MXPA05013201A - Composition comprising triptans and nsaids - Google Patents

Abstract

A pharmaceutical composition comprising a 5HT1 receptor agonist or a pharmaceutically acceptable derivative thereof in combination with an NSAID or pharmaceutically acceptable derivative thereof wherein the 5HT1 receptor agonist and NSAID are located in discrete zones with respect to each other wherein each zone comprises the active ingredient and optionally a carrier. A preferred composition comprises sumatriptan succinate and naproxen sodium.

Description

PHARMACEUTICAL COMPOSITION Field of the Invention The present invention relates to pharmaceutical compositions comprising more than one active ingredient for oral administration comprising a 5HT? Receptor agonist. in combination with an NSAID (non-spheroidal anti-inflammatory drug) as active ingredients, in particular, a composition in solid dosage form that is proposed to be ingested.

BACKGROUND OF THE INVENTION The compound 5-hydroxytryptamine (5HT or 5-HT), also known as serotonin or enterolamine is a known vasoactive agent and endogenous neurotransmitter that acts on receptors both inside and outside the central nervous system and in blood vessels. The drugs that act on these receptors can be agonists or antagonists. These receivers have been further classified into several sub-classes of the receiver, some of which also contain sub-classes by themselves. The 5HT receptor agonists! They are useful in a variety of conditions, notably the treatment of conditions associated with cephalic pain such as migraine, headache by zones, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or their separation, pain Rebound head and tension headache.

The dHTi receptor agonists are well known in the art and the term should be broadly understood to include 5HT-1 receptor agonists of all types, including, but not limited to, dHT-like receptor agonists? , 5HT1B receptor agonists, 5HT1 D receptor agonists and 5HT1 F receptor agonists. Particular reference is made to the sumatriptan compounds (described, for example, in GB Patent No. 2162522, incorporated herein by reference), naratriptan, rizatriptan , zoimitriptan, frovatriptan, eletriptan, almotriptan, avitriptan, donitriptan, alniditan, ALX-0646, LY334370, U 109221, IS159 and PNY142633. Special reference is made to the sumatriptan compound. An extensive program of clinical trials worldwide has demonstrated the efficacy and tolerability of sumatriptan (marketed in subcutaneous, oral, intranasal and rectal formulations) as an acute treatment for migraine. Although 5HT-I agonists are useful in the treatment of migraine, it has been found in some patients that they alter the initial therapeutic effect, the migraine symptoms are observed again within approximately 1-24 hours after the initial relief. That is, after a dose of the therapeutic agent has been administered to a subject in an amount to effectively treat a migraine, and migraine relief has been observed, migraine symptoms occur again as soon as approximately 1 -8. hours after the first relief until approximately 12-24 hours later. It will be appreciated that individuals suffering from migraine show individualized symptoms and synchronization for this phenomenon as will treatment with particular therapeutic agents. Although not related to any particular theory, sumatriptan and other 5-HT agents are thought to exert their beneficial effect in migraine patients by reducing either the release of pro-inflammatory mediators around certain nerves and blood vessels or by vasoconstriction of selected blood vessels in the head or both. However, it is thought that they lack analgesic activity and it is believed that their pharmacological actions depend on reaching and / or maintaining certain blood concentrations and that these concentrations are relatively short-lived. Recurrence within the first 24 hours is well documented and occurs in up to 40-50% of patients who initially get relief but the cause is unknown. The headache, which occurs under the circumstances described above, has been variously and interchangeably called a "rebound", "recidivism" headache., "recurrent" or "secondary". Despite the terms, it is currently unknown whether this last headache is a continuation of the physiological chain of events that originated the original headache, or a new headache due to another underlying pathology, or repeated but unrelated. It is also possible that the continuation of the headache is a response to the therapeutic agents that were initially successful in treating the initial symptoms of migraine. The terms "rebound", "reoccurrence", "recurrent" and "secondary" (as defined below) are considered synonymous, as used herein, without interfering with a mechanism or cause of the headache described above. In some forms of migraine, certain patients have found total or partial relief with the use of analgesics such as acetaminophen and phenacetin and other non-narcotic, non-spheroidal analgesics, generally not classified as anti-inflammatory. Although these agents, when taken alone, are rarely effective in the proportion of complete and rapid relief of all migraine symptoms, especially when the symptoms of the attack already include nausea and vomiting, in combination with therapy of the present invention their efficacy is It increases surprisingly. NSAIs Ds are well known in the art and particular reference is made to diclofenac, nabumetone, naproxen, ketorolac, ibuprofen, flurbiprofen, acetoprofen, oxaprozin, etodolac, indomethacin, mefanamic acid, tolfenamic acid and collective inhibitors of COX-2 such as celecoxib , rofecoxib (VIOXX), valdecoxib, parecoxib, 4- (4-cyclohexyl-2-methyl-5-oxazoyl) -2-fluorobenzenesulfonamide (JTE-522), MK633 (etoricoxib), nimesulide, flosulide, DFP, 2- (4 -ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine, meloxicam, RS57067, piroxicam, NS398, L-745,337 and COX-189. NSAIDs such as naproxen sodium are thought to relieve migraine pain through their known analgesic action, but they can also alleviate symptoms by reducing neurogenic and vascular inflammation secondary to their known anti-inflammatory actions or by other mechanisms such as, but without limit, inhibition of platelets or inhibition of prostaglandin synthesis. In addition, naproxen and naproxen sodium have average lifetimes of the order of 12-15 hours and produce a long-lasting effect. U.S. Patent Number 6,060,499 discloses a method for the treatment of migraine in a human, comprising the co-synchronized administration of a therapeutically effective amount of a coordinated 5HT agonist to a therapeutically effective amount of an analgesic, particularly a long-lasting NSAID. . Such administration is contemplated in separate or combined formulations in unit dose forms. U.S. Patent No. 6,060,449 states that, without being related to any theory, it is believed that the combination of a 5HT agonist with a long-lasting NSAID can achieve an improved initial therapeutic effect together with a lower incidence of recurrence headaches. Although not related to any particular theory, it is believed that the "recurrence" headache often associated with 5-HT agonists is due to the original beneficial effect of attrition of 5-HT agonists due to its short duration of action. while a) the underlying activator for the original migraine episode is still present and / or b) while there is still the causative agent of pain and other symptoms, presumably vascular and / or neurogenic inflammation. In this context, the addition of an NSAID to a 5-HT agonist extends the period of effective anti-migraine action and prevents recurrent headache (or "moderate rebound") from occurring, whatever the cause. Oral administration constitutes a preferred route of administration for pharmacists since this route is particularly convenient and acceptable for patients. For combination therapy, administration of a formulation comprising two or more active ingredients may also be preferred. An important consideration in the preparation of formulations containing more than one active ingredient is the stability and efficacy of the ingredients, since the mutual interaction of the agents themselves or of the agents with excipients can lead to instability of one or all of the active ingredients or altering the effectiveness of one or all of the active ingredients. The present inventors have surprisingly found that when the granular preparations of sumatriptan and sodium of naproxen were mixed and formulated in a tablet, for example, by direct compression, the resulting formulation had an unacceptable dissolution time. For example, the dissolution of both components was less than expected, leading to less absorption. This is possibly due to the fact that naproxen sodium disables the dissolution of granules containing sumatriptan. Surprisingly, when the active ingredients were separated from each other in discrete discrete zones with respect to each other and formulated in a solid oral dosage form, the resulting formulation exhibited a satisfactory dissolution rate of sumatriptan and naproxen sodium.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, the invention provides a pharmaceutical composition comprising a 5HT-I receptor agonist or a pharmaceutically acceptable derivative thereof, in combination with a NSAI D or pharmaceutically acceptable derivative thereof, wherein the agonist 5HT receiver? and NSAIDs are located in discrete zones with respect to each other, wherein each zone comprises the active ingredient and optionally a vehicle.

Description of the Drawings Figure 1 Dissolution profile sodium naproxen from 550 mg tablets of Anaprox® Figure 2 Dissolution Profiles of sumatriptan succinate granulation using direct compression FDT and naproxen sodium, Figure 3 Profiles dissolution of bilayer tablets containing FDT granulation of sumatriptan succinate and direct sodium compression of naproxen. Figure 4 Solution profile for bilayer tablets containing FDT granulation of sumatriptan succinate and sodium granulation of naproxen.

DETAILED DESCRIPTION OF THE INVENTION agonists 5HT receptors, suitable for use according to the invention include sumatriptan, naratriptan, zolmitriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, avitriptan, donitriptan, alniditan, ALX-0646, LY334370, U 1092291, IS159 ( ie, 3- (2-aminoethyl) -5- [acetamidil-3- (4-hydroxyphenyl) -propionamidil-acetamidil-oxy] indole) and PNY142633 (ie, (s) -3,4-dihydro-1 - [2- [4- [4-aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl-1 H-2-benzopyran-6-carboxamide). Naratriptan and sumatriptan are preferred, with sumatriptan being particularly preferred. A preferred form of sumatriptan is the succinate salt, particularly the 1: 1 succinate. The dHT receptor agonists? they can be used alone or in combination with each other. Suitable NSAI DSs include diclofenac, nabumetone, naproxen, ketorolac, ibuprofen, flurbiprofen, acetoprofen, oxaprozin, etodolac, indomethacin, mefanamic acid, tolfenamic acid and collective COX-2 inhibitors such as celecoxib, rofecoxib (VIOXX), valdecoxib, parecoxib, 4- (4-cyclohexyl-2-methyl-5-oxazolyl) -2-fluorobenzenosulfonamida (JTE-522), MK633 (etoricoxib), nimesulide, flosulide, DFP, 2- (4-ethoxyphenyl) -3- (4 -methanesulfonyl-phenyl) -pyrazolo [1, 5-b] pyridazine, meloxicam, RS57067, piroxicam, NS398, L-745,337 and COX-189. COX-189 and naproxen are preferred. Particularly preferred is naproxen, more preferably in the form of a sodium of naproxen. By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such an ester or amide of the active ingredient or any other compound which, upon administration to the container is capable of providing (directly or indirectly) indirect) the active ingredient or a metabolic or active residue thereof. Pharmaceutically acceptable salts suitable according to the invention include acid addition salts formed with inorganic acids such as hydrochlorides, hydrobromides, phosphates and sulphates with organic acids, for example, tarbratos, maleavos, fumarates and sulfonates. In one aspect of the invention, discrete zones can be provided by the addition of excipients. Accordingly, the invention provides a pharmaceutical composition, comprising a 5HT? Receptor agonist. or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, in combination with an NSAID, wherein the 5HT? receptor agonist. and NSAI D are each dispersed within their own pharmaceutically acceptable carrier in the pharmaceutical composition. Suitably, the vehicle for the 51-receptor agonist is different in composition to that of the vehicle for NSAIDs. In one embodiment of the invention, the dHTi receptor agonist and its carrier are substantially in admixture with the NSAID and its carrier. Suitably, the dHTi receptor agonist and its carrier are substantially in a homogeneous mixture with the NSAID and its vehicle. Properly, the pre-formed dHTi receptor agonist / vehicle mixture is mixed with the pre-formed NSAID / vehicle mixture after preparation of the composition of the invention. For example, the dHTi / vehicle receptor agonist mixture is mixed with the NSAID / vehicle mixture in a capsule form. More preferably, the dHTi / vehicle receptor agonist mixture is compacted with the NSAI D / vehicle mixture in the composition, suitably to form a tablet. For example, the mixture of the dHTi / vehicle receptor agonist mixture with the NSAID / vehicle mixture is compacted to form a tablet. A suitable vehicle for the 51-1 ^ receptor agonist comprises one or more components selected from: a linking agent, a filler, a lubricant and effervescent couple, a wicking agent, a slip agent, a disintegrant and a wetting agent. Suitable vehicles for the NSAI D comprise one or more components selected from: a bonding agent, a filler, a lubricant, an effervescent couple, a wicking agent, a slip agent, a disintegrant and a wetting agent . In a more preferred aspect of the invention, a stratum provides a suitable zone, generally a compressed stratum, of the active agent. In this way, the formulation may comprise strata, generally configured layers of the active agents. A suitable formulation is a tablet formulation. Thus, a particular formulation is a multi-layer tablet wherein the active agents are in separate layers. A particular formulation comprises a compressed form, for example, a tablet, of an active agent formulated with a powder form of the other active agent. Alternatively, a tablet may be prepared by over-compression, such that it includes a core of an active ingredient surrounded by a top cover of another active ingredient. More preferably, tablets containing active agents in discrete areas with respect to each other can be multi-layered tablets. For example, they can be bilayer tablets, where one stratum of the form of an active agent is compressed, the form of the other active agent is then added and compressed onto the stratum of the first active agent. They can be trilayer tablets prepared in an analogous manner. The active ingredients can be formulated as granulates if appropriate. The discrete zones can be separated by a barrier layer, preferably an inert barrier layer. The barrier layer preferably comprises a filler material, such as lactose, and a lubricant, such as magnesium stearate. As indicated, such compositions may conveniently be produced as tablets or capsules. The tablets and capsules can be produced by mixing granular forms of the active agents followed by compression. The granules of each agent can be obtained by combining the active agent with suitable excipients, for example, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate, followed by granulation by the use of conventional techniques. When the granules of any active agent are produced, high shear granulation techniques are preferably employed. In a preferred embodiment, the granulation of both active agents is carried out. Capsules can be produced by mixing pellet forms or granular forms of the active agents, followed by encapsulation. The pellets of each active agent can be obtained by combining the active agent with suitable excipients, for example, microcrystalline cellulose and lactose, followed by pelletization by the use of conventional techniques. The granules are prepared as described herein. The production of tablets and capsules can be carried out by the use of techniques that are well known in the art. In the context of the present invention, by "for oral administration" it is understood that the pharmaceutical composition is in a solid dosage form that is intended to be swallowed completely and is basically not intended for dissolution or suspension in water prior to administration; however, the composition of the present invention may meet in certain embodiments the requirements of a dispersible tablet in terms of dispersion fineness and dispersion rate, as defined by the European Pharmacopoeia and / or the British Pharmacopoeia. Such dosage forms can take the form of tablets and capsules and can be prepared according to conventional techniques well known in the pharmacy field for the preparation of solid dosage forms. Preferably, the composition of the present invention is in the form of a "swallowable" tablet. To put an end to the doubts, a 'swallowable' tablet is a tablet that is proposed to swallow completely (usually with a small amount of liquid, for example, water); basically it is not proposed for dissolution or suspension in water before administration (such as, for example, a tablet as described in WO 92/1 003 and which also contains a substantial amount of both components of an effervescent couple) and nor is it basically proposed for dissolution 'in the mouth' (in a form of 'oral fusion'). WO 92/15295 (Glaxo Group Ltd.) incorporated herein by reference, discloses pharmaceutical compositions in known solid dosage form, in particular, film-coated tablets, useful in the treatment of conditions associated with cephalic pain. These formulations can form the zone containing the 5HT- receptor agonist | . Unfortunately, there may be certain disadvantages when treating conditions associated with head pain. For example, such conditions, particularly migraine, are associated with nausea, vomiting and gastrointestinal dysfunction in the form of reduced gastric mobility and delayed gastric emptying, which can potentially lead to delay and / or dysfunction of drug absorption. Therefore, it would be desirable to have the active ingredients, particularly the dHT-i receptor agonist, formulated to ensure rapid dissolution and absorption. Thus, in a preferred aspect of the invention, a pharmaceutical composition comprising a 5HT? Receptor agonist is provided. or a pharmaceutically acceptable derivative thereof in combination with an NSAID or pharmaceutically acceptable derivative thereof, wherein the dHTi receptor agonist and NSAID are located in discrete zones with respect to each other, wherein each zone comprises the active ingredient and optionally a carrier and wherein at least the zone comprising the dHTi receptor agonist is formulated to ensure rapid absorption. By "rapid absorption" applied to 5HT receptor agonist? it is understood that more than about 70%, preferably greater than about 80%, more preferably greater than about 90% of the active ingredient is dissolved in simulated gastric fluid (SGF) within five minutes in USPII apparatuses at the rate of discrimination palette of 1 0 rpm. In a preferred aspect, the formulation is a tablet comprising 2 or more strata, wherein a stratum comprising a 5HTi receptor agonist or pharmaceutically acceptable derivative thereof is formulated to ensure rapid absorption and another stratum comprises an NSAID or a pharmaceutically derived derivative. acceptable thereof and optionally a vehicle. More preferably, the tablet is a bilayer tablet comprising a stratum comprising a 5HT1 receptor agonist or pharmaceutically acceptable derivative thereof, which is formulated to ensure rapid absorption, and a stratum comprising an NSAID or pharmaceutically acceptable derivative thereof. same and optionally a vehicle. Therefore, in a preferred aspect, in a stratum of 0 dHTi receptor agonist formulated for rapid absorption, the dHTα receptor agonist. or pharmaceutically acceptable derivative thereof, is formulated together with an effervescent couple in combination with a disintegrant, a filler material (preferably an insoluble filler material), and a wicking agent. This formulation has been shown to have a faster onset of action and / or a greater speed of efficacy for a patient suffering from cephalic pain. A stratum of the pharmaceutical formulation comprising the NSAI D or pharmaceutically acceptable derivative thereof can be formulated in accordance with well-known NSAI D formulations. This will be apparent to a person skilled in the art. For example, compositions of several different formulations of naproxen sodium tablets are shown in the table below.

Bansal, P., Haribhakti, K., Subramanian, V., Plakogiannis, F., "Effect of Formulation and Process Variables in the Naproxen Sodium Dissolution Profile from Tablets", Drug Development and Industrial Pharmacy , 20 (13), 21 51 -21 56, 1994. In a further aspect of the invention, the NSAID stratum can also be formulated for rapid absorption, for example, by the inclusion of an effervescent couple. By "rapid absorption" applied to the NSAID is meant that more than about 25%, preferably more than about 50%, more preferably more than about 7d% of the active ingredient is dissolved in simulated intestinal fluid within five minutes in the USPI apparatus. the blade speed of discrimination of 30 rpm. Thus, in a further aspect of the invention, in a NSAID stratum, the NSAI D or pharmaceutically acceptable derivative thereof is formulated together with an effervescent couple in combination with a disintegrant, an insoluble filler and a wicking agent. . Accordingly, in a preferred embodiment, the present invention provides in a dHTa receptor agonist layer, formulated for rapid absorption, the dHT-i receptor agonist or a pharmaceutically acceptable derivative thereof, formulated together with the base component of a partner effervescent, a disintegrant and an insoluble filler material, wherein the base component comprises from about 5 to about 50% by weight, the disintegrant comprises from about 0.5 to about 10% by weight, and the insoluble filler material comprises from about 20 to about 99% by weight, said insoluble filler material comprising a wicking agent comprising from about 1 to about 99% by weight, based on the dry weight of the stratum of the dosage form, wherein more than about 70% , preferably about 80%, more preferably about 90% of the active ingredient is dissolved lve in simulated gastric fluid (SGF) within five minutes in the USPI I apparatus at the palette rate of 1 0 rpm. When the NSAID is also formulated for rapid absorption, the invention provides a layer of NSAID formulated for rapid absorption comprising the NSAI D or a pharmaceutically acceptable derivative thereof, formulated together with the base component of an effervescent couple, a disintegrant and a material insoluble filler, wherein the base component comprises from about 5 to about 50% by weight, the disintegrant comprises from about 0.5 to about 20% by weight, and the insoluble filler material comprises from about 30 to about 80% by weight, said insoluble filler material including a wicking agent comprising from about 1 to about 60% by weight, based on the dry weight of the stratum of the dosage form, wherein more than about 25%, preferably about 50%, more preferably approximately 75% of the active ingredient dissolves in intestinal fluid simul In five minutes on the USPII device at the speed of the 30 rpm palette. Suitably, in a stratum of 5HT receptor agonist! formulated for rapid absorption, the dHT-i receptor agonist comprises from about 0.001 to about 65% by weight, preferably about 0.01 to about 45%, more preferably about 0.01 to about 40%, especially about 1 to about 3d%, more especially about 20 up to about 3d% based on the dry weight of the stratum. Suitably, in a NSAID stratum, the NSAID comprises from about 1 to about 90% by weight, preferably about 2 to about 90%, more preferably about d to about 8d%, especially about 10 to about 7d%, more especially about 60 to about 7d% based on the dry weight of the stratum. In one embodiment of the present invention, the strata formulated for rapid absorption, the pharmaceutical composition further comprises the acidic component of the effervescent couple. An effervescent couple consists essentially of an acid component and a base component, whose components react in the presence of water to form a gas. In the 5HT-I receptor agonist stratum formulated for rapid absorption, the acidic component may comprise, for example, the dHT receptor agonist, or a pharmaceutically acceptable derivative thereof itself (where it has an acidic character or may provide a component with character). acidic in an aqueous environment), or an aliphatic carboxylic acid or a salt thereof, such as citric acid or tartaric acid and salts thereof. Alternatively, the acid component can be provided by acid in the NSAID stratum or stomach acid instead of being part of the dHT-i receptor agonist zone of the pharmaceutical composition, d Preferably, the acid component is the dHT1 receptor agonist. or a pharmaceutically acceptable derivative thereof (such as sumatriptan or naratriptan, especially in the form of salts thereof, for example, the succinate salt, such as sumatriptan succinate (1: 1)). The acid components can be used alone or 0 in combination with each other. Suitably, the acid component comprises the dHT receptor agonist! or a pharmaceutically acceptable derivative thereof, together with an aliphatic carboxylic acid or a salt thereof, such as citric or tartaric acid and salts thereof. Suitably, the acid component (including the 5HT! Receptor agonist or pharmaceutically acceptable derivative of the miso when functioning as an acid component) comprises up to about 55% by weight, preferably from about 5 to about 50%, more preferably about 10 up to about 0 about 45%, especially about 1 d up to about 40%, more especially about 20 up to about 3d%, based on the dry weight of the stratum of the dosage form. The base component may comprise, for example, an alkali metal or alkali earth metal carbonate or bicarbonate, such as sodium bicarbonate, potassium bicarbonate, magnesium carbonate or calcium carbonate. The base component is preferably sodium bicarbonate. The base components can be used alone or in combination with each other. Suitably, the base component comprises from about d to about 10% by weight, preferably about 7 to about 20%, more preferably about 8 to about 15%, especially about 9 to about 12%, based on the dry weight of the stratum. of the dosage form. Acids can be monoprotic or polyprotic; similarly, the bases can be monobasic or polybasic. Calculated in terms of acid / base (N) normalities, the ratio of acid component to base component may conveniently be within the range of from about 1: 1 to about 10: 1, preferably from about 1: 5 to about 5. : 1, more preferably from about 1: 3 to about 3: 1, more preferably from about 1: 2 to about 2: 1. In the NSAI D layer formulated for rapid absorption, the acid component may comprise, for example, the NSAID such as naproxen or a pharmaceutically acceptable derivative thereof (where it has an acidic character or may provide a component with an acidic character in a aqueous environment), or an aliphatic carboxylic acid or a salt thereof, such as citric acid or tartaric acid or salts thereof. Alternatively, the acidic component can be provided by acid in the dHT1 receptor agonist stratum or the stomach acid instead of being part of the NSAID stratum of the pharmaceutical composition or as a separate pharmaceutical agent, such as citric acid included in either the dHTi receptor agonist stratum and / or the NSAID stratum. Preferably, the acid component is provided as a separate pharmaceutical agent such as citric acid. The acid components can be used alone or in combination with each other. Suitably, the acid component comprises the 5HT? Receptor agonist? or a pharmaceutically acceptable derivative thereof, together with an aliphatic carboxylic acid or a salt thereof, such as citric acid or tartaric acid and salts thereof. Suitably, the acid component included as a separate pharmaceutical agent, such as citric acid, up to about 30% by weight, preferably from about 0.001 to about 20%, more preferably about 0.01 to about 15%, especially about 1 to about 15 %, more especially about 3 to about 10%, based on the dry weight of the stratum of the dosage form. The base component may comprise, for example, an alkali metal carbonate or bicarbonate or alkaline earth metal, such as sodium bicarbonate, potassium bicarbonate, magnesium carbonate or calcium carbonate. The base component is preferably sodium bicarbonate. The base components can be used alone or in combination with each other. Suitably, the base component comprises from about 5 to about 50% by weight, preferably from about 7 to about 20%, more preferably from about 8 to about 1%, especially from about 9 to about 12%, based on dry weight of the stratum of the dosage form. The acids can be monoprotic or polyprotic; similarly, the bases can be monobasic or polybasic. Calculated in terms of acid / base (N) normalities, the ratio of acid component to base component can conveniently be in the range of from about 1: 10 to about 10: 1, preferably from about 1: 5 to about 5: 1, more preferably from about 1: 3 to about 3: 1, more preferably from about 1: 2 to about 2: 1. Disintegrants, when used in the compositions of the present invention, dilate when contacted with water. Suitable disintegrants will be known to those skilled in the art and a non-limiting list of examples includes croscarmellose sodium, sodium starch glycolate, degraded polyvinylpyrrolidone, povidone, starch (eg, corn starch, progelatinized starch), low hydroxypropylcellulose. substituted, alginic acid, sodium alginate, tribasic calcium phosphate, calcium sulfate, calcium carboxymethylcellulose, microcrystalline cellulose, cellulose powder, colloidal silicon dioxide, docusate sodium, guar gum, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, polyacrylline potassium and polyvinylpyrrolidone. Croscarmellose sodium is preferred. The disintegrants can be used alone or in combination with each other. Suitably, in d the receptor agonist zone 51-1 ^ the disintegrant comprises from about 0.5 to about 10% by weight, preferably from about 2 to about 8%, more preferably from about 3 to about 7%, especially from about 4 to approximately 6 &; 0 more especially about 5%, based on the dry weight of the stratum of the dosage form. In the NSAID stratum, the disintegrant comprises from about Od to about 10% by weight, preferably from about 1 to about 8%, d more preferably from about 1.5 to about 6%, especially from about 2 to about 4% , more especially about 3% based on the dry weight of the dose form of the stratum. Insoluble fillers are inert substances that provide bulk and stability when used in the compositions of the present invention. Some insoluble fillers can also act as wicking agents. Wicking agents, when used in the compositions of the present invention, have a porous nature and entrain water into and through the solid dosage form. Suitable wicking agents will be known to those skilled in the art and a non-limiting list of examples includes microcrystalline cellulose (available as, for example, Avicel ™), croscarmellose sodium, crospovidone, starch, calcium carboxymethylcellulose, silicified microcrystalline cellulose , magnesium oxide and tragacanth. Microcrystalline cellulose is preferred. The wicking agents can be used alone or in combination with each other. Suitably, the wicking agent comprises from about 1 to about 99% by weight, preferably from about 1 to about 80%, more preferably from about 5 to about 6d%, especially from about 12 to about dd%, more especially from about 1 8 to about 50%, based on the dry weight of the stratum of the dosage form. Other suitable insoluble fillers include dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate (available as, for example, Emcompress ™), tribasic calcium phosphate, calcium carbonate, magnesium carbonate, magnesium carbonate, calcium sulfate. , cellulose acetate, cellulose powder, kaolin, polymethacrylates and talc. Anhydrous dibasic calcium phosphate is preferred. The insoluble fillers can be used alone or in combination with each other. Suitably, in the 5HTL receptor agonist layer the insoluble filler material, including the wicking agent, comprises from about 30 to about 99% by weight, preferably from about 35 to about 80%, more preferably from about 40 to about 70%, especially from about 45 to 65%, based on the dry weight of the stratum of the dosage form. In the NSAID stratum, the insoluble filler material, including the wicking agent, comprises from about 1.0 to about 99% by weight, preferably from about 15 to about 55%, more preferably from about 25 to about 45%, especially from about 30 to 40%, based on the dry weight of the stratum of the dosage form. Thus, in one embodiment of the present invention, a pharmaceutical composition is provided in solid dosage form, as described hereinabove, wherein the 5HT! Receptor agonist stratum. it comprises a 5HT receptor agonist! or a pharmaceutically acceptable derivative thereof, which comprises from about 0.001 to about 55% by weight, preferably from about 0.01 to about 45%, more preferably from about 0.1 to 40%, especially from about 1 to about 35%, more especially from about 20 to about 35%, the base component of the effervescent couple comprises from about 5 to about 50% by weight, preferably from about 7 to about 20%, more preferably from about 8 to about 15%, especially from about 9 to about 12%, the disintegrant comprises from about Od to about 10% by weight, preferably from about 2 to about 8%, more preferably from about 3 to about 7%, especially from about 4 to about 6 %, more especially of about d%, the insoluble filler material, which includes the wicking agent, comprises from about 3d to about 80% by weight, preferably from about 40 to about 70%, more preferably from about 45 to about 65 %, and the wicking agent comprises from about 1 to about 80% by weight, preferably from about 5 to about 65%, more preferably from about 12 to about 5d%, especially from about 1 8 to about 60%, based on dry weight of the stratum of the dosage form . Thus, in the embodiment of the present invention, there is provided a pharmaceutical composition in solid dose form, as described above, wherein the NSAID stratum comprises an NSAID or a pharmaceutically acceptable derivative thereof, which comprises from about 1 to about 90% by weight, preferably from about 2 to about 90%, more preferably from about d to about 8d%, especially from about 10 to about 75%, more especially from about 60 to about 75%, the component base of the effervescent couple comprises from about 5 to about 50% by weight, preferably from about 7 to about 20%, more preferably from about 8 to about 15%, especially from about 9 to about 12%, the disintegrant comprises from about 0.05 up to about 1 0% by weight, preferably from about 1 to about 8%, more preferably from about 1.5 to about 6%, especially from about 2 to about 4%, more especially about 3%, the insoluble filler material, including the Wicking agent, comprises from about 10 to about 99% by weight, preferably from about 15 to about 5d%, more preferably from about 2d to about 46%, based on the dry weight of the stratum of the dosage form. Thus, in a particularly preferred embodiment of the present invention, a bilayer tablet of solid dosage form, as described hereinbefore, is provided, wherein the dHT-i receptor agonist stratum comprises a receptor agonist. dHT-i or a pharmaceutically acceptable derivative thereof, which comprises from about 0.001 to about dd% by weight, preferably about 0.01 to about 4d%, more preferably about 0.1 to 40%, especially about 1 to about 36%, more especially from about 20 to about 3d%, the base component of the effervescent couple comprises from about 6 to about 0% by weight, preferably from about 7 to about 20%, more preferably from about 8 to about 15%, especially about 9. up to about 12%, the 0 disintegrating comp from about 0.5 to about 10% by weight, preferably from about 2 to about 8%, more preferably from about 3 to about 7%, especially from about 4 to about 6%, more especially 5 of about 5%, the Insoluble filler, including the wicking agent, comprises from about 35 to about 80% by weight, preferably from about 40 to about 70%, more preferably from about 45 to about 65%, and the wicking agent comprises from about 1 to about 80% by weight, preferably about 5 to about 65%, more preferably about 12 to about 5d%, especially about 1 8 to about 10%, based on the dry weight of the stratum of the dose form, and the NSAID stratum comprises an NSAID or a pharmaceutically acceptable derivative thereof, comprising from about 1 to about 90% by weight, preferably about 2 to about 90%, more preferably from about 5 to about 86%, especially from about 10 to about 76%, more especially from about 60 to about 7d%, the base component of the effervescent couple comprises from about 5 to about 50% by weight, preferably from about 7 to about ximately 20%, more preferably from about 8 to about 15%, especially from about 9 to about 12%, the disintegrant comprises from about 0.05 to about 10% by weight, preferably from about 1 to about 8%, more preferably about 3 %, the insoluble filler material, including the wicking agent, comprises from about 10 to about 99% by weight, preferably from about 15 to about 55%, more preferably from about 25 to about 45, based on the dry weight of the stratum of the dosage form. In a further embodiment of the present invention, there is provided a pharmaceutical composition, as described herein above, wherein the 5HT1 receptor agonist zone comprises a dHTi receptor agonist or a pharmaceutically acceptable derivative thereof, which comprises sumatriptan. or naratriptan or a pharmaceutically acceptable derivative thereof, preferably sumatriptan or a pharmaceutically acceptable derivative thereof, more preferably in the form of its succinate salt (1: 1), the base component of the effervescent couple comprises sodium bicarbonate, the The disintegrant comprises croscarmellose sodium and the insoluble filler material comprises microcrystalline cellulose. In a further embodiment of the present invention, a pharmaceutical composition is provided in solid dosage form, as described herein above, wherein the dHTi receptor agonist region comprises a dHT receptor agonist! or a pharmaceutically acceptable derivative thereof, which comprises sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, preferably sumatriptan or a pharmaceutically acceptable derivative thereof, more preferably in the form of its succinate salt (1: 1), The base component of the effervescent couple comprises sodium bicarbonate, the disintegrant comprises croscarmellose sodium and the insoluble filler material comprises dibasic calcium phosphate, preferably anhydrous dibasic calcium phosphate. In a further embodiment of the present invention, there is provided a pharmaceutical composition in solid dose form, as described herein above, wherein the dHTi receptor agonist region comprises a dHTi receptor agonist or a pharmaceutically acceptable derivative of the dHTi receptor agonist. same, which comprises sumatriptan or a pharmaceutically acceptable derivative thereof, preferably in the form of its succinate salt (1: 1), the base component of the effervescent couple comprises sodium bicarbonate, the disintegrant comprises croscarmellose sodium and the material Insoluble filler comprises anhydrous dibasic calcium phosphate or microcrystalline cellulose or a mixture thereof. The inclusion of one or more insoluble filler materials in the compositions of the present invention also provides the composition with improved handling properties during processing., compared to a conventional tablet formulation (eg, a formulation as disclosed in WO92 / 15295). In addition to the ingredients described above, the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable carriers and excipients such as binding agents (e.g., pre-gelatinized starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose) and lubricants (e.g., stearic acid, stearate magnesium, talcum, sodium benzoate and hydrogenated vegetable oil). Many drug substances have an inherent bitter taste. The unpleasant taste that is sometimes associated with oral administration of a composition comprising a 5HT-I receptor agonist or a pharmaceutically acceptable derivative thereof can be eliminated by the use of a film cover in the solid core. The solid core comprises the 5WT receptor agonist <; [o. a pharmaceutically acceptable derivative thereof. Furthermore, when used in the compositions of the present invention, the film cover delays the disintegration of the solid dosage form until it reaches the stomach. A film cover can also help to be swallowable, can make the solid dosage form more aesthetically pleasing and generally makes the solid dosage form less fragile. According to the foregoing, in one embodiment, the present invention provides a pharmaceutical composition, as described hereinabove, in the form of a tablet that is covered by a film. The film cover may suitably comprise a polymer. Suitable polymers will be well known to those skilled in the art and a non-limiting list of examples includes cellulose ethers, for example, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, or methylcellulose and copolymers of methacrylic acid and methyl methacrylate. Preferably, the film cover will comprise hydroxypropylmethylcellulose. The total film cover solids are generally applied to the solid dosage form, for example, the tablet core, in an amount of from about Od up to 10% by weight, preferably from about 1 to about 4%, more preferably from about 2 to about 3%, based on the dry weight of the dosage form. For example, about 8 mg of the shell are used for a tablet core weight of about 300 or about 400 mg, and about 4 mg of shell are used for a tablet core weight of about 175 mg. The film cover may additionally comprise any pharmaceutically acceptable dye or opacifier, including water-soluble dyes, aluminum lakes of water-soluble dyes and inorganic pigments such as titanium dioxide and iron oxide. The film cover may also contain one or more plasticizing agents conventionally used in polymeric film casings, for example, polyethylene glycol, propylene glycol, dibutyl sebacate, mineral oil, sesame oil, diethyl phthalate and triacetin. Proprietary film covering materials, such as Opaspray and Opadry, obtainable from Colorcon Ltd. may be used. The flavor of the oral compositions may also be improved by the use of flavoring and / or sweetening agents. Suitable flavoring agents will be known to persons skilled in the art and a non-limiting list of examples includes lemon, orange, blackberry, vanilla, caramel, butter, hazelnut or mint flavor. Suitable sweetening agents for use in the compositions of the invention will be well known to those skilled in the art and a non-limiting list of examples includes sucrose, saccharin, cyclamic acid and alkali metal or alkaline earth metal salts thereof, mannitol , acesuIfame-K, stevioside, thaumatin and aspartame. The flavoring agent and / or the sweetening agents can be used alone or in combination with each other. In a further aspect, the present invention provides a solid dosage form pharmaceutical composition for oral administration, as described hereinabove, for use in the treatment of conditions associated with cephalic pain, such as concentrated headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or withdrawal, rebound headache, tension headache and, in particular, migraine. Suitably, the 5HT-] receptor agonist is sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, more preferably sumatriptan succinate salt (1: 1). Suitably, the NSAID is naproxen or COX-189 or pharmaceutically acceptable salts thereof, more preferably naproxen sodium. It will be appreciated that reference to treatment is proposed to include prophylaxis, as well as relief of established symptoms. According to a further aspect of the present invention, there is provided the use of a pharmaceutical composition in solid dosage form for oral administration, as described hereinbefore, in the manufacture of a medicament for the treatment of associated conditions with cephalic pain, such as concentrated headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or withdrawal, rebound headache, tension headache and, in particular, migraine . Suitably, the 5HT receptor agonist? or a pharmaceutically acceptable derivative thereof is sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, preferably sumatriptan or a pharmaceutically acceptable derivative thereof, more preferably sumatriptan succinate salt (1: 1). Suitably, the NSAID is naproxen or COX-189 or pharmaceutically acceptable salts thereof, more preferably naproxen sodium. A further aspect of the present invention provides a method for the treatment of a mammal, including a human, suffering from or is susceptible to conditions associated with cephalic pain, such as concentrated headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or withdrawal, rebound headache, tension headache and, in particular, migraine, which comprises the oral administration of a pharmaceutical composition in solid dosage form as described hereinbefore, suitably, the dHTi receptor agonist or a pharmaceutically acceptable derivative thereof is sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, preferably sumatriptan or a pharmaceutical derivative acceptable prodrug thereof, more preferably sumatriptan succinate salt (1: 1). Suitably, the NSAID is naproxen or COX-189 or pharmaceutically acceptable salts thereof, more preferably naproxen sodium. It will be appreciated that the amount of compounds employed as the active ingredient in the solid dosage form compositions of the invention will depend on the particular compounds used. In addition, the precise therapeutic dose employed will depend on the age and condition of the patient and the nature of the condition to be treated and will be at the discretion of the attending physician. When the 6HTT receptor agonist is sumatriptan or naratriptan, the amount of compound employed in the compositions of the invention will be in the range of 0.1 mg to 250 mg. The compositions can be administered, for example, 1 to 4 times per day, preferably once or twice. When the dHT receptor agonist? is sumatriptan, the amount of sumatriptan, preferably in the form of a pharmaceutically acceptable salt, will be in the range of 1 mg to 200 mg, preferably 20 mg to 1 50 mg, for example 25, 50, 85 or 100 mg, expressed as the free base weight. When the 5HT receptor agonist! is naratriptan, the amount of naratriptan, preferably in the form of a pharmaceutically acceptable salt, will be in the range of 0.1 mg to 25 mg, preferably 1 or 2.5 mg, expressed as the free base weight. When the NSAI D is naproxen or COX-189, the amount of compound employed in the compositions of the invention will be in the range of 26 mg to 1 100 mg. When the NSAI D is naproxen, the amount of naproxen, preferably in the form of a pharmaceutically acceptable salt, will be in the range of 100 mg to 1 100 mg, preferably 260 mg to 800 mg, eg 464.5 mg 0 500 mg, expressed as the weight of free acid, or 275, 350, 400, 600 or 650 mg, expressed as the weight of the sodium salt. In a particularly preferred embodiment, the pharmaceutical composition of the invention is a bilayer tablet comprising 85 mg of sumatriptan in the form of 1 1 9 mg of sumatriptan succinate and 560 mg of naproxen sodium, equivalent to 500 mg of naproxen, where at least sumatriptan is formulated for rapid absorption. In a particularly preferred embodiment, the pharmaceutical composition of the invention is a bilayer tablet comprising 85 mg of sumatriptan in the form of 1 1 9 mg of sumatriptan succinate and 500 mg of naproxen sodium equivalent to 454.6 mg of naproxen, in where at least sumatriptan is formulated for rapid absorption. Typically, in the treatment of cephalic pains, in particular migraine, the composition is administered as a single dose; If a patient experiences rebound pain or recurrence, then a single subsequent dose may be administered, after an appropriate period of time according to the instructions provided by the attending physician. Thus, the treatment of cephalic pain, in particular migraine, provided in the context of the present invention, is essentially by means of the acute administration of a single dose of the active ingredient. The compositions can be administered, for example, 1 to 4 times per day, preferably once or twice. The invention will now be illustrated by the following Examples, which should not be considered as a limitation thereto.

EXAMPLE 1 Tablets by Granulation of Sumatriptan Succinate and Direct Naproxen Sodium Compression The tablets were prepared by compression in a Carver hydraulic press using conventional techniques. The purpose was to prepare a single tablet that provides rapid dissolution of 1 19 mg of sumatriptan succinate (equivalent to 86 mg of sumatriptan free base) and adequate release rate of 650 mg of naproxen sodium (equivalent to 500 mg of free acid of naproxen). An objective dissolution profile for sumatriptan succinate was to dissolve 95% in 5 minutes under dissolution test conditions previously described. As for naproxen sodium, the target profile was one that was competitive with the gold standard, Anaprox® DS (550 mg of naproxen sodium, Roche), which releases approximately 57% in 15 minutes, under the same conditions as dissolution test. Figure 1 shows the dissolution profile obtained for naproxen sodium from commercial Anaprox® tablets of 550 mg. The initial stage of formulation development was to determine the feasibility of a combined direct compression of the two drug substances. The formulations were prepared with various fillers and binders (Anhydrous Emcompress®, 'Avicel PH® 102, and Prosolv SMCC ™ 90) and select disintegrants, slip agents and lubricants, and the sumatriptan succinate of available Montrose origin and USP of sodium of naproxen, from Albemarie Corporation. Representative formulations are presented in Table 1.

Problems with these formulations lead to further investigations that employ different types of naproxen sodium that have superior physical characteristics along with an effervescent to facilitate disintegration. Table 2 below shows the formulation.

Table 2 Baking soda, USP or "modified on the surface" Effersoda rie; ñPi By combinations of carbonate bases (ie, sodium bicarbonate) and an acid, an effervescent reaction would spontaneously take place in the presence of moisture to form water and carbon dioxide. Effer-Soda ™, by SPI Pharma, is a "highly stable surface modified sodium bicarbonate powder, which has a larger particle size range and, in turn, better flow characteristics and less propensity to stickiness". However, it has been found that despite the superior physical characteristics of 90-micron naproxen sodium, the combined direct compression efforts of the two drug substances are unsuccessful.

Example 2 Granulation of Rapid Dispersible Tablet (FDT) of Succinate Sumatriptan v Direct Naproxen Sodium Compression One of the formulations investigated by combining a rapid dispersible formulation of sumatriptan in the combination product was to have the rapid disintegration of the sumatriptan succinate material. The formulation is shown in Table 3. Table 3. Granulation of Sumatriptan Succinate and Direct Naproxen Sodium Compression As a result of using the formulation approach of FDT Suma, the apparent stickiness problems observed with the previous formulations of the formulation were reduced, but not eliminated. Figure 2 shows a dissolution profile for sumatriptan succinate (left) indicating 33% of sumatriptan released in 5 minutes, compared to 96% in 5 minutes for granulation of FDT alone. The Naproxen Sodium solution (right) is 67% in 15 minutes, comparable with Anaprox DS. The dissolution of both components was lower than expected with FDT granulation incorporated in the formulation. This result led to the conclusion that naproxen sodium disabled the dissolution of sumatriptan granules when mixed together.

Example 3 The next approach was a bilayer tablet. The introduction of the FDT granule formulation as a separate stratum containing sumatriptan succinate allowed a reduced tack on the sumatriptan side. The direct compression processing of the naproxen sodium material included disintegrants, lubricants and fillers. A representative formulation composition is shown in Table 4.

Table 4 Formulation Composition for Bicapa Tablet Containing FDT Granulation of Sumatriptan Succinate and Direct Naproxen Sodium Compression Flexibility index = 18.5 Hardness in the Compression Force of 1 5.7 k = 1 5 kp The combination of two formulations as separate strata in a bilayer tablet allowed the rapid release of sumatriptan succinate from the tablet, without much interference from naproxen sodium. Figure 3 shows the dissolution profile for this bilayer approach. The dissolution profiles for sumatriptan and sodium succinate of naproxen from the bilayer combination tablet based on FDT showed that sumatriptan succinate was dissolved at 95% in 5 minutes. This result confirmed the benefit of a bilayer tablet by allowing sumatriptan succinate to be released rapidly. Additionally, naproxen sodium released is approximately 59% in 15 minutes, very close to the Anaprox® DS gold standard.

Examples 4 to 6 Additional bilayer formulations are illustrated in Table 5; all of these involved processing of both the sumatriptan succinate FDT stratum and the naproxen sodium stratum by granulation methods. Table 5 The preparation of Examples 4 to 6 involved the following standard formulation steps: • Naproxen Sodium Stratum: High Shear Granulation d - Granulate fluid bed drying; grinding Dry mixing of granulation and other excipients • Sumatriptan Succinate layer: High Shear Granulation Drying of granulation fluid bed; milling 0 - Dry mixing of granulation and other excipients • Compression as a Bilayer Tablet • Conventional aqueous film cover, for example, with Opadry, Opaglos The dissolution profile for the tablet formulation of d Example 4 is shown in Figure 4 (Apparatus USP I, pH 6.8, phosphate buffer, 60 rpm, n = 6 tablets). This shows that the sumatriptan succinate was 95% dissolved in 5 minutes. This result also confirmed the benefit of a bilayer tablet by allowing sumatriptan succinate to be released rapidly. In addition, the sodium of Naproxen released is greater than 70% in 5 minutes, above the gold standard Anaprox® DS. The application of which this description and claims form a part can be used as a priority basis with respect to any subsequent application. These claims 5 of such subsequent applications may be directed to any novel feature or combination of features described herein. This may take the form of product, composition, process or use claims and may include, by way of example and without limitation, one or more of the following claims.

Claims (17)

1. CLAIMS 1. A pharmaceutical composition comprising a dHT-i receptor agonist or pharmaceutically acceptable derivative thereof in combination with an NSAID or pharmaceutically acceptable derivative thereof, wherein the 5HT? Receptor agonist. and NSAI D are located in discrete zones with respect to each other, wherein each zone comprises the active ingredient and optionally a vehicle.
2. 2. The pharmaceutical composition according to claim 1, characterized in that it comprises a dH ^ receptor agonist selected from the group comprising sumatriptan, naratriptan, zolmitriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, avitriptan, donitriptan, alniditan, ALX-0646, LY334370 , U1092291, IS169 and PNY142633.
3. 3. The pharmaceutical composition according to claim 2, characterized in that the receptor agonist 6HT! it is sumatriptan or naratriptan.
4. 4. The pharmaceutical composition according to claim 3, characterized in that the 5HT1 receptor agonist is sumatriptan.
5. 5. The pharmaceutical composition according to claim 4, characterized in that it comprises sumatriptan succinate.
6. 6. The pharmaceutical composition according to claim 1, characterized in that it comprises an NSAID selected from the group consisting of diclofenac, -60-nabumetone, naproxen, ketorolac, ibuprofen, flurbiprofen, acetoprofen, oxaprozin, etodolac, indomethacin, mephamnamic acid, acid tolfenámico and collective inhibitors of COX-2 such as celecoxib, rofecoxib (VIOXX), valdecoxib, parecoxib, 4- (4-cyclohexyl-2-d methyl-d-oxazoiil) -2-fluorobenzenesulfonamide (JTE-522), MK633 (etoricoxib ), nimesulide, flosulide, DFP, 2- (4-ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine, meloxicam, RS57067, piroxicam, NS398, L-745,337 and COX-1 89.
7. 7. The pharmaceutical composition according to claim 6, characterized in that the NSAI D is COX-189 or naproxen.
8. 8. The pharmaceutical composition according to claim 7, characterized in that the NSAID is naproxen.
9. 9. The pharmaceutical composition according to claim 8, characterized in that the naproxen is sodium of naproxen.
10. 10. The pharmaceutical composition comprising a 5HT-I receptor agonist or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier in combination with an NSAID, wherein the 5HT? Receptor agonist. and NSAIDs are each dispersed within their own pharmaceutically acceptable vehicle in the pharmaceutical composition. eleven .
11. The pharmaceutical composition according to claim 10, characterized in that the vehicle for the dHTi receptor agonist is different in composition from that of the vehicle for the -61-NSAID.
12. 12. The pharmaceutical composition according to claim 10, characterized in that the receptor agonist dHT? and your vehicle are substantially mixed with the NSAID and your vehicle.
13. 13. The pharmaceutical composition according to claim 10, characterized in that it is in the form of a tablet.
14. The pharmaceutical composition according to claim 1, characterized in that the carriers suitable for the dHTi receptor agonist comprise one or more components selected from: a binder, a filler, a lubricant, and an effervescent couple, a broaching agent , a slip agent, a disintegrant and a wetting agent.
15. The pharmaceutical composition according to claim 1, characterized in that the vehicles suitable for the NSAID comprise one or more components selected from: a binder, a filler, a lubricant, an effervescent couple, a wicking agent, a slip agent, a disintegrant and a wetting agent.
16. The pharmaceutical composition according to claim 1, characterized in that it is a multi-capable tablet wherein the active agents are in separate layers.
17. 17. The pharmaceutical composition according to claim 16, characterized in that it is a bilayer tablet. 1 8. The pharmaceutical composition according to claim 1, characterized in that it comprises a dHTi receptor agonist or a pharmaceutically acceptable derivative thereof, in combination with an NSAID or pharmaceutically acceptable derivative thereof, wherein the 5HT1 receptor agonist and NSAID are located in discrete zones with respect to each other, wherein each zone it comprises the active ingredient and optionally a carrier and wherein in addition at least the area comprising the dHT receptor agonist? It is formulated to ensure rapid absorption. 9. The pharmaceutical composition according to claim 18, characterized in that it is a tablet comprising two or more strata, wherein a stratum comprising a dHT? Receptor agonist. or pharmaceutically acceptable derivative thereof is formulated to ensure rapid absorption and another stratum comprises an NSAI D or pharmaceutically acceptable derivative thereof and optionally a carrier. 20. The pharmaceutical composition according to claim 1, characterized in that it is a bilayer tablet comprising a stratum comprising a 5 HT? Receptor agonist. or pharmaceutically acceptable derivative thereof, which is formulated to ensure rapid absorption and a stratum comprising an NSAI D or pharmaceutically acceptable derivative and optionally a carrier. twenty-one . The pharmaceutical composition according to claim 1 8, characterized in that the dH ^ receptor agonist or pharmaceutically acceptable derivative thereof is formulated in conjunction with an effervescent couple in combination with a disintegrant, an insoluble filler and a wicking agent. The pharmaceutical composition according to claim 18, characterized in that the 5HTi receptor agonist or pharmaceutically acceptable derivative thereof is formulated in conjunction with the base component of an effervescent couple, a disintegrant, and an insoluble filler material, wherein the base component it comprises from about 5 to about 50% by weight, the disintegrant comprises from about 0.5 to about 10% by weight, and the insoluble filler material comprises from about 20 to about 99% by weight, said insoluble filler including an agent of wick comprising from about 1 to about 99% by weight, based on the dry weight of the stratum of the dosage form, wherein more than about 70% of the additive ingredient is dissolved in simulated gastric fluid (SGF) within five minutes in USPI I apparatus at the speed of palette of discrimination of 1 0 rpm. 23. The pharmaceutical composition according to claim 1, characterized in that the 5HT receptor agonist stratum comprises a dHTi receptor agonist or a pharmaceutically acceptable derivative thereof, which comprises from about 0.001 to about 56% by weight, the base component of the effervescent couple comprises from about 5 to about 60% by weight, the disintegrant comprises from about 0.5 to about 10% by weight, the insoluble filler material, including the wicking agent, comprises from about 36 to about 80% by weight, and the wicking agent comprises from about 1 to about 80% by weight, based on the dry weight of the stratum of the dosage form. 24. The pharmaceutical composition according to claim 1 8, characterized in that in the NSAID stratum, the NSAID or pharmaceutically acceptable derivative thereof is formulated for rapid absorption. 26. The pharmaceutical composition according to claim 18, characterized in that in the stratum of NSAI D, the NSAI D or pharmaceutically acceptable derivative thereof is formulated in conjunction with an effervescent couple in combination with a disintegrant, an insoluble filler and a wicking agent. 26. The pharmaceutical composition according to claim 18, characterized in that the NSAI D or a pharmaceutically acceptable derivative thereof is formulated together with the base component of an effervescent couple, a disintegrant, and an insoluble filler material, wherein the base component comprises from about 0.5 to about 50% by weight, the disintegrant comprises from about 0.5 to about 20% by weight, and the insoluble filler material comprises from about 30 to about 80% by weight, said insoluble filler including a wicking agent comprising from about 1 to about 60% by weight, based on the dry weight of the stratum of the dosage form, wherein more than about 25% of the active ingredient is dissolved in simulated intestinal fluid within five minutes in USPI devices. the blade speed of discrimination of 30 rpm. The pharmaceutical composition according to claim 1, characterized in that the NSAID layer comprises an NSAID or pharmaceutically acceptable derivative thereof, which comprises from about 1 to about 90% by weight, the base component of the effervescent couple comprises from about 5. up to about 50% by weight, the disintegrant comprises from about 0.05 to about 10% by weight, the insoluble filler material, including the wicking agent, comprises from about 10 to about 99% by weight based on the dry weight of the stratum of the dosage form. 28. The pharmaceutical composition according to claim 1, characterized in that it is a bilayer tablet wherein the dHT- receptor agonist stratum comprises a dHTi receptor agonist or a pharmaceutically acceptable derivative thereof, which comprises from about 0.001 to about - 66 - 56% by weight, the base component of the effervescent couple comprises from about d to about 50% by weight, the disintegrant comprises from about 0.5 to about 10% by weight, the insoluble filler material, including the wicking agent, comprises from about 36 to about 80% by weight and the wicking agent comprises from about 1 to about 80% by weight, based on the dry weight of the stratum of the dosage form and the NSAID stratum comprises an NSAID or a pharmaceutically acceptable derivative of the same, comprising from about 1 to about 90% by weight, the base component of the effervescent couple comprises from about 5 to about 60% by weight, the disintegrant comprises from about O.Od to about 10% by weight, the insoluble filler material, including the wicking agent, comprises from about 10 to about 99% by weight, based on the dry weight of the stratum of the dosage form. 29. The pharmaceutical composition according to claim 1, characterized in that the zone of 5HT receptor agonist? comprising a 5HT-I receptor agonist or a pharmaceutically acceptable derivative thereof, which comprises sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, the base component of the effervescent couple comprises sodium bicarbonate, the disintegrant comprises croscarmellose sodium, and the insoluble filler material comprises microcrystalline cellulose. 30. The pharmaceutical composition according to claim 1, characterized in that the zone of 5HT receptor agonist? comprises a 5HTi receptor agonist or a pharmaceutically acceptable derivative thereof, which comprises sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, the base component of the effervescent couple comprises sodium bicarbonate, the disintegrant comprises croscarmellose sodium, and the material Insoluble filler comprises dibasic calcium phosphate, preferably anhydrous dibasic calcium phosphate. 31 The pharmaceutical composition according to claim 1, characterized in that the 5HT1 receptor agonist zone comprises a 5HT-I receptor agonist or a pharmaceutically acceptable derivative thereof, which comprises sumatriptan or naratriptan or a pharmaceutically acceptable derivative thereof, the base component of the effervescent couple comprises sodium bicarbonate, the disintegrant comprises croscarmellose sodium, and the insoluble filler material comprises anhydrous dibasic calcium phosphate or microcrystalline cellulose or a mixture thereof. 32. The pharmaceutical composition according to claim 20, characterized in that it comprises 85 mg of sumatriptan in the form of 1 19 mg of sumatriptan succinate and 550 mg of naproxen sodium equivalent to 500 mg of naproxen. 33. The pharmaceutical composition according to claim 20, characterized in that it comprises 85 mg of sumatriptan in the form of 1 19 mg of sumatriptan succinate and 560 mg of naproxen sodium equivalent to 454.6 mg of naproxen. 34. The pharmaceutical composition according to claim 1, characterized for use in the treatment of conditions associated with cephalic pain, selected from the group consisting of concentrated headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, pain of head associated with substances or withdrawal, rebound headache, tension headache and migraine. 36. A method for the treatment of a mammal suffering from or susceptible to conditions associated with cephalic pain selected from the group consisting of concentrated headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or withdrawal, rebound headache, tension headache and migraine, which comprises the oral administration of a pharmaceutical composition in the form of oral dose according to claim 1, 36. The method according to claim 36, characterized in that the mammal is a human. 37. The method according to claim 36, characterized in that the condition is migraine.