WO2005120456A2

WO2005120456A2 - Formulation of eletriptan

Info

Publication number: WO2005120456A2
Application number: PCT/IB2005/001828
Authority: WO
Inventors: Hassan Benameur; Michael Paul Fitzgerald
Original assignee: Pfizer Limited; Pfizer Inc.
Priority date: 2004-06-09
Filing date: 2005-05-30
Publication date: 2005-12-22
Also published as: WO2005120456A3

Abstract

The present invention relates to a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan, or a pharmaceutically acceptable salt or solvate thereof.

Description

New formulation of eletriptan

The present invention relates to a liquid formulation of eletriptan or a pharmaceutically acceptable salt thereof. In particular, it relates to a water-in-oil microemulsion comprising eletriptan, or a pharmaceutically acceptable salt thereof, suitable for filling into soft gelatine capsules and to the uses of such a formulation.

Eletriptan, 3-{[1 -methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulfonylethyl)-1 H-indole (also known as 5-(2-benzenesulfonylethyl)-3-(1-methylpyrrolidin-2-ylmethyl)-1 H- indole) is disclosed in US-B-5, 607,951 and various salts of eletriptan, including the hydrobromide and hemisulphate salts, are disclosed in WO-A-96/06842. These salts both exist in a variety of crystalline polymorphic forms, including the α- polymeric form of the hydrobromide salt disclosed in WO-A-96/06842 and the form I polymorph of the hemisulphate salt disclosed in WO-A-01/23377. Both of these crystalline polymorphs are stable and non-hygroscopic, making them ideal for formulation in solid dosage forms.

A tablet form of eletriptan hydrobromide, in its -polymorphic form, is currently marketed under the trade mark Relpax for the treatment of migraine. However, it is desirable to be able to present a drug such as eletriptan in a variety of different dosage forms, particularly in a variety of dosage forms suitable for oral administration, in order to satisfy the different needs and expectations of different patient populations. A particularly desirable oral dosage form, in addition to a tablet form, is soft gelatine capsule containing a liquid fill. Such a soft gelatine capsule formulation is particularly popular with patients, being perceived as easy to swallow and fast acting. Because of their properties and advantages, soft gelatine capsules are used extensively in many pharmaceutical, cosmetic and nutritional products. The primary pharmaceutical applications of soft gelatine capsules include oral dosage forms, chewable softgels, suppositories, and topical products.

Such a formulation, comprising eletriptan, that is suitable for filling into soft gelatine capsules, should preferably be clear in order to maximise its acceptability to patients. Furthermore, in order to satisfy regulatory requirements, is desirable that such an encapsulated liquid formulation should be substantially bioequivalent to the corresponding tablet form, having a similar Cmax (maximum plasma concentration) and AUC (total dose delivered to the plasma) and an equivalent or shorter T_maχ (time from administration to peak plasma concentration). At the same time, the capsule must be sufficiently small so that it is easy to swallow if the formulation is to be acceptable to patients. Typically, a fill volume of from 0.3 to 0.8 ml is required. Compliance with these diverse criteria represents a considerable technical challenge in relation to a formulation of eletriptan since the recommended effective dose of eletriptan is relatively high (20 or 40mg) and eletriptan, and some of its salt forms, have a low solubility. For instance, as disclosed in WO-A-02/09675, eletriptan has an aqueous solubility of 2.5mg/ml at 20°C and eletriptan hydrobromide has an aqueous solubility of 4mg/ml at 20°C. An aqueous solution, however, is not a suitable liquid with which to fill a gelatine capsule, since it would dissolve the capsule itself. This compounds the problem since the solubility of eletriptan and eletriptan salts in the hydrophobic excipients commonly used to manufacture liquid fills suitable for use with gelatine capsules is even lower. Even the hemisulphate salt, which has a higher aqueous solubility, has a solubility in typical excipients such as polyethylene glycol 400, sorbitan trioleate, diethylene glycol monoethyl ether and propylene glycol monolaurate of less than 10 mg/g. For these reasons, it has not been possible to prepare a clear, liquid formulation of eletriptan, or one of its salts, in a mixture of conventional hydrophobic filling agents for gelatine capsules that is sufficiently concentrated to deliver the required dose in a convenient volume.

Surprisingly, however, it has now been found that by using a water-in-oil microemulsion of eletriptan, or a salt thereof, a clear, liquid formulation can be provided which is suitable for filling into gelatine capsules and is sufficiently concentrated to deliver a dose which is substantially bioequivalent to a corresponding tablet formulation in a convenient volume.

The invention therefore provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan, or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan, or a pharmaceutically acceptable salt or solvate thereof, water, a pharmaceutically acceptable hydrophilic co-solvent, a surfactant and a co-surfactant.

In a further preferred embodiment the invention provides a water-in-oil microemulsion, suitable for encapsulation, consisting of eletriptan, or a pharmaceutically acceptable salt or solvate thereof, water, a pharmaceutically acceptable hydrophilic co-solvent, a surfactant and a co-surfactant.

A microemulsion is an apparently homogeneous, transparent system of low viscosity containing both hydrophilic and hydrophobic components. Microemulsions form spontaneously when suitable components are mixed in appropriate ratios and are thermodynamically stable. In its simplest form, a microemulsion consists of small droplets (having a diameter of 10-200 nm) of one liquid dispersed throughout another liquid. A microemulsion can thus be a dispersion of oil droplets in water (an oil-in-water microemulsion) or a dispersion of water droplets in oil (a water-in-oil microemulsion), the latter being the case with the present invention. A microemulsion is characterized by a very low interfacial tension, which is an important factor in its formation and stability.

Being basic, eletriptan forms pharmaceutically acceptable salts with many acids. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, hemisulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Hemisalts, such as the hemisulphate salt, are also formed.

Eletriptan and its pharmaceutically acceptable salts may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

Eletriptan, or a pharmaceutically acceptable salt thereof, may be used in the present invention in a solvated or unsolvated form and in any polymorphic or isotopically-labelled form.

The concentration of eletriptan, or a salt thereof, that can be solubilised by the microemulsion will vary depending on the characteristics, particularly the aqueous solubility, of the salt or free base selected. The microemulsion preferably comprises a salt of eletriptan having an aqueous solubility of greater than 200 mg/ml at 20°C. An example of such a salt is eletriptan hemisulphate. The crystalline form I polymorph of eletriptan hemisulphate disclosed in WO-A-01/23377 is particularly preferred. Preferably, the microemulsion contains about 15% by weight of eletriptan hemisulphate.

The amount of water present is preferably from 5 to 40% by weight. More preferably the amount of water present is from 5 to 15% by weight, most preferably about 5% by weight.

Suitable pharmaceutically acceptable hydrophilic co-solvents include propylene glycol, ethanol, glycerol, polyethylene glycol, diethylene glycol monoethyl ether, Poloxamer™, Glycofurol™ and N-methyl-2-pyrrolidone. Propylene glycol is preferred. The microemulsion may comprise one of more of these co-solvents.

Such a pharmaceutically acceptable hydrophilic co-solvent, in particular propylene glycol, preferably comprises from 5 to 50% by weight of the microemulsion, more preferably from 10 to 30% by weight, more preferably still from 15 to 25% by weight. Most preferably, the microemulsion comprises about 20% by weight of the hydrophilic co-solvent (e.g. of propylene glycol).

Providing both a surfactant and a co-surfactant advantageously achieves a low interfacial tension (see above). A surfactant (or co-surfactant) is a compound of low to moderate molecular weight which contains a hydrophobic part, which is generally readily soluble in oil but sparingly soluble or insoluble in water and a hydrophilic part which is sparingly soluble or insoluble in oil but readily soluble in water. The microemulsion according to the present invention preferably contains both a surfactant and a co-surfactant which act together to reduce the interfacial tension between the two immiscible phases of the microemulsion, the dispersed aqueous phase (hydrophilic) and the continuous water-immiscible phase (lipophilic).

The surfactant should have a high hydrophilic lipophilic balance (HLB), preferably greater than 10 and the co-surfactant should have a low hydrophobic lipophilic balance, preferably from 3 to 10. Hydrophilic lipophilic balance is a characteristic feature of a surfactant and may be easily measured using techniques well known to the person skilled in the art - see, for example, Ηydrophile - Lipophile Balance of Surfactants and Solid Particles: Physicochemical Aspects and Applications', Pyotr M. Kruglyakov, Elsevier, 2000.

Suitable surfactants are polyoxyethylene sorbitan fatty acids derivates, castor oil or hydrogenated castor oil ethoxylates, fatty acid ethoxylates, alcohol ethoxylates and polyoxyethylene-polyoxypropylene co-polymers.

A preferred surfactant is polysorbate 20.

The microemulsion preferably contains from 15 to 25% by weight, more preferably about 20% by weight, of surfactant (particularly of polysorbate 20).

Suitable co-surfactants are the mono-, di- and tri glycerides of fatty acids, propylene glycol mono and/or di- esters of fatty acids, polyglycerol esters of fatty acids and sorbitan esters of fatty acids.

A preferred co-surfactant is sorbitan monolaurate.

The microemulsion preferably contains from 35 to 45% by weight, more preferably about 40% by weight, of co-surfactant (particularly of sorbitan monolaurate). Examples of specific microemulsions according to the invention are shown below in Table 1.

Table 1

Samples of these microemulsions were prepared on a 5ml scale and tested for physical stability. Each microemulsion was stored at 20°C/50% relative humidity in clear vials and microscopic observations using polarised light were made at 24h, 48h and 1 week. A centrifugation test (3000 rpm for 1000 seconds) was also performed after 1 week's storage. In every case, the microemulsions proved to be completely stable.

In a preferred aspect the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan hemisulphate, water, propylene glycol, polysorbate 20 and sorbitan monolaurate.

A particularly preferred microemulsion according to the invention is Example 1 , described above. In order to deliver a dose of 20mg of eletriptan (as the hemisulphate salt), such a formulation would comprise 22.574mg of eletriptan hemisulphate, 7.525mg of water, 30.098mg of propylene glycol, 30.098mg of polysorbate 20 and 60.196mg of sorbitan monolaurate.

The microemulsion provided by the present invention is made by thoroughly mixing the relevant components. The eletriptan or salt thereof is first solubilised in the aqueous phase consisting of water and co-solvent. This aqueous phase is then mixed with the lipophilic components.

The microemulsion is preferably filled into a hard or soft gelatine capsule, particularly the latter, though other capsules such as pullulan capsules and HMPC capsules may also be used. A soft gelatine capsule is a hermetically-sealed, one- piece capsule capable of taking a liquid or semisolid fill. The gelatine shell is primarily composed of gelatin, a plasticizer and water. It may also contain materials that impart the desired appearance (colorants and/or opacifiers), flavouring agents, preservatives and cross-linking inhibitors.

Gelatine provides structural support and typically forms 40 to 50% (preferably about 45%) by weight of the wet gel formulation (i.e. the mixture used to make the_, capsule). The gelatine can be either Type A (acid processed) or Type B (alkali processed). The steps involved in the gelatine manufacturing process include extraction, neutralization, drying, and grinding. The physicochemical properties of gelatine are largely controlled by the source of collagen, extraction method, pH, thermal history, and electrolyte content.

Plasticizers are used to make the capsule shell elastic and pliable. The ratio of plasticizer to gelatine determines the theoretical hardness of the shell. Plasticizers generally account for 20 to 30% by weight of the wet gel formulation and are commonly glycerin, sorbitol, or propylene glycol, either individually or in combination. Several commercially available blends of sugar mixtures with sorbitol anhydrides can also be used and are well known to the skilled person.

Water usually accounts for 30 to 40% (preferably about 37%) by weight of the wet gel formulation and is critical to ensure proper processing during gel preparation and fill encapsulation. Following encapsulation, excess water is removed through controlled drying, leaving the final water content of the filled capsule typically at less than 10% by weight.

Colorants and opacifiers are typically used at low concentrations in the wet gel formulation. A wide range of colorants such as water-soluble dyes, certified lakes, pigments, and vegetable colors have been incorporated into gelatine shells alone or in combination. An opacifier is sometimes added to the gelatine shell to obtain an opaque shell or to protect light-sensitive fill ingredients. Titanium dioxide is the most commonly used opacifier. A flavouring agent such as ethyl vanillin or an essential oil is sometimes included in the capsule shell to impart a desirable odour or flavour.

The soft gelatine capsule is formed and filled at the same time. The shell constituents are dissolved in water and the resulting solution is then heated and pumped onto two cooling drums to form two gelatine ribbons which are fed into a filling machine. The liquid fill is pumped between the gelatine ribbons as they pass between the two die rolls of the filling machine, forcing the gelatine to adopt the shape of the die. The two ribbons are sealed together by heat and pressure and the capsules are cut from the ribbon. They then pass through a tumble dryer to remove excess water before being conditioned under conditions of controlled temperature and relative humidity.

Pharmaceutical formulations, such as the microemulsion formulation of eletriptan provided by the present invention, are usually stored for a period of time before use. The storage period typically extends to months or even years and the conditions under which a formulation is stored may vary in terms of temperature and humidity. During such storage, a pharmaceutical formulation should be stable, so that its composition does not change significantly and the dose of active compound does not diminish over time. Obtaining such a stable liquid formulation has proved to be a considerable technical challenge with eletriptan and its salts due to their instability in solution. For instance, as disclosed in WO-A-99/01135, eletriptan hemisulphate is unstable and considerably degraded in aqueous solution. Advantageously, it has now been found that the stability of the microemulsion provided by the present invention (in its broadest aspect or any of the preferred aspects described above) may be increased, and its shelf-life hence extended, by the addition of an antioxidant.

Thus, in a preferred aspect, the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan, or a pharmaceutically acceptable salt or solvate thereof and an antioxidant. In a further preferred aspect, the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan, or a pharmaceutically acceptable salt thereof, water, a pharmaceutically acceptable hydrophilic co-solvent, a surfactant, a co-surfactant and an antioxidant.

In these formulations containing an antioxidant, the preferred features relating to water content, form of eletriptan and choice and content of co-solvent, surfactant and co-surfactant are as described above.

The shelf-life of a capsule filled according to the present invention can be further extended by removing oxygen from the liquid fill, typically by sparging with nitrogen and/or by storing the capsule in packaging which is not permeable to oxygen (for example, an aluminium blister pack or an HOPE bottle).

With the use of such appropriate measures (antioxidants, removal of oxygen, suitable packaging) the shelf life of capsules filled with the formulation provided by the present invention may be increased considerably.

Suitable antioxidants include acetone sodium bisulfite, acetylcysteine, α-tocopherol acetate, α-tocopherol (natural and synthetic), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, calcium ascorbate, calcium bisulfite, calcium sulfite, cysteine, cysteine hydrochloride, δ-tocopherol, dilauryl thiodipropionate, dithiothreitol, dodecyl gallate, ethoxyquin, ethyl gallate, gallic acid, γ-tocopherol, glutathiona, gossypol, hydroquinone, 4-hydroxymethyl-2,6-di-te/t- butylphenol, hypophosphorus acid, isoascorbic acid, lecithin, α-lipoic acid (sodium salt), methionine, monothioglycerol, α-naphthol, β-naphthoquinone, nordihydroguaiaretic acid, octyl gallate, phenol, m- and p-diphenol, potassium metabisulfite, propyl gallate, sesamol, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulphoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, tannic acid, thioglycerol, tert-bufy/-hydroquinone, thioglycolic acid, thiolactic acid, thiosorbitol, thiourea and 2,4,5-trihydroxybutyrophenone. Preferred antioxidants are those that are soluble in both the hydrophobic and hydrophilic phases of the present microemulsion formulation and which are universally acceptable as pharmaceutical excipients. Ascorbic acid is a particularly preferred antioxidant. Surprisingly, ascorbic acid stabilises the liquid formulations of the invention more effectively then any other antioxidant tested. For example, a formulation corresponding to Example 1 (as described above) was aerated and then stored in a glass vial for 6 weeks at 50°C and 20% relative humidity, either without any antioxidant or with one of a number of typical antioxidants. The level of antioxidant chosen in each case was the level that would be acceptable to regulatory authorities (i.e. would not exceed the maximum daily recommend dose), if a patient took two 80mg doses of eletriptan on the same day (the maximum contemplated daily dose of eletriptan). The results are summarised in Table 2 below.

Table 2

Thus, in a preferred aspect the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan hemisulphate, water, propylene glycol, polysorbate 20, sorbitan monolaurate and ascorbic acid. The level of ascorbic acid is preferably from 0.1 to 4% by weight of the total formulation, most preferably about 1% by weight.

Another preferred antioxidant is a mixture of ascorbic acid and α-tocopherol.

Thus, in a preferred aspect the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan hemisulphate, water, propylene glycol, polysorbate 20, sorbitan monolaurate, ascorbic acid and α-tocopherol.

The level of ascorbic acid is preferably from 0.1 to 4% by weight of the total formulation, most preferably about 1% by weight and the level of α-tocopherol is preferably about 0.2% by weight.

When a formulation corresponding to Example 1 above but also containing 1 % by weight of ascorbic acid and 0.2% by weight of α-tocopherol was stored for 12 months under nitrogen, in either HDPE vials or aluminium-aluminium blisters and under standard ICH conditions (25°C/60% relative humidity and 30°C/65% humidity), essentially no degradation was observed. Based on these data a shelf life of 24 months or more is expected for the microemulsion formulations of the present invention at or below 25°C.

The formulation of the present invention, comprising eletriptan, or a pharmaceutically acceptable salt thereof, are primarily useful in the treatment of migraine and in the prevention of migraine recurrence (see WO-A-00/06161). Migraine includes early migraine, menstrual migraine, migraine in children, mild migraine and recurrent migraine. They may also be used in the treatment of any disease for which a 5-HT-IB/ID receptor agonist is indicated. Examples of other potential uses include use in the treatment of anxiety, chronic paroxysmal hemicrania, cluster headache, depression, drug abuse, emesis, eating disorders, headache associated with vascular disorders, hypertension, mixed headaches, post-traumatic head and neck injury, obesity, pain, tension headaches and as a vasodilator. Apart from eletriptan, or a pharmaceutically acceptable salt thereof, the microemulsion formulation provided by the present invention may also contain one or more further drugs, such as:

(i) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine; (ii) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac; (iii) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental; (iv) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

(v) an Hi antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; (vi) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone; (vii) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine; (viii) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), ketamine, memantine, pyrroloquinoline quinone or cis-4- (phosphonomethyl)-2-piperidinecarboxylic acid;

(ix) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine or 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl) quinazoline; (x) a tricyclic antidepressant, e.g. desipramine, imipramine, amytriptiline or nortriptiline;

(xi) an anticonvulsant, e.g. carbamazepine or valproate;

(xii) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl- 5-(4-methylphenyl)-7H-[1 ,4]diazocino[2, 1 -g][1 ,7]naphthridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)-4-morpholinyl]methyl]-1 ,2-dihydro-3H-1 ,2,4-triazol-3-one (MK- 869), lanepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine (2S,3S);

(xiii) a muscarinic antagonist, e.g oxybutin, tolterodine, propiverine, tropsium chloride or darifenacin;

(xiv) a selective COX-2 inhibitor, e.g. celecoxib, rofecoxib or valdecoxib;

(xv) a non-selective COX inhibitor (preferably with Gl protection), e.g. nitroflurbiprofen (HCT-1026);

(xvi) a coal-tar analgesic, in particular paracetamol;

(xvii) a neuroleptic such as droperidol;

(xviii) a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine); (xix) a beta-adrenergic such as propranolol;

(xx) a local anaesthetic such as mexiletine;

(xxi) a corticosteriod such as dexamethasone

(xxiii) a cholinergic (nicotinic) analgesic;

(xxiv) Tramadol (trade mark); (xxv) a PDEV inhibitor, such as sildenafil, vardenafil, taladafil, 5-[2-ethoxy-5-(4- ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6- dihydro-7H-pyrazolo[4,3-G(]pyrimidin-7-one, 5-(5-acetyl-2-butoxy-3-pyridinyl)- 3-ethyl-2-(1 -ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c |pyrimidin-7- one, 1 -{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyI)-7-oxo-2H- pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine, or Λ/-[1 -(2- ethoxyethyl)-5-(Λ/-ethyl-/V-methylamino)-7-(4-methylpyridin-2-ylamino)-1 H- pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide;

(xxvi) a canabinoid;

(xxvii) a metabotropic glutamate subtype 1 receptor (mGluRI) antagonist; (xxviii) a serotonin reuptake inhibitor such as sertraline; (xxix) a noradrenaline reuptake inhibitor, especially a selective noradrenaline reuptake inhibitor such as (S,S)-reboxetine; (xxx) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1- iminoethyl)amino]ethyl]-2-methyl-L-cysteine or (2S,5Z)-2-amino-2-methyl-7- [(1 -iminoethyl)amino]-5-heptenoic acid; (xxxi) an acetylcholine esterase inhibitor such as donepezil; (xxxii) a dopamine type 2 (D2) antagonist such as ziprazidone; (xxxiii) an prostaglandin E₂ subtype 4 (EP4) antagonist such as Λ/-[({2-[4-(2-ethyl- 4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl)phenyl]ethyl}amino)carbonyl]-4- methylbenzenesulfonamide or 4-[(1 S)-1-({[5-chloro-2-(3- fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

or a pharmaceutically acceptable salt or solvate thereof. A combination of eletriptan, or a pharmaceutically acceptable salt thereof, and an NSAID (such as naproxen, or a pharmaceutically acceptable salt thereof) or a selective COX-2 inhibitor (such as celecoxib, valdecoxib, rofecoxib or a pharmaceutically acceptable salt thereof) is particularly advantageous.

The microemulsion formulation provided by the present invention is primarily intended for oral administration in a capsule, particularly a soft gelatine capsule. However, it is possible to imagine other suitable routes of administration for the formulation, particularly sub-cutaneous injection.

The microemulsion formulation of the present invention is potentially applicable not just to eletriptan but to any indole 5-HT-|_B/ID receptor agonist other than eletriptan, such as almotriptan, alnatriptan, avitriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.

In a further embodiment, the invention therefore provides a water-in-oil microemulsion, suitable for encapsulation, comprising an indole 5-HTI._B/ID receptor agonist, or a pharmaceutically acceptable salt or solvate thereof. In a preferred further embodiment the invention provides a water-in-oil microemulsion, suitable for encapsulation, comprising an indole 5-HT-_IB/_ID receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, water, a pharmaceutically acceptable hydrophilic co-solvent, a surfactant and a co- surfactant.

The indole 5-HT_{1 B}/I_D receptor agonist is in one case naratriptan. The indole 5- HT-1B_/1D receptor agonist is in another case sumatriptan. The indole 5-HT-IB/ID receptor agonist is in another case rizatriptan. The indole 5-HT_1B/ID receptor agonist is in another case zolmitriptan. The indole 5-HTI_B/ID receptor agonist is in another case frovatriptan. The indole 5-HT_{1 B}/ID receptor agonist is in another case avitriptan. The indole 5-HT-_IB/ID receptor agonist is in another case alnatriptan. The indole 5- HT-_I8/1D receptor agonist is in another case almotriptan.

Clinical results

A microemulsion formulation of the present invention comprising eletriptan hemisulphate was compared with a standard tablet formulation of eletriptran comprising eletriptan hydrobromide in an open label, randomised, single dose, three-way crossover study in healthy male volunteers. A selection of the pharmacokinetic results obtained under fasted conditions are summarised below in Table 3, where 'Test' indicates the results for 42 mg eletriptan delivered as the hemisulphate salt in a microemulsion formulation enclosed in a soft gelatine, data dose-normalized to 40mg, and 'Reference' indicates the results for 40 mg eletriptan hydrobromide delivered as an immediate release tablet.

Table 3

AUC(O-infinity) = Area under the plasma concentration versus time curve from time zero to infinity AUC(O-t) = Area under the plasma concentration versus time curve from zero to time t (time of last observed concentration) Cmax = maximum plasma concentration

The microemulsion formulation was safe and well tolerated following single dose administration to healthy volunteers. The results indicate that the two formulations tested had similar pharmacokinetic parameters but, advantageously, the microemulsion formulation was slightly more bioavailable. Both formulations had a similar T_maχ (time to maximal plasma concentration). The mean T_maχ for the microemulsion formulation was 1.6 hours and for the mean T_max for the tablet formulation was 1.5 hours.

Claims

1. A water-in-oil microemulsion, suitable for encapsulation, comprising eletriptan, or a pharmaceutically acceptable salt or solvate thereof.

2. A water-in-oil microemulsion, as claimed in claim 1 , comprising eletriptan, or a pharmaceutically acceptable salt or solvate thereof, water, a pharmaceutically acceptable hydrophilic co-solvent, a surfactant and a co-surfactant.

3. A water-in-oil microemulsion, as claimed in claim 1 or claim 2, wherein the selected form of eletriptan is eletriptan hemisulphate.

4. A water-in-oil microemulsion, as claimed in claim 2 wherein the pharmaceutically acceptable hydrophilic co-solvent is propylene glycol.

5. A water-in-oil microemulsion, as claimed in claim 2 or claim 4, wherein the surfactant is polysorbate 20.

6. A water-in-oil microemulsion, as claimed in claim 2, claim 4 or claim 5 wherein the co-surfactant is sorbitan monolaurate.

7. A water-in-oil microemulsion, as claimed in claim 2, comprising eletriptan hemisuphate, from 5 to 40% by weight of water, from 5 to 50% by weight of propylene glycol, from 15 to 25% by weight of polysorbate 20 and from 35 to 45% by weight of sorbitan monolaurate.

8. A water-in-oil microemulsion, as claimed in claim 2, comprising about 5% by weight of water, 15% by weight of eletriptan hemisulphate, about 20% by weight of propylene glycol, about 20% by weight of polysorbate 20 and about 40% by weight of sorbitan monolaurate.

9. A water-in-oil microemulsion, as claimed in any preceding claim, further comprising an antioxidant.

10. A water-in-oil microemulsion, as claimed in claim 9, wherein the antioxidant comprises ascorbic acid.

11. A water-in-oil microemulsion, as claimed in claim 9 or claim 10, wherein the antioxidant comprises α-tocopherol.

12. A soft gelatine capsule filled with a microemulsion as claimed in any one of claims 1 to 11.

13. The use of a microemulsion, as claimed in any one of claims 1 to 11 , or a soft gelatine capsule as claimed in claim 12, for the manufacture of a medicament for the treatment of migraine or the prevention of migraine recurrence.

14. A method of treating migraine or of preventing migraine recurrence in a mammal, including a human being, including administration of an effective amount of a microemulsion as claimed in any one of claims 1 to 11 or a soft gelatine capsule as claimed in claim 12.

15. A water-in-oil microemulsion, suitable for encapsulation, comprising an indole 5-HTι_B/1D receptor agonist, or a pharmaceutically acceptable salt or solvate thereof.