goodman, L. and Gilman, A., Chapter 15, (1975).
[0005] Combinations of non-opioid analgesics have also been prepared to avoid the
side effects associated with opioid analgesics. Some of these combination products are reported to have a benefit of requiring less of each ingredient and produce a synergistic effect. G.Stacher et.al.' Int.J. Clin. Pharmacol. Biopharmacy, 17, 250 (1979) report that
25 the combination of non-opioid analgesic, i.e tolmetin (another NSAID) and acetaminophen allows for a marked reduction in the amount of tolmetin required to produce analgesia. In addition U. S. Patent No. 4,260,629 disclose that an orally administered composition of acetaminophen and zomepirac, a non-opioid analgesic, in particular weigth ratio range produces a synergistic effect for the relief of pain in animals.
30 Furthermore, U.S. Patent No. 4,132,788 discloses that that 5-aroyl-l-(lower)alkylpyrrole-2-acetic acid derivatives, non-opioid analgesics, when combined with acetaminophen or aspirin exhibit synergistic anti-arthritic effect. However, there have been warnings against the daily consumption of non-opioid analgesic mixtures and of the consumption of a single non-opioid analgesic in large amounts or over long periods (see, D. Woodbury
35 and E. Fingl at page 349). In addition, naproxen, aspirin and some other NSAIDs may cause gastrointestinal side effects especially if used repeatedly. See, for example, M. J. S.
2

WCK 2006/06/22 5 Langman, Am. J. Med. 84 (Suppl. 2A): 15-19, 1988; P. A. Insel in "The Pharmacological
Basis of Therapeutics" 8th Ed.; Gilman, A.G. et al., Chapter 26, pp. 664-668,1990.
[0006] Opioid analgesics have been combined with other drugs, including non-
opioid analgesic agents, to reduce side effect problems of the opioid analgesics, which
lower the amountnof opioid needed to produce an equivalent degree of analgesia.For
10 example, A. Takemori, Annals New York Acad. Sci., 281,262 (1976) discloses that compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., sub additive (inhibitory), additive or synergistic. R. Taber et al., J. Pharm. Expt. Thera., 169(1), 29 (1969) disclose that the combination of morphine and methadone, another opioid analgesic, exhibits an additive
15 effect. U.S. Pat. No. 4,571,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides super additive effects when the components are within certain ratios. See also U.S. Pat. Nos. 4,587,252 and 4,569,937, which disclose other naproxen opioid combinations. A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) report super additive analgesia with a 1:125 mixture of
20 butorphanol, another opioid analgesic, and acetaminophen, a non-opioid analgesic, whereas a 1:10 mixture did not show any statistical synergism to analgesia.
[0007] Tramadol is a centrally acting synthetic opioid analgesic. The chemical name for tramadol is (±) cis-2-[(dimethylamino)methyl]-l-(3-methoxyphenyl) cyclo-hexanol hydrochloride. It is commercially available in form of its hydrochloride salt (Formula I)
3
25 as UltramR tablets. Tramadol is indicated in the treatment of the management of moderate to moderately severe pain in adults. Tramadol is reported to a centrally acting synthetic opioid analgesic. Tramadol has the formula:


WCK 2006/06/22 5 [0008] The bioavailability of a Tramadol ER 200 mg tablet is approximately 85-90%.
The mean peak plasma concentrations of tramadol and a key metabolite O-desmethyl
tramadol (Ml) after administration of Tramadol ER tablets to healthy volunteers are
attained after about 12 hours and about 15 hours, respectively, after dosing. Following
administration of the Tramadol ER, steady-state plasma concentrations of both tramadol
10 and Ml are achieved within four days with once daily dosing. The mean terminal plasma
elimination half-lives of racemic tramadol and racemic Ml after administration of
Tramadol ER are approximately 6.3 and 7.4 hours, respectively.
[0009] Tramadol is typically initiated at a dose of 100 mg once daily and can be titrated up as necessary by 100-mg increments every five days to relief of pain and depending
15 upon tolerability. Tramadol ER administration at a dose exceeding 300 mg per day is not recommended.
[0010] Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs) that exhibits anti-inflammatory, analgesic and antipyretic activities.. It is selective COX-2 inhibitor. The chemical name
20 for meloxicam is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-1,1-dioxide (Formula I).

[0011] The bioavailability of meloxicam capsules is reported to be 89% following a 25 single oral dose of 30 mg. The time reported to achieving maximum concentration
(Tmax) was about 5 to 6 hours. Meloxicam is reported to be almost completely metabolized to four pharmacologically inactive metabolites. The major metabolite reported is 5'-carboxy meloxicam (60% of dose), formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose).
30 Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal
4

WCK 2006/06/22 5 extents in the urine and feces. The mean elimination half-life (t1/2) ranges from 15 hours to
20 hours.
[0012] The recommended starting dose and maintenance oral dose of meloxicam is
7.5 mg once daily. The maximum recommended daily oral dose of meloxicam is 15 mg
regardless of formulation.
10 [0013] Inflammation results whenever there is a tissue injury. Tissue injuries can be caused by an acute mechanical injury or an injury produced by a chronic condition such as rheumatoid arthritis. Inflammation can bring about many changes locally. The most important indication of inflammation is pain. Pain is a symptom perceived by the patient. To relieve pain and inflammation in the wide range of conditions (acute or chronic) the
15 most competent combination can be of opioid analgesics and NSAIDs.
[0014] Non Steroidal Anti Inflammatory drugs (NSAIDs) are believed to act by inhibition of the enzyme cyclooxygenase. This inhibits the release of various inflammatory mediators at the local site such as prostaglandin's, leukotrienes and thromboxane A2. This action of NSAIDs relieves pain and inflammation at the local site.
20 [0015] Opioids are believed to act by inhibiting the transmission of pain signals to the brain and activating the pain inhibitory neurons. It has also been seen that the opioid antinociceptive effects are more pronounced in inflamed tissue.
[0016] U.S. Patent No. 6,685,964 assigned to Gruenethal discloses orally administered preparation with controlled lease of an opioid analgesic in the form of
25 crystals having particle size of 10 um to 3 mm, preferably of 50 um to 1 mm, which have at least one controlled release coating. Tramadol is an opioid analgesic that is the subject matter of invention and has been claimed. The controlled release is achieved by using a coating using a polymer.
[0017] U.S. Patent No. 6,558,701 assigned to Grunenthal discloses a combination as
30 a multiplayer tablet for a fixed dose combination of tramadol and diclofenac with a separating layer between the tramadol and diclofenac layers. The invention uses polymers to achieve the controlled release of both substances. The release profile can be varied so as to achieve a dosage form adaptable to administration either once or twice a day.
[0018] U.S. Patent No. 6,451,350 assigned to Grunenthal relates to a process for
35 producing an oral, controlled release preparation of tramadol or a physiologically
5

WCK 2006/06/22
5 compatible tramadol salt having a storage stable active substance release profile by
i coating the active substance preparation with an aqueous ethylcellulose dispersion which
contains at least one physiologically compatible, lipophilic diester of a dicarboxylic acid
and an aliphatic alcohol as plasticizer, and, during coating, and an optional heat treatment
in order to increase the active substance release profile without impairing the storage
10 stability.
[0019] U.S. Patent No. 6,254,887 assigned to Euro-Celtique discloses a controlled release composition of tramadol for once or twice a day administration comprising a multiplicity of spheroidal beads comprising tramadol and coated with a coating to achieve the release in a controlled fashion using a material selected from water insoluble
15 wax, a water insoluble polymer, a water insoluble cellulose and mixtures thereof
[0020] U.S. Patent Application No. 2005/0266072 disiscloses a pharmaceutical formulation comprising: a substrate comprising an opioid antagonist; a diffusion barrier coating comprising an anionic polymer coated over said substrate; and a coating comprising a hydrophobic material coated over said diffusion barrier coating. The active
20 agent is loaded over non-pareil seeds and is coated with a diffusion barrier coat, followed by a hydrophobic coat, to provide a formulation having a controlled release.
[0021] U.S. Patent Application No 2005/0265955 discloses sustained release formulations that include a drug-ion exchange resin complex and a water-permeable, diffusion barrier surrounding at least a portion of the drug-ion exchange resin complex.
25 The active agent can be release in a sustained release form using this technology of ion exchange. DowexR and AmberliteR are commercially available ion-exchange resins used in formulations.
[0022] U.S. Patent Application No 2005/0089558 discloses a method for the treatment of pain comprising the administration of a combined formulation comprising
30 tramadol and propoxyphene to a subject with pain.
[0023] U.S. Patent Application No S 2004/0115267 discloses an oral administration unit containing the active substances Tramadol and Diclofenac and/or physiologically acceptable salts thereof, in which both active substances are contained in the same administration unit as two separately formulated subunits.
35 [0024] US Patent Application 2005/0090517 discloses a combination COX 2 inhibitor or a pharmaceutically acceptable salt or derivative thereof and an opiate or a
6

WCK 2006/06/22 5 pharmaceutically acceptable salt or derivative thereof wherein COX 2 inhibitor is
meloxicam and opiate is Tramadol. However there are no disclosures in this application
regarding the combination of a controlled release formulation of tramadol with
meloxicam.
[0025] Combination of opioids (immediate release) with other drugs like non-opioid
10 analgesic agents is well known in the prior art but with the limitations of shorter duration of action, frequent dosing, poor patient compliance and moreover increased side effects due to frequent dosing.
[0026] There is a need for a pharmaceutical composition including a controlled release centrally acting opioid analgesic such as tramadol and an NSAID such as
15 meloxicam. There is a need for a composition having an immediate release active agent and an extended release active agent.
Summary of the Invention.
[0027] The present invention provides a pharmaceutical composition, for once a day administration, including meloxicam, in an immediate release form and tramadol in an
20 extended release form with a pharmaceutically acceptable carrier so as to provide better pain management, reduced side effects and improved patient compliance.
[0028] In one embodiment, the present invention provides a combination of 100mg - 300mg tramadol in an extended release form and 7.5mg - 15 mg meloxicam in an immediate release form in a composition with a pharmaceutically acceptable carriers that
20 can be administered as once a day formulation. Such a combination can provide (a) better pain management, (b) reduced dosing frequency, (c) improved patient compliance and (d) reduced side effects when compared to chronic use of tramadol alone in the management of therapy.
[0029] The above summary of the present invention is not intended to describe each
30 disclosed embodiment or every implementation of the present invention. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations.
35 In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
7

WCK 2006/06/22
5 Detailed description of the Invention
[0030] The present invention provides pharmaceutical compositions including
tramadol and meloxicam. Tramadol is commercially available from Grunenthal or may
be made by the process described in U.S. Pat. No. 3,652,589, which is herein
incorporated by reference.
10 [0031] As used herein "tramadol" includes (1R, 2R or IS, 2S)-(dimethylaminomethyl)-l-(3-methoxyphenyl)-cyclohexanol (tramadol), its N-oxide derivative ("tramadol N-oxide"), and its O-desmethyl derivative ("O-desmethyl tramadol") or mixtures thereof. It can also include the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts of the
15 amines, such as the hydrochloride salt, solvates and polymorphs of the tramadol material and mixtures thereof.
[0032] According to the present invention "NSAIDs" are non-opioid analgesics that are nonsteroidal drugs, which act as anti-inflammatory, analgesic or anti-pyretic agents. This class of drugs is well known in the art. See for example, Goodman, L. and Gilman,
20 A., supra, in Chapter 26 (1990). These drugs share certain therapeutic actions and side effects. Within this broad class of drugs are salicylates, such as aspirin; pyrazolone derivatives such as phenylbutazone, onyphenbutazone, antipyrine, aminopyrine, dipyrone and apazone; indomethacin; sulindac; fenamates such as mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamice acids; aryl acetic acid and propionic acid
25 compounds such as 2-(p-isobutylphenyl)propionic acid (generic name ibuprofen); alphamethyl-4-(2-thienylcarbonyl) benzene acetic acid (generic name suprofen); 4,5-diphenyl-2-oxazole propionic acid (generic name oxprozin); rac-6-chloro-alphamethyl-carbazole-2-acetic acid (generic name carprofen); 2-(3-phenyloxyphenyl)-propionic acid, particularly the calcium salt dihydrate thereof (these compounds being referred to
30 genetically as fenoprofen and fenoprofen calcium); 2-(6-methoxy-2-naphthyl) propionic acid (generic name naproxen; the generic name of the sodium salt is naproxen sodium); 4-(l,3-dihydro- l-oxo-2H-isoindol-2-yI)-.alpha.-methylbenzene acetic acid (generic name indoprofen); 2-(3-benzoylphenyl)propionic acid (generic name ketoprofen); and 2-(2-fluoro-4-biphenylyl) propionic acid (generic name flurbiprofen) and l-5-(4-
35 methylbenzoyl)-lH-pyrrole-2-acetic acid (generic name tolmetin). Also included within NSAIDs are compounds within the class including sodium 5-(4-chlorobenzoyl)-l,4-
8

WCK 2006/06/22 5 dimethyl-lH-pyrrole-2-acetate dihydrate (generically referred to as zomepirac sodium);
4-hydroxy-2-methyl-N-(2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-l, 1 -dio xide
(generic name piroxicam); 2\ 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid (generic
name diflunisal) or l-isopropyl-7-methyl-4-phenyl-2(lH)-quinozolinone (generic name
proquazone), phenylacetic acid derivatives such as diclofenac; etodolac, nabumetone and
10 the like. For the purposes of this invention, para-aminophenol derivatives such as acetaminophen are not considered NSAIDs because of their general lack of anti- inflammatory activity. All of the NSAIDs are commercially available materials.
[0033] The invention provides a pharmaceutical composition that includes tramadol and meloxicam as active ingredients, wherein tramadol is present in an extended release
15 form and meloxicam in an immediate release form along with a pharmaceutically acceptable carrier. The pharmaceutical composition can be matrix or polymer coated. [0034] In another embodiment, the doses of tramadol and meloxicam of the invention can be administered individually as single ingredients or as a dual combination of from about 37.5 to about 300mg of tramadol, and from about 7.5 to about 15 mg of
20 meloxicam.
[0035] The present invention provides pharmaceutical compositions including from about 25mg to about 400mg of tramadol in an extended release form and from about 5 mg to about 20 mg of meloxicam in an immediate release form in admixture with a pharmaceutically acceptable carrier. Preferably the pharmaceutical compositions include
20 from about 30mg to about 300mg of tramadol and from about 7.5 mg to about 15 mg of meloxicam. More preferably the pharmaceutical compositions include from about 100mg to about 3OOmg of tramadol in an extended release form and from about 7.5 mg to about 15 mg of meloxicam.
[0036] In another embodiment, the present invention provides a pharmaceutical
30 compositions including about 100mg of tramadol in an extended release form and about 7.5 mg meloxicam in an immediate release form with a pharmaceutically acceptable carrier
[0037] In another embodiment, the present invention provides a pharmaceutical compositions including about 200mg of tramadol in an extended release form and about
35 7.5 mg meloxicam in an immediate release form with a pharmaceutically acceptable carrier.
9

WCK 2006/06/22 5 [0038] In another embodiment, the present invention provides a pharmaceutical
compositions including about 300mg of tramadol in an extended release form and about
7.5 mg meloxicam in an immediate release form with a pharmaceutically acceptable
carrier
[0039] In another embodiment, the present invention provides a pharmaceutical
10 compositions including about 100mg of tramadol in an extended release form and about 15 mg meloxicam in an immediate release form with a pharmaceutically acceptable carrier
[0040] In another embodiment, the present invention provides a pharmaceutical compositions including about 200mg of tramadol in an extended release form and about
15 15 mg meloxicam in an immediate release form with a pharmaceutically acceptable carrier
[0041] In another embodiment, the present invention provides a pharmaceutical compositions including about 300mg of tramadol in an extended release form and about 15 mg meloxicam in an immediate release form with a pharmaceutically acceptable
20 carrier
[0042] In another embodiment, the present invention provides a method of treating moderate to severe pain by adminsstering to a subject in need thereof, a pharmaceutical compositions including from about 25mg to about 400mg of tramadol in an extended release form and from about 5 mg to about 20 mg of meloxicam in an immediate release
25 form in admixture with a pharmaceutically acceptable carrier. Preferably the pharmaceutical compositions include from about 30mg to about 300mg of tramadol and from about 7.5 mg to about 15 mg of meloxicam. More preferably the pharmaceutical compositions include from about 100mg to about 300mg of tramadol in an extended release form and from about 7.5 mg to about 15 mg of meloxicam.
30 [0043] The pharmaceutical compositions of the invention can include granules of active ingredients prepared individually and mixed together or active ingredients are blended together and then granulated. In another embodiment, the granules of one active ingredient can be prepared and mixed with the other active ingredient. The formulation can be prepared in parts or in one single step by dry granulation, wet granulation or direct
35 compression.
10

WCK 2006/06/22 5 [0044] In another embodiment, the he pharmaceutical composition of the present
invention can be prepared in two parts. The first part includes intragranular and
extragranular material. The intragranular material includes tramadol with a
pharmaceutically acceptable carrier. Tramadol and the pharmaceutically acceptable
carrier components are granulated using wet granulation or dry granulation. The
10 granules are mixed with extragranular material(s) that can be selected from a group including of one or more fillers, lubricants, glidants, disintegrants, and the like.
[0045] The pharmaceutical compositions can be in the form of granules, powder, sachets, pellets, suspensions, capsule or compressed to form immediate release tablets, extended release tablets, controlled release or delayed release tablet wherein the tablet
15 can bilayer tablet, multilayer tablet, tablet in tablet, effervescent tablet, mini tablet.
[0046] In another embodiment, the pharmaceutical composition of the present invention is intended for oral administration and the said preferred subject is a mammal. In another embodiment, the pharmaceutical composition of the present invention is intended for once daily administration.
20 [0047] The pharmaceutically acceptable carriers can be selected from a group consisting of one or more of binder, filler, lubricant, glidant, disintegrant, pharmaceutically acceptable rate controlling polymer and the like.
[0048] Non-limiting examples of suitable binders include starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and
25 hydroxypropyl cellulose, and the like.
[0049] Non-limiting examples of suitable fillers include lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like.
[0050] Non-limiting examples of suitable lubricants include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate,
30 sodium benzoate and the like. Non-limiting examples of suitable glidants include colloidal silicon dioxide, talc, magnesium stearate and the like. Non-limiting examples of suitable disintegrants include starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
[0051] Non-limiting examples of suitable pharmaceutically acceptable rate
35 controlling polymer can be selected from a group comprising of one or more of cellulose ethers, acrylic acid polymers and mixtures thereof. Non-limiting examples of suitable
11

WCK 2006/06/22 5 cellulose ethers include ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl
cellulose and other suitable cellulose ethers or a mixture thereof. Non-limiting examples
of suitable acrylic acid polymers include any suitable polyacrylic acid polymers or
carboxyvinyl polymers such as those available under the brand name carbopol and the
like.
10 [0052] The following experimental examples descibe the invention in greater
particularity and are intended to be a way of illustrating but not limiting the invention.
Examples 1 -3

S.No. Ingredients Example 1 mg/tab Example 2 mg/tab Example 3 mg/tab
Part 1
Intragranular
1 Tramadol Hydrochloride 300 200 100
2 Ethyl cellulose FP 10 40 26.7 13.3
3 Xanthan gum 50 33.3 16.7
4 Microcrystalline cellulose (Avicel PH 101) 68.5 45.7 22.8
Extragranular
5 Magnesium stearate 7 4.7 2.3
6 Talc 9.5 6.3 3.2
Part 2
7 Meloxicam 7.5 7.5 7.5
8 Lactose monohydrate 100 100 100
9 Microcrystalline cellulose 60 60 60
10 Sodium citrate dihydrate 10 10 10
11 Povidone K 30 8 8 8
12 Crospovidone 7.5 7.5 7.5
13 Magnesium stearate 2 2 2
14 Talc 5 5 5
15
12

5 Examples 4 -6

WCK 2006/06/22

S.No. Ingredients Example 1 mg/tab Example 2 mg/tab Example 3 mg/tab
Part 1
Intragranular
1 Tramadol Hydrochloride 300 200 100
2 Ethyl cellulose FP 10 40 26.7 13.3
3 Xanthan gum 50 33.3 16.7
4 Microcrystalline cellulose (Avicel PH 101) 68.5 45.7 22.8
Extragranular
5 Magnesium stearate 7 4.7 2.3
6 Talc 9.5 6.3 3.2
Part 2
7 Meloxicam 15 15 15
8 Lactose monohydrate 92.5 92.5 92.5
9 Microcrystalline cellulose 60 60 60
10 Sodium citrate dihydrate 10 10 10
11 Povidone K 30 8 8 8
12 Crospovidone 7.5 7.5 7.5
13 Magnesium stearate 2 2 2
14 Talc 5 5 5
Procedure:
[0053] The pharmaceutical analgesic compositions mentioned in examples 1-6 are prepared in two parts. Part I includes the intragranular components and extragranular
10 components. The intragranular components are prepared by sifting the components individually and then mixing specified quantities of tramadol, Ethyl cellulose FP 10, Xanthan Gum, Microcrystalline cellulose (Avicel 101) and then granulating using purified water. The granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate.
13

WCK 2006/06/22 5 [0054] Part 2 is prepared by sifting the individual components and mixing specified
quantities of Meloxicam, Lactose Monohydrate, Microcrystalline cellulose, Sodium
citrate dihydrate, Povidone K -30 and Crospovidone. The blend is lubricated with talc
and magnesium stearate.
[0055] The first and second parts are mixed and compressed to form a bilayer tablet.
10 [0056] In another embodiment the extended release component comprising tramadol
in an extended release form is prepared as described in examples 7 to 9 below. This
dosage form is coated with an aqueous dispersion of meloxicam (Example 10) which
may futher be seal coated using Opadry.
Example 7
15
S.No. Ingredient mg/tab
1. Tramadol hydrochloride 301.96
2. Ethyl cellulose FP10 40.0
3. Xanthan gum (Xantural 75 USP) 50
4. Microcrystalline cellulose (Avicel PH 101) 66.54
5. Magnesium stearate 7.0
6. Talc 9.5
7. Purified water q.s
TOTAL 475mg
Procedure:
[0057] Tramadol, Ethylcellulose, Xantural & Avicel were mixed together and granulated with water. The granules were dried in a fluidized bed drier and passed 20 through 20-mesh sieve. The dried granules were lubricated with magnesium stearate and talc and were compressed using suitable tooling.
Example 8

S.No. Ingredient mg/tab
1. Tramadol hydrochloride 301.96
2. Ethyl cellulose FP 10 67.5
3. Sodium alginate (Keltone HVCR) 20.0
4. Calcium carbonate (Calcarb 4457) 31.75
5. Microcrystalline cellulose (Avicel PH 101) 13.04
6 Magnesium stearate 6.75
7. Talc 9.0
8. Purified water q.s
TOTAL 450mg
14

WCK 2006/06/22
5
Procedure:
[0058] Tramadol, Ethylcellulose, sodium alginate, calcium carbonate and Avicel were mixed together and granulated with water. The granules were dried in a fluidized bed drier and passed through 20-mesh sieve. The dried granules were lubricated with 10 magnesium stearate and talc and were compressed using suitable tooling.
S.No. Ingredient mg/tab
1. Tramadol hydrochloride 301.96
2. HPMCK100MCR 100.0
3. Hydroxypropyl cellulose (HPC-H) 40.0
4. Microcrystalline cellulose (Avicel PH 101) 15.54
5. Glyceryl behenate (Compritol 888 ATO) 25.0
6 Magnesium stearate 7.5
7. Talc 10.0
8. Purified water q.s
TOTAL 500mg
Example 9

15
Procedure:
[0059] Tramadol, HPMC, hydroxypropoyl cellulose, Avicel and Compritol were
mixed together and granulated with water. The granules were dried in a fluidized bed
drier and passed through 20-mesh sieve. The dried granules were lubricated with
20 magnesium stearate and talc and were compressed using suitable tooling.
Example 10
S.No. Ingredient mg/tab
1. Meloxicam 15
2. Opadry 30
3. Purified water q.s
Procedure:
25 [0060] Opadry was dispersed in water and meloxicam was added to it. The dispersion was homogenized and used for coating the tablets of tramadol extended release prepared as per examples 7 to 9.
15

WCK 2006/06/22 5 Example 11: Evaluation of Analgesic Effect:
[0061] Preliminary studies indicated a better efficacy and time to analgesia for the
Tramadol extended release / meloxicam combination when compared to Tramadol
extended release or meloxicam alone in subjects with moderate to severe pain following
oral dental surgery. A multicentric, double blind, randomized, parallel-group comparative
10 study was chosen as the study design on 36 subjects (12 in each treatment group). The total duration of the study is for two months for the completion of 30 evaluable patients from all sites. For each patient, the maximum duration of analgesic therapy with the study medications was chosen as 5 days.
[0062] Comparisons of the onset of analgesia and other measures of analgesic
15 efficacy with this combination are compared to the individual agents for the management of acute pain. Subjects in the study are evenly randomized to the three treatment groups;
A. Tramadol extended release
B. Meoxicam, and
C. Tramadol extended release and meloxicam.
20 [0063] Pain relief and pain intensity parameters are recorded on a defined timeline. The evaluation parameters include efficacy, which are evaluated by the mean pain relief, pain intensity, total pain relief and sum of pain intensity differences. Time to onset of pain relief on first day is determined by double-stopwatch technique Results are compiled according to the efficacy/ safety parameters and interpreted on the
25 basis of appropriate statistical tests.
[0064] All references cited herein are expressly incorporated herein by reference in
their entirety into this disclosure. Illustrative embodiments of this disclosure are discussed and reference has been made to possible variations within the scope of this disclosure. These and other variations and modifications in the disclosure will be
30 apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that this disclosure and the claims shown below are not limited to the illustrative embodiments set forth herein.
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5 CLAIMS:

WCK 2006/06/22

We claim:
1. A pharmaceutical composition comprising tramadol in an extended release form and
meloxicam, wherein the dose of tramadol is from about 20 mg to about 400 mg and the
dose of meloxicam is from about 5 mg to about 20 mg.
10 2. The pharmaceutical composition of claim 1, wherein the tramadol used is tramadol
hydrochloride
3. The pharmaceutical composition of claims 1 or 2, wherein the dose of tramadol is from
about 30 mg to about 300 mg and the dose of meloxicam is from about 7.5 mg to about
15 mg.
15 4. The pharmaceutical composition of claim 3, wherein the dose of tramadol is from
about 100 mg to about 300 mg of tramadol in an extended release form and from about
7.5 mg to about 15 mg of meloxicam.
5. The pharmaceutical composition of any of claims 1-4, further comprising a
pharmaceutically acceptable carrier.
20 6. The pharmaceutical composition of any of claims 1-5, wherein the composition is in
the form of a tablet.
7. The pharmaceutical composition of any of claims 1-6, wherein the composition is in
the form of a kit.
8. The pharmaceutical composition of any of claims 1-7, wherein the composition is
25 administered orally.
9. The pharmaceutical composition of any of claims 1-8, wherein the composition is
administered once a day.
10. A method of treating pain in a mammal in need thereof comprising administering to
the mammal an effective amount of a pharmaceutical composition of any of claims 1-9.
30 11. The method of claims 9 or 10, wherein the composition is administered orally.
12. The method of claims 9 or 10, wherein the composition is administered once a day.
13. Use of a composition of any of the claims 1-9, to prepare a medicament useful for treating pain or pyrexia in a mammal in need thereof.
14. Use of claim 13, to prepare a medicament useful for treating pain in a mammal.
35 For Wockhardt Limited
V.R. Srinivas
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WCK 2006/06/22
5 ABSTRACT;
[0065] The present invention provides a pharmaceutical composition comprising a centrally acting opioid analgesic agent and a peripherally acting non-opioid analgesic agent. The compositions of the present invention provide improved analgesia when compared to the individual agents taken alone. The compositions of the invention can
10 employ smaller amounts of each ingredient than typically required to provide a similar analgesic response than when the agents are administered alone.
For Wockhardt Limited V.R. Srinivas
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