WO2003080183A1

WO2003080183A1 - Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids

Info

Publication number: WO2003080183A1
Application number: PCT/GB2003/001182
Authority: WO
Inventors: David Sackler Mortimer
Original assignee: Euro-Celtique S.A.; Ruffles, Graham, Keith
Priority date: 2002-03-19
Filing date: 2003-03-19
Publication date: 2003-10-02
Also published as: AU2003226496A1; GB0206505D0

Abstract

Etodolac with an opioid analgesic is of use in treating pain.

Description

PHARMACEUTICAL COMBINATION OF THE COX-2 INHIBITOR ETODOLAC AND OPIODS

This invention relates to pharmaceutical preparations containing a cyclooxygenase-2 inhibitor and at least one opioid.

BACKGROUND OF THE INVENTION

Non-steroidal anti-inflammatory drugs, NSAIDs, exert most of their anti- inflammatory, analgesic and antipyretic activity and activity in reducing hormone-inclined uterine contractions through the inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Fatty acid cyclooxygenase (COX) is the source of prostaglandins, thromboxanes and various other biologically active hydroxylated metabolites derived from arachidonic acid and higher unsaturated fatty acids.

Although it was initially believed that COX induction was the simple result of oxidative inactivation of COX, which happens after only a few substrate turnovers, cyclooxygenase is induced to a much greater degree than necessary to replace the lost enzyme. Careful investigation of the induced material reveals that expression of a second COX enzyme, named COX-2, was responsible for the previously observed excess COX activity. COX-2 is largely absent from many cells under basal conditions but is rapidly induced by several cytokines and neuro transmitters.

It is believed that COX- 1 is responsible, in many cells, for endogenous based release of prostaglandins and is important in the physiological functions of prostaglandins which include the maintenance of gastro-intestinal integrity and renal blood flow. Inhibition of COX-I causes a number of side effects including inhibition of platelet aggregation associated with disorders of coagulation, and gastro-intestinal toxicity leading potentially to ulcerations and haemorrhage. The gastro-intestinal toxicity is due to a decrease in the biosynthesis of prostaglandins which are cytoprotective of the gastric mucosa.

A high incidence of side effects has historically been associated with chronic use of classic cyclooxygenase inhibitors, for example those which are COX-I selective or those which are about equipotent for COX-I and COX-2.

It has been proposed that rapid induction of COX-2 is mainly responsible for the pathological effects of prostaglandins in response to agents such as inflammatory agents, hormones, growth factors and cytokines. A compound which has a high specificity for COX-2 over COX-I may, therefore, have anti- inflammatory, antipyretic and analgesic activity but concurrently with a diminished ability to introduce some of the mechanism-based side effects such as a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in acetylsalicylic acid-sensitive asthmatic subjects.

The elucidation of COX-2 responsibility for gastrointestinal epithelial prostaglandins production and contribution to renal synthesis led to the recognition that several COX inhibitors, including nimesulide and Dup-697, which were known to cause little or no gastrointestinal irritation, are COX-2 selective.

The general concept of combining an COX-2 inhibitor with an opiate to achieve enhanced analgesic action is known.

WO 9 13799 (Euro-Celtique) describes the use of a combination of a selective COX-2 inhibitor and an opiate in the treatment of pain. The preferred COX-2 inhibitors have at least 9 fold greater specificity for COX-2 over COX-1 and preferably demonstrate an in vitro IC50 and/ or in vivo ED50 ratio for COX- 1 to COX-2 of approximately 20 fold or greater, more preferred inhibitors 100 fold or greater, and the most preferred inhibitors 1000 fold or greater.

WO 0029022 (Algos) describes a method of alleviating a pain state not associated with a cough by administering a COX-2 inhibitor and a centrally active analgesic which may be for example codeine or hydrocodone. A large number of diverse COX-2 inhibitors are mentioned. The compositions may contain another non-narcotic analgesic in addition to the COX-2 inhibitor and the centrally active analgesic.

WO 0029023 (Algos) describes a method of alleviating a pain state not associated with a cough condition which comprises administering a COX-2 inhibitor with a non toxic NMDA receptor antagonist such as dextromethorphan or its metabolite dextrorphan.

WO 0158447 (Euro-Celtique) relates to controlled-release compositions containing opioid agonist and antagonist. The compositions may contain a further non-opioid drug, which can be a cyclooxygenase-II inhibitor.

Although the above disclosures provide useful combinations of opioids and COX -2 selective inhibitors there is still a demand for other combination products to provide effective pain relief with reduced undesirable side effects.

OBJECTS OF THIS INVENTION

An object of the present invention is to provide an alternative pharmaceutical composition comprising a combination of a COX-2 inhibitor and an opioid analgesic.

A further object of the invention is to provide an alternative method for effectively treating pain by administering a COX-2 inhibitor together with a dose of opioid analgesic.

SUMMARY OF THE INVENTION

The present invention employs etodolac as the COX-2 inhibitor in a combination therapy of COX-2 inhibitor and opioid analgesic.

According to the present invention, there is provided a pharmaceutical composition comprising a combination of etodolac in an amount sufficient to render a therapeutic effect together with an opioid analgesic. The compositions are useful as analgesics and in the treatment of inflammatory disorders such as arthritis.

The present invention also encompasses a method of inhibiting COX- 1 and COX-2 mediated diseases comprising administering to a patient in need of such treatment a non-toxic therapeutically effective amount of etodolac and opiate analgesic.

To this end, the invention also provides for the use of etodolac in the preparation of a medicament for treating pain by administering etodolac and an opioid analgesic.

The etodolac is employed as the COX-2 inhibitor, and the invention does not require the presence of other COX-2 inhibitors. More especially, the invention provides compositions and methods free from other COX-2 inhibitors such as those with higher selectivity for COX-2.

In this respect, the preferred compositions of this invention consist of two active ingredients, the etodolac and the opioid analgesic, with no other active ingredients. DETAILS OF THE INVENTION

Etodolac, the compound 1,8-diethyl- l, 3, 4, 9 -tetrahydropyrano [3,4 b] indole- 1 -acetic acid, was first disclosed in 1973 in German Patent No. 2,301,525 (Wyeth-Ayerst). It has been used as active ingredient in various analgesic and anti-inflammatory preparations for a number of years, such as those sold under the Trade Marks Lodine, Todolac, Etogesic and Ultradol.

Etodolac can form salts and esters. References in here to etodolac include pharmaceutically salts and esters. Where a dosage is given, it is calculated as etodalc, but the active ingredient can be a pharmaceutically active salt or ester.

Etodolac is an NSAID which is effective for for both COX-1 and COX-2, the ratio of selectivity having been reported as about 10: 1 for COX-2:COX-l. This figure is in contrast to the selectivity ratios of the latest generation of COX-2 inhibitors which have a ratio of about 1000: 1 in favour of COX-2. Despite the significantly lower ratio of selectivity, etodolac has been shown in comparative trials against COX-1 selective NSAIDs to be as good or better in terms of adverse events.

Etodolac is listed in WO 00/29022 together with inter alia aspirin, as a possible third component, a non-narcotic analgesic, but is not included as a primary ingredient. The compositions of this invention employ the etodolac as the COX-2 inhibitor, and do not require the presence of another COX-2 inhibitor.

The opioid analgesic such as oxycodone or morphine may be the drug in its true form, or a pharmaceutically acceptable salt or complex thereof. A non- limiting list of suitable opioid analgesic drugs which may be used in the combination products of this invention includes alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbuturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene. ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentonil, tilidine, tramadol, salts thereof, complexes thereof; mixtures of any of the foregoing, mixed mu-agonists/ antagonists, mu-antagonist combinations, salts or complexes and the like.

In certain preferred embodiments, the opioid analgesic is chosen from oxycodone, morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, diamorphone, tramadol, oxymorphone, salts therof, or mixtures thereof. Other preferred opioid analgesics include oxymorphone and fentanyl.

Dosage levels of etodolac or salts or esters thereof will generally be in the range of 600 mg to 1200 mg daily (calculated as etodolic acid). The dosage will usually be an immediate release oral dosage form or a controlled release oral dosage form. For oral application particularly suitable are tablets, effervescent or chewable tablets, dragees, liquids, drops, capsules, caplets and gelcaps. Other suitable dosage forms include suppositories and oils or aqueous solutions, suspensions or emulsions for oral or parenteral use.

The etodolac and opioid analgesic are preferably formulated as a single composition, but the invention does not exclude the administration of separate compositions of etodolac and opioid analgesic, either simultaneously or serially.

Immediate release dosage forms may contain for example 200 to 400 mg of etodolac for administration every six to eight hours in combination with a suitable amount of opioid. In one embodiment the etodolac, preferably 200 mg to 400 mg, is combined with an opioid to provide dosage forms for administration for example 4 or 6 times a day. Preferred dosage forms contain one of the following:

Codeine sulphate 16 mg to 60 mg

Oxycodone hydrochloride 5 mg to 40 mg

Morphine sulphate 5 mg to 60 mg

Dihydrocodeine tartrate 15 mg to 60 mg

Hydromorphone hydrochloride 1 mg to 4 mg

Hydrocodone tartrate 5 mg to 10 mg

Dextropropoxyphene hydrochloride 12 mg to 65 mg Buprenorphine hydrochloride(sub lingual) 0.2 mg to 0.4 mg

Oxymorphone hydrochloride 0.25 mg to 0.5 mg

Fentanyl citrate 0.5 mg to 2.5 mg

The amount of opioid and etodolac to be dosed in combination will vary depending upon the patient, the severity of the pain, the particular mode of adminsitration, and other factors familiar to the skilled person.

In general, the daily dosage rates are in the following ranges, where the opioid is in the form of the appropriate base or salt:

Codeine 16 mg to 240 mg

Oxycodone 5 mg to 160 mg

Morphine 5 mg to 240 mg

Dihydrocodone 15 mg to 240 mg

Hydromorphone 1 mg to 16 mg

Hydrocodeine 5 mg to 40 mg Dextropropoxyphene 12 mg to 260 mg

Buprenorphine (sub lingual) 0.2 mg to 1.6 mg

Oxymorphone 0.25 mg to 2 mg

Fentanyl 0.5 mg to 10 mg

In the case of controlled or sustained release formulations of this invention, preferably 600 mg to 1200 mg etodolac is combined with a suitable amount of opioid and may be formulated for once or twice a day dosage forms of a suitable size. The required dose may be divided between two to four tablets, capsules or other dosage forms. The amount of opioid can be derived from the above figures given for the immediate release products.

In a related aspect of this invention, synergistic compositions are provided, especially those which permit a reduced dose of opioid analgesic to be employed. Thus, in such compositions the etodolac is provided in order to give an opioid sparing effect, where effective pain relief is achieved using a reduced dosage of the opioid analgesic and preferably with fewer side effects. For example, the amount of opioid analgesic might be less than 90%, 75%, 50%, 40% or 25% of the conventional dose.

Illustratively, the daily dosage of the opioid might be in the following ranges:

The daily doses can be subdivided, as for example for administration 2, 3, 4 or 6 times a day.

The diseases which may be treated by the present invention include moderate to severe pain arising from many aetiologies, including but not limited to cancer pain and post surgical pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and anal strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis. bursitis, burns and injuries.

The combination of etodolac and opioid is of particular interest as an alternative to conventional NSAIDs or combinations of other NSAIDs with other drugs particularly where such non-steroidal anti-inflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastro-intestinal lesions; GI bleeding, coagulation disorders including anaemia such as hypoprothrombinaemia, haemophilia or other bleeding problems; kidney disease; those prior to surgery or taking anticoagulants.

The dosage form of the invention, especially the sustained release dosage forms, achieve and maintain therapeutic levels of opiate without significant increases in the intensity and/ or degree of concurrent side effects such as nausea, vomiting or drowsiness, which are often associated with high blood levels of opiate analgesics.

The etodolac and opioid analgesic combination can be formulated as a controlled or sustained release oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art. The etodolac or opioid analgesic or both may be in sustained release form. The sustained release dosage form may include a sustained released carrier which is incorporated into a matrix or which is applied as a sustained release coating.

The sustained release dosage form may include the opioid analgesic in sustained release form and etodolac in sustained release form or in immediate release form. The etodolac may be incorporated into the sustained release matrix along with the opioid; incorporated into the sustained release coating; incorporated as a separated sustained release layer or immediate release layer; or may be incorporated as a powder, granulation, etc. in a gelatin capsule with the substrates of the present invention. Alternatively, the sustained release dosage form may have the etodolac in sustained release form and the opioid analgesic in sustained release form or immediate release form.

The combination of etodolac and opiate analgesics may thus be formulated to provide for an increased duration of analgesic action allowing once or twice daily oral dosing. These formulations, at comparable daily dosages of conventional immediate release drug are associated with a lower incidence in severity of adverse drug reactions. The combination of etodolac and opioid analgesic of this invention can be provided in compositions in association with conventional excipients, for example pharmaceutically acceptable organic or inorganic carriers or diluents suitable for oral, parenteral, intravenous, subcutaneous, or any other mode of administration known to the art. Suitable carriers include, for example, water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycols and diglycerides, pentaerythritol fatty acid.

Suitable dosage forms may include those described in our EP 220,805, or EP 253,104, EP 654,263, EP 1,014,886, WO 9913799 or WO 0158447, the contents of which are incorporated herein in full by way of reference.

The compositions may be prepared according to methods known in the art. In the case of tablets these may contain excipient, an inert diluent such as lactose, and granulating and disintegrating agents such as cornstarch, binding agents such as starch, and lubricating agents such as magnesium stearate. The tablets may for example, alternatively contain waxes or oils as inert diluents, for example hydrogenated vegetable or hydrogenated castor oil, or acrylic resins and fatty alcohols, for example Eudragit and stearyl alcohol. Beads or spheroids contained in capsules will usually include a spheronising agent and possibly binding agent, for example microcrystalline cellulose and hydroxypropylmethyl cellulose.

Delayed or controlled release may be achieved by appropriate dose of the excipients used to manufacture the tablet or bead or spheroid according to known technique. Tablets and beads may alternatively be coated with suitable coating material to achieve delayed release.

Aqueous and oily suspensions, syrups, elixirs, and injectable suspensions may be prepared using conventional excipients and techniques. It is also possible to freeze-dry the active compounds and use the obtained lyophilised compounds, for example, for the preparation of products for injection.

An oral dosage form according to the invention may be provided as, for example, granules, spheroids, beads, pellets and/ or particles. Such particulate ingredients are hereinafter collectively referred to as multiparticulates. An amount of the multiparticulates which is effective to provide the desired dose of opioid over time may be placed in a capsule or may be incorporated in any other suitable oral solid form.

In one preferred embodiment of the present invention, the sustained release dosage form comprises the particles or other form of multiparticulates containing or comprising the active ingredient, wherein the multiparticulates have a diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.25 mm to about 2 mm.

In certain embodiments, the particles or other form of multiparticulates comprise normal release matrixes containing the opioid analgesic with or without the todolac. These particles or other form of multiparticulates are then coated with the sustained release carrier. In embodiments where the etodolac is immediately released, the etodolac may be included in separate normal release matrix particles or other form of multiparticulates in the same dosage unit or in a separate dosage unit, for example gelatin capsules, to be administered separately. In other embodiments, the multiparticulates comprise inert beads which are coated with the opioid analgesic with or without the etodolac. Thereafter, a coating comprising the sustained release carrier is applied onto the beads as an overcoat.

The particles or other form of multiparticulates are preferably film coated with a material that permits release of the opioid (or salt or ester) and if desired, the etodolac at a sustained rate in an aqueous medium. The film coat is chosen to as to achieve, in combination with the other stated properties, a desired in-vitro release rate. The sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack- free.

Typical procedures for preparing combination preparations of this invention include the following:

Processes For Preparing Matrix - Based Beads

Solid, controlled release, oral dosage preparations according to this invention with the active ingredients in a matrix may be prepared by methods known in the art. For example, incorporation in a matrix may be effected by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose, etodolac and opioid or an opioid salt; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C12 - C36 aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the granules are formed by wet granulating the hydroxyalkyl cellulose/ opioid with water.

In one alternative embodiment, a spheronizing agent, together with the active ingredients can be spheronized to form spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose. In such embodiments, the sustained release coating will generally include a hydrophobic material such as (a) a wax, either alone or in admixture with a fatty alcohol; (b) shellac or zein; or (c) a water insoluble polymer such as Eudragit or ethyl cellulose.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation or melt-extrusion techniques. Generally, melt- granulation techniques involve melting a normally solid hydrophobic material, for example a wax, and incorporating a powdered drug therein. To obtain a sustained release dosage form, it may be necessary to incorporate an additional hydrophobic substance, for example ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic material. Examples of sustained release formulations prepared via melt-granulation techniques are found in U.S. Patent No. 4,861,598, hereby incorporated by reference in its entirety. The additional hydrophobic material may comprise one or more water- insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances. In order to achieve constant release, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Useful water-insoluble wax-like substances may be those with a water- solubility that is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a sustained release matrix may also contain suitable quantities of other materials, for example diluents, lubricants, binders, granulating aids, colorants, flavourants and glidants that are conventional in the pharmaceutical art. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated by reference herein.

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix formulation may, for example, include the steps of blending the opioid analgesic, together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture. The homogenous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same. The resulting homogenous mixture is then extruded to form strands. The extrudate or strands are preferably cooled and cut into multiparticulates by any means known in the art. The multiparticulates are the divided into unit doses. The extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.

An optional process for preparing the melt extrusions of the present invention includes directly metering into an extruder a hydrophobic material, a therapeutically active agent, and an optional binder; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogenous mixture; cutting the strands into particles or other form of multiparticulates having a size from about 0.1 mm to about 12 mm; and dividing said multiparticulates into unit doses. In this aspect of the invention, a relatively continuous manufacturing procedure is realised.

The diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands. Furthermore, the exit part of the extruder need not be round; it can be oblong, rectangular, etc. The exiting strands can be reduced to particles or other form of multiparticulates using a hot wire cutter, guillotine, pelletizer, etc.

The melt extruded multiparticulate system can be, for example, in the form of granules. Spheroids or pellets depending upon the extruder exit orifice. For purposes of the present invention, the melt-extruded multiparticulates, melt-extruded multiparticulate systems and melt-extruded particles or other form of multiparticulates refer to a plurality of units, preferably within a range of similar size and/ or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described herein. In this regard, the melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm. In addition, it is to be understood that the melt-extruded multiparticulates can be any geometrical shape within this size range. Alternatively, the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.

Gelatin capsules may be filled with melt-extruded multiparticulates in known manner.

In another preferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorporated by reference herein.

In yet another preferred embodiment, the extrudate can be shaped into tablets as set forth in U.S. Patent No. 4,957,681 (Klimesch, et.al.) described in additional detail above and hereby incorporated by reference.

Optionally, the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained release coating such as the sustained release coatings described above. Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the physical properties of the particular opioid analgesic compound utilized and the desired release rate, among other things.

The melt-extruded unit dosage forms of the present invention may further include combinations of melt-extruded muliparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated. Furthermore, the unit dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effect. The immediate release therapeutically active agent may be incorporated, for example as separate pellets within a gelatin capsule, or may be coated on the surface of the multiparticulates after preparation of the dosage forms (for example controlled release coating or matrix-based). The unit dosage forms of the present invention may also contain a combination of controlled release beads and matrix multiparticulates to achieve a desired effect.

In other embodiments of the invention, the melt extruded material is prepared without the inclusion of the therapeutically active agent, which is added thereafter to the extrudate. Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation. Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/ or the retardant material.

Melt pelletisation

Formulations in accordance with the invention may be prepared, with the etodolac, or opiate or both, in a controlled release matrix by the process of mechanically working a hydrophobic or hydrophilic fusible carrier or diluent in finely divided form and active ingredient in particulate s form in a high- shear mixer at a speed such that the energy input from the mixing process and any external energy input melts or softens the carrier or diluent whereby it forms particles with the active ingredient. Such a process is described in WO 9206679 and WO 9318753, incorporated herein in full by reference.

Another preferred process for making such formulations comprises (a) mechanically working the drugs with a particulate hydrophobic or hydrophilic fusible carrier or diluent in a high-shear mixer at a speed and energy input which allows the carrier or diluent to melt or soften, whereby it forms agglomerates, (b) breaking down the agglomerates to give controlled release seeds, (c) continuing mechanically working with optionally a further addition of particulate hydrophobic or hydrophilic fusible carrier; and (d) optically repeating step (c) and possible (b) one or more times.

If desired, optionally a release modifying component such as a water soluble fusible material for example a polyethleneglycol or particulate, soluble or insoluble organic or inorganic material, for example dicalcium phosphate or lactose.

Such a process is described in EP 654,263, incorporated herein in full by reference.

Bi-layer tablets

Bi-layer tablets may take the form described in EP 220,805, incorporated herein in full by reference.. This is a multiphase tablet comprising a first phase containing the opiate or an analgesically effective salt or ester thereof and at least one other phase containing etodolac or a therapeutically effective salt or ester thereof, in which the first phase is preferably free from etodolac or salt or ester thereof, stearic acid and a stearate salt, and the at least one other phase is free from opiate or salt or ester thereof, stearic acid and a stearate salt, and each phase contains at least one self lubricating compression acid such as a self-lubricating direct compression acid for example Elcema G-250 (Trade Mark, Degussa, cellulose granules derived from powdered cellulose N.F.), Starch 1500 (Trade Mark, Colorcon, a free flowing, directly compressible starch) and microcrystalline cellulose (for example Avicel, Trade Mark FMC).

The etodolac phase or phases and/ or the opiate phase may also contain substances suitable for the formation of a controlled release formulation. Thus, the phase or phases may contain, for example, a hydrated water soluble hydroxyethylcellulose, especially hydroxyethylcellulose, and a higher aliphatic alcohol, especially cetostearyl alcohol as described in British Patent No. 1,405,088 (equivalent to US 3965256 and US 4235870) the contents of which are incorporated herein in full by way of reference.

Formulations of this type may be made by direct compression or, preferably, by wet granulation techniques. The wet granulation process comprises:

(a) granulating an opiate or analgesically effective salt or ester thereof with at least one self-lubricating, compression aid;

(b) granulating etodolac or a pharmaceutically effective salt or ester thereof with at least one self-lubricating compression aid to form granules;

(c) compressing the granules from steps (a) and (b).

In both steps (a) and (b) two methods of granulation may be used.

In the first method, the drug, the compression acid and the binder are dry mixed. The mixed powders are then granulated by wetting with a solvent. In the second method, the dry and the compression aid are dry mixed and then granulated by wetting with a solution of binder.

Coatings

The dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH-independent release, for example when exposed to gastrointestinal fluid. A pH-dependent coating serves to release the opioid in desired areas of the gastro-intestinal (GI) tract, for example the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least about twelve hour and preferably up to twenty-four hour analgesia to a patient. pH-independent coatings are designed to achieve optimal release regardless of pH-changes in the GI tract. It is also possible to formulate compositions which release the active ingredient in one desired area of the GI tract, for example the stomach, or which release a portion thereof in one desired area and release the remainder of the dose in another area of the GI tract, for example the small intestine. Such a formulation is described in our International Patent Application PCT/GB 01/04423, incorporated herein in full by reference.

Formulations according to the invention that utilise pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over an enteric coat and is released in the stomach, while the remainder, being protected by an enteric coating, is released further down the gastrointestinal tract. Coatings which are pH- dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PNAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (for example tablet core bead, matrix particle) containing the opioid analgesic (with or without the Etodolac) is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The coating may be applied in the form of an organic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile. Such formulations are described, for example in detail in U.S. Patent Νos. 5,273,760 and 5,286,493, assigned to the Assignee of the present invention and hereby incorporated by reference.

Other examples of sustained release formulations and coatings which may be used in accordance with the present invention include Assignee's U.S. Patent Νos. 5,324,351; 5,356,467 and 5,472,712 hereby incorporated by reference in their entirety.

Cellulosic materials and polymers, including alkycelluloses, provide hydrophobic materials well suited for coating the beads according to the invention. A preferred alkylcellulosic polymer is ethylcellulose, but other cellulose and/ or alkylcellulose polymers known in the art can be used singly or in any combination, as all or part of a hydrophobic coating in the practice of the invention.

One commercially-available aqueous dispersion of ethylcellulose is Aquacoat ® (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat ® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabiliser. After homogenisation to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat ® with a suitable plasticizer prior to use.

Another aqueous dispersion of ethylcellulose is commercially available as Surelease ® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.

In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid) poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparing pH- dependent coatings which may be used in accordance with the present invention. For example, there are a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit ® from Rohm Tech, Inc. There are several different types of Eudragit ®. For example, Eudragit ® E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media. Eudragit ® L is a methacrylic acid copolymer which does not swell at about pH < 5.7 and is soluble at about pH > 6. Eudragit ® S does not swell at about pH < 6.5 and is soluble at about pH > 7. Eudragit ® RL and Eudragit ® RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent.

In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Trade names Eudragit ® RL30D and Eudragit ® RS30D, respectively. Eudragit ® RL30D and Eudragit ® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth) acrylic esters being 1 :20 in Eudragit ® RL30D and 1 :40 in Eudragit ® RS30D. The mean molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit ® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit ® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit ® RL, 50% Eudragit ® RL and 50% Eudragit ® RS, and 10% Eudragit ® RL:Eudragit ® 90% RS. Of course, one skilled in the art will recognise that other acrylic polymers may also be used, such as, for example, Eudragit ® L.

In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, for example most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water- insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate and possible 1 ,2-propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit ® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing.

Processes For Preparing Coated Beads

When the aqueous dispersion of hydrophobic material is used to coat inert pharmaceutical beads such as nu pareil 18/20 beads, a plurality of the resultant stabilised solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, for example gastric fluid or dissolution media.

The stabilised controlled release bead formulations of the present invention slowly release the therapeutically active agent, for example when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic material, altering the manner in which the plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. The dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.

Spheroids or beads coated with a therapeutically active agent are prepared, for example by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu pareil 18/20 beads, using a Wuster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the binding of the opioid to the beads, and/ or to colour the solution, etc. For example, a product which includes hydroxypropylmethylcellulose, etc. with or without colourant (for example Opadry ®, commercially available from Colorcon, Inc.) may be added to the solution and the solution mixed (for example for about 1 hour) prior to application of the same onto the beads. The resultant coated substrate, in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating. An example of a suitable barrier agent is one which comprises hydroxypropylmethylcellulose. However, any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of the hydrophobic material. The aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, for example triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat ® or Surelease ®, may be used. If Surelease ® is used, it is not necessary to separately add a plasticizer. Alternatively, pre-formulated aqueous dispersions of acrylic polymers such as Eudragit ® can be used.

The plasticized aqueous dispersion of hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art. In a preferred method, a Wurster fluidised-bed system is used in which an air jet, injected from underneath, fluidises the core material and effects drying while the acrylic polymer coating is sprayed on. A sufficient amount of the aqueous dispersion of hydrophobic material to obtain a predetermined controlled release of said therapeutically active agent when said coated substrate is exposed to aqueous solutions, for example gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, etc. After coating with the hydrophobic material, a further overcoat of a film-former, such as Opadry ®, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.

The release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, i.e. adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating. The ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose .

The sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain. The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like which may be formed by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby incorporated by reference) .

Matrix Bead Formulations

The present invention may also utilise a controlled release matrix that affords in-vitro dissolution rates of the opioid within the preferred ranges and that releases the opioid in a pH-dependent or pH-independent matter. The materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix.

For example, a matrix in addition to the opioid analgesic and (optionally) Etodolac may include:

Hydrophilic and/ or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials.

Digestible, long chain (Cs -C50, especially C12 - C40) substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol; and polyalkylene glycols. Of the polymers, acrylic polymers, especially Eudragit ® RSPO - the cellulose ethers, especially alkylcellulose, hydroxyalkylcelluloses and 'carboxyalkylcelluloses, are preferred.

The oral dosage form may contain between 1% and 80% (by weight) of at least one hydrophilic or hydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25 and 90 C. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60% (by weight ) of at least one digestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of at least one polyalkylene glycol.

The hydrophobic material is prefeably selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In certain preferred embodiments of the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material is selected from materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing. Preferred hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/ or hydrophobic trends. Preferably, the hydrophobic materials useful in the invention have a melting point from about 30 to about 200 °C, preferably from about 45 to 90 °C. Specifically, the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides;), hydrogenated fats, hydrocarbons, normal waxes, stearic a[c]id, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones. Suitable waxes include, for example, beeswax, glycowax, castor wax and carnauba wax. For purposes of the present invention, a wax-like substance is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to 140 °C.

Amongst the preferred materials are hydrophobic or hydrophilic fusible materials having melting points of from 35 to 140 °C, for example hydrogenated vegetable oil and hydrogenated castor oil. Such material may melt or soften to enable working by way of extrusion or intensive mixing to form muliparticulates for example pellets or spheroids.

Suitable hydrophobic materials which may be used in accordance with the present invention include digestible, long chain (Cs - C50 especially C12 -C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25 and 90 °C are suitable. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments. The oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.

Preferably, a combination of two or more hydrophobic materials are included in the matrix formulations. If an additional hydrophobic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive.

One particular suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C12 - C36 , preferably C14 - C22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy (Ci to Cβ ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially hydroxyethylcellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of opioid release required. The at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the at least one aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of opioid release required. The formulation may contain at least one polyalkylene glycol or other release modifying agent for example dicalcium hydrogen phosphate is present in or absent from the oral dosage form. For example, in the absence of a release modifying agent, the oral dosage form may contain between 20% and 50% (by wt) of the at least one aliphatic alcohol, whereas when at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20% and 50% (by wt) of the total dosage.

In one embodiment, the ratio of, for example the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/ polyalkylene glycol determines, to a considerable extent, the release rate of the opioid from the formulation. A ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/ polyalkylene glycol of between 1:2 and 1 :4 is preferred, with a ratio of between 1 :3 and 1 :4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled release matrix would comprise an alkylcellulose (especially ethylcellulose), a C12 to C36 aliphatic alcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials.

EXAMPLES OF THE INVENTION

Example 1

Direct compression /encapsulation blend

The drugs are blended with the excipients in the amounts given which are expressed per tablet or capsule

Etodolac 200 mg

Codeine phosphate 30 mg

Microcrystalline cellulose 50 mg

Lactose 50 mg

Croscarmellose sodium 1.5 mg

Colloidal anhydrous silica 1.5 mg

Magnesium stearate 1.5 mg Blend the powders to achieve a uniform mix using a suitable blender, for example bin blender, Y-cone or high-shear mixer such as a Collette Gral. Fill the resulting blend into hard gelatin capsules using an automatic capsule filler such as those manufactured by Bosch, MG2 or Zanasi.

Alternatively compress the powder directly into tablets using appropriate shape and size of tooling fitted to a tablet press such as those made by Fette, Kilian and Manesty.

If desired film coat the tablet with a cosmetic coating using a film forming polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose or Eudragit E. Suitable plasticizers, colouring agents and anti-tack agents may be included in the coating as required.

Example 2

Wet granulation

Working with the ingredients given below in amounts per tablet or capsule, granulate the blend of drug, lactose and microcrystalline cellulose with a solution of povidone as a binder (other binders such as hydroxypropylmethyl cellulose can be used) in a mixer, for example a high shear mixer such as a Collette Gral, Fielder or Diosna. Dry the granules in a drier, for example a tray drier or a fluid bed drier such as a Glatt or an Aeromatic.

Classify the granules using a screen fitted to a mill/granulator, for example a Jackson Crockatt, Co-mill or Glatt QuickSieve. Blend the granules with disintegrant, lubricant and glidant. Compress into tablets or encapsulate the granules in hard gelatin capsules.

Etodolac 200 mg

Codeine phosphate 30 mg Microcrystalline cellulose 50 mg

Lactose 50 mg

Povidone 7.0 mg

Croscarmellose sodium 7.0 mg

Colloidal anhydrous silica 1.5 mg

Magnesium stearate 1.5 mg

Alternatively, the etodolac and codeine phosphate may be incorporated in separate layers of a bi-layered tablet.

Controlled Release Formulations

Etodolac 600 mg to 1200 mg daily is combined with suitable doses of opioid such as those listed below:

Codeine phosphate 16 to 240 mg

Oxycodone hydrochloride 5 to 40 mg

Morphine sulphate 5 to 120 mg

Dihydrocodeine tartrate 15 to 240 mg Hydromorphone hydrochloride 1 to 16 mg

Hydrocodone tartrate 1 to 40 mg

The products may be formulated for once daily or twice daily administration. To enable achievement of a once a day dosage form of acceptable size, the required dose may be divided between two to four tablets /capsules.

The two active ingredients may be formulated in a range of different controlled release dosage forms known in the art, including tablets and capsules using a range of controlled release technologies also known in the art. This will include matrix tablets and multiparticulates, coated beads, spheroids and multiparticulates, osmotically controlled systems. Optionally controlled release etodolac may be combined with an immediate release opioid, for example by use of a bi-layered tablet, for example as described in our European Patent No. 220,805, or dual filled capsule.

Example 3

Melt Granulation

Etodolac 300 mg

Codeine phosphate 60 mg

Hydrogenated vegetable oil 300 mg

Colloidal anhydrous silica 6.6 mg

Magnesium stearate 6.6 mg

Granulate the etodolac, codeine phosphate and hydrogenated vegetable oil using a mixer equipped with a heating jacket, for example a high shear mixer such as a Collette Gral, Fielder or Diosna, or preferably equipped for microwave heating, for example Colette Vactron or Fielder Spectrum. Classify the granules using a screen fitted to a mill/granulator, for example a Jackson Crockatt, Co-mill or Glatt QuckSieve. Blend the granules with lubricant and glidant. Compress into tablets using appropriate shape and size tooling fitted to a tablet press such as those made by Fette, Kilian and Manesty. If desired, film coat the tablets with a cosmetic coating using a film forming polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose or Eudragit E. Suitable plasticisers, colouring agents and anti- tack agents may be included in the coating as required

An alternate formulation is as follows:

Etodolac 300 mg

Codeine phosphate 60 mg

Hydrogenated vegetable oil 300 mg

Talc 26 mg Magnesium stearate 4 mg Alternate wax materials include hydrogenated castor oil, carnauba wax, 'microcrystalline wax, glyceryl behenate, bees wax and glyceryl monostearate. These should have a melting point between 35 °C to 140 °C preferably 45 °C to 110 °C. The type and ratio of hydrophobic release controlling agents to drug may be varied to control the release rate of the active ingredient. A release modifying agent such as polyethylene glycol, for example, polyethylene glycol 6000, may be added if required.

Example 4

Spray Granulation

The following ingredients per tablet are used

Etodolac 300 mg

Codeine phosphate 60 mg

Eudragit RS30D (solids) 100 mg

Stearyl acid 50 mg

Colloidal anhydrous silica 6.6 mg

Magnesium stearate 6.6 mg

Spray granulate the etodolac and codeine phosphate with a suspension of the Eudragit in a fluid bed granulator such as those made by, for example Glatt or Aeromatic. After drying, classify the granules using a screen fitted to a mill/granulator, for example a Jackson Crockatt, Co-mill or Glatt QuckSieve. Blend the granules with disintegrant, lubricant and glidant and compress into tablets.

Examples of alternate formulations may include:

Etodolac 300 mg Codeine phosphate 60 mg

Eudragit RS30D (solids) 50 mg

Triacetin 10 mg

Povidone K30 25 mg

Stearyl alcohol 125 mg

Talc 5 mg

Magnesium stearate 2.5 mg

Etodolac 200 mg

Codeine phosphate 30 mg

Eudragit NE 30D 40 mg

Hydrogenated castor oil 50 mg

Talc 20 mg

Magnesium stearate 4 mg

Example 5

Extrusion and Spheronisation

The following ingredients per capsule are used:

Etodolac 300 mg Hydrocodone tartrate 20 mg

Microcrystalline cellulose 200 mg hydroxypropyl cellulose 12 mg

Water QS

Release controlling coat:

Ethyl cellulose N10 14 mg Dibutyl sebacate 1.4 mg

Colloidal anhydrous silica 1.4 mg olysorbate 80 1.4 mg

Dichloromethane QS

Methanol QS

Blend the powders in a suitable mixer and granulate by addition of water. Pass the wet granulate through an extruder such as those made by Nica or Caleva. Spheronise the extrudate to obtain round particles or spheroids. Dry the spheroids in for example a fluid bed dryer. Sieve to remove over and undersize spheroids. Coat the spheroids with a release controlling film coating in a fluid bed dryer.

Alternative coating materials may include water insoluble waxes and polymers such as polymethacrylates (for example Eudragit). Optionally water soluble polymers such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose or hydroxypropyl cellulose may be incorporated to modify the release rate. Alternative plasticizers include triethyl citrate and triacetin. Optionally other release modifying agents such as surface active agents for example polysorbate may be included in the coating. Optionally aqueous dispersions of water insoluble coating materials may be used to apply the release controlling membrane for example Aquacoat, Surelease, Eudragit.

As an alternative to extrusion and spheronisation, the drugs loaded core may be produced by applying the active ingredients onto inert non pareil beads or by forming beads by powder laying onto a starting crystal or seed.

Example 6

Matrix Tablet by wet granulation

The following ingredients per table are used:

Etodolac 300 mg Morphine sulphate 20 mg

Lactose 50 mg

Hydroxyethyl cellulose 20 mg

Cetostearyl alcohol 50 mg

Magnesium stearate 4 mg

Talc 4mg

Mix the etodolac, morphine sulphate, lactose and hydroxyethyl cellulose in a mixer for example a Collette Gral. Granulate by addition of water. Dry the granules, and classify them by passage through a sieve/ screen. Add molten cetostearyl alcohol to the classified granules, whilst blending in a high shear mixer and further classify the granules. Add lubricant and glidant to the granules, blend and then compress into tablets.

Alternative polymers include gums such as xanthan and guar gum, cellulose ethers such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and ethyl cellulose, acrylic resins such as Eudragit RS and RL. Alternative long chain hydrocarbons include stearic acid, stearic alcohol, hydrogenated vegetable oil, glyceryl monostearate, hydrogenated castor oil, beeswax, or carnauba wax.

Example 7

Melt Extrusion

The following ingredients per capsule or tablet are used:

Etodolac 300 mg

Hydrocodone tartrate 20 mg

Eudragit RSPO 100 mg

Stearyl alcohol 20 mg

Stearic acid 80 mg Sieve the ingredients and blend in a suitable blender or high shear mixer. Pass the blend through an extruder, such as those manufactured by Brabender or Leistritz, at a controlled rate, temperature and extrusion pressure to obtain strands 0.1 to 2.5 mm in diameter. Cool the strands on a conveyor and feed into a cutter or pelletizer to cut the strands into lengths of 0.1 to 2.5 mm. Sieve the pellets to remove over and undersize material, blend with lubricant and glidant if required and fill into hard gelatin capsules. Alternatively the pellets may be compressed into tablets.

Claims

1. A pharmaceutical composition comprising a combination of etodolac in an amount sufficient to render a therapeutic effect together with an opioid analgesic.

2. A pharmaceutical composition according to claim 1, wherein the opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbuturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentonil, tilidine, and tramadol.

3. A pharmaceutical composition according to claim 2, wherein the opioid analgesic is chosen from oxycodone, morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, diamorphone, tramadol, oxymorphone and fentanyl.

4. A pharmaceutical composition according to any preceding claim, which is an immediate release oral dosage form.

5. A pharmaceutical composition accoridng to claim 4 which contains 200 to 400 mg of etodolac.

6. A pharmaceutical composition according to claim 4 or 5, for administration at least three times a day, wherein the daily dosage rate of opioid analgesic is in the following range, calculated as the free opioid but where the opioid may be in the form of an appropriate base or salt: Codeine 16 mg to 240 mg

Oxycodone 5 mg to 160 mg

Morphine 5 mg to 240 mg

Dihydrocodone 15 mg to 240 mg

Hydromorphone 1 mg to 16 mg

Hydrocodeine 5 mg to 40 mg

Dextropropoxyphene 12 mg to 260 mg

Buprenorphine 0.2 mg to 1.6 mg

Oxymorphone 0.25 mg to 2 mg

Fentanyl 0.5 mg to 10 mg

7. A pharmaceutical composition according to claim 4, 5 or 6, which contains one of the following:

Codeine sulphate 16 mg to 60 mg

Oxycodone hydrochloride 5 mg to 40 mg

Morphine sulphate 5 mg to 60 mg

Dihydrocodeine tartrate 15 mg to 60 mg

Hydromorphone hydrochloride 1 mg to 4 mg

Hydrocodone tartrate 5 mg to 10 mg

Oxymorphone hydrochloride 0.25 mg to 0.5 mg

Fentanyl citrate 0.5 mg to 2.5 mg

8. A pharmaceutical composition according to any of claims 1 to 3, which is a controlled release oral dosage form.

9. A pharmacutical composition according to claim 8 which contains 600 mg to 1200 mg etodolac.

10. A pharmaceutical composition for administration once or twice a day, wherein the daily dosage rate of opioid analgesic is in the following range, calculated as the free opioid but where the opioid may be in the form of an appropriate base or salt:

Codeine 16 mg to 240 mg

Oxycodone 5 mg to 160 mg

Morphine 5 mg to 240 mg

Dihydrocodone 15 mg to 240 mg

Hydromorphone 1 mg to 16 mg

Hydrocodeine 5 mg to 40 mg

Dextropropoxyphene 12 mg to 260 mg

Buprenorphine 0.2 mg to 1.6 mg

Oxymorphone 0.25 mg to 2 mg

Fentanyl 0.5 mg to 10 mg

11. A pharmaceutical composition according to any preceding claim, wherein the etodolac is in the form of a pharmaceutically acceptable salt or a pharmaceutically acceptable ester.

12. A pharmaceutical composition according to any preceding claim, wherein the opioid analgesic is in the form of a pharmaceutically acceptable salt or pharmaceutically acceptable complex.

13. The use of etodolac in the preparation of a medicament for treating pain by administering etodolac and an opioid analgesic.

14. A method of treating pain comprising administering to a patient in need of such treatment a non-toxic therapeutically effective amount of etodolac and opioid analgesic.

15. A method according to claim 14, wherein the etodolac and opioid analgesic are adminstered as a single composition.

16. The use of etodolac in the preparation of a medicament for inhibiting a COX- 1 or COX-2 mediated disease by administering etodolac and an opioid analgesic.

17. A method of inhibiting a COX-1 or COX-2 mediated disease comprising administering to a patient in need of such treatment a non-toxic therapeutically effective amount of etodolac and opioid analgesic.

18. A method according to claim 17, wherein the etodolac and opioid analgesic are adminstered as a single composition.