HK1038198B - Use of eletriptan in the manufacture of a medicament for the prevention of migraine recurrence - Google Patents

Description

Application of eletriptan in preparation of medicine for preventing migraine recurrence

The present invention relates to the use of eletriptan for the manufacture of a medicament for the prevention of migraine recurrence.

It was shown that 5HT_1B/1DReceptor agonists, such as the compounds known as "triptans", are highly effective in the treatment of migraine. Examples of such triptan derivatives include eletriptan, sumatriptan, naratriptan, rizatriptan (rizatriptan), zolmitriptan (zolmitriptan), ormotriptan (almotriptan), and frovatriptan (frovatriptan).

Eletriptan, 3- ([ 1-methylpyrrolidin-2 (R) -yl ] methyl) -5- (2-phenylsulfonylethyl) -1H-indole, is disclosed in WO-A-92/06973. A preferred eletriptan hydrobromide salt is disclosed in WO-A-96/06842. WO-A-99/01135 discloses pharmaceutical preparations comprising eletriptan hemisulphate and caffeine.

Migraine headaches are generally divided into two types, "migraine with aura" and "migraine without aura". The aura is a focal neuropathy symptom that begins to cause or accompanies an attack.

Migraine headaches with aura are generally defined as a spontaneous, recurrent condition that manifests itself as an attack of neuropathic symptoms, with the attack clearly concentrated in the cerebral cortex or brainstem, usually progressing gradually for 5-20 minutes and lasting less than 60 minutes. Headache, nausea and/or photophobia usually occur immediately after the precursor symptoms of neuropathy, or after a less than 1 hour interval of symptom elimination. This migraine usually lasts 4-72 hours, but may be completely eliminated.

Migraine without aura is generally defined as a spontaneous, recurrent condition whose own manifestations are attacks lasting 4-72 hours. This migraine is typically characterized by pain located unilateral, throbbing nature, moderate or severe intensity, aggravated by regular physical activity, and with nausea, photophobia, or phonophobia.

Most patients suffer only from migraine attacks without aura. Also patients who frequently suffer from aura migraine attacks seem to suffer from aura-free migraine attacks. An "aura" may occur hours or one or two days before a migraine attack (with or without aura). These symptoms usually consist of systemic features such as hyperactivity, hypoactivity, depression, craving for special foods, repeated yawning, and similar atypical symptoms.

Migraine recurrence is classified as a condition distinct from migraine itself, and can be defined as recurrence to moderate or severe migraine within 24 hours after first treatment, from a state without any or mild migraine within 2 hours after first treatment.

There is evidence that although triptan derivatives are effective in relieving migraine, such derivatives actually cause migraine recurrence in a rate that is characteristic of the particular triptan derivative used. In fact, when triptan derivatives are used, the incidence of typical migraine recurrence is approximately 30% for each migraine attack.

The treatment of migraine, i.e. the treatment of already occurring migraine, or the treatment of migraine recurrence, i.e. the treatment of already occurring migraine recurrence, must be clearly distinguished from the prevention of migraine recurrence, i.e. the treatment of patients in whom migraine recurrence is expected to occur, to prevent migraine recurrence. It should be noted that not all patients suffer from the above-mentioned migraine recurrence.

To date, there is no 5HT whatsoever_1B/1DReceptor agonists have been shown to prevent migraine recurrence and for any particular compound, it cannot be simply predicted that they will prevent migraine recurrence, even though the compounds are indicated in the prior art to be capable of treating migraine. Indeed, no "triptans" are currently indicated to prevent migraine recurrence. The reason why the prevention of migraine recurrence cannot be predicted is that the etiology of migraine recurrence is unknown. Furthermore, little is known about the characteristics of patients who are prone to develop migraine recurrence, or about migraine headaches that are likely to recur.

Headache (Cephalalgia), 14, 330, 338(1994) discloses that oral administration of sumatriptan at a dose of 100mg eliminates 60% of migraine attacks within 2 hours, but headache can recur within 24 hours. If another sumatriptan tablet is taken after 2 hours, this does not improve the initial efficacy and neither prevents nor delays migraine recurrence. However, the administration of a further sumatriptan tablet is highly effective in treating migraine recurrence which has already occurred. In addition, Neurology, 45, 1505-1509(1995) discloses that for migraine attacks successfully treated by subcutaneous administration of 6mg sumatriptan, approximately 40% of them are likely to develop migraine recurrence within 24 hours. However, 6mg of sumatriptan administered subcutaneously followed by 100mg of sumatriptan administered orally did not prevent migraine recurrence, but significantly delayed the time of migraine recurrence.

It has now surprisingly been found that eletriptan can be used to prevent migraine recurrence.

Accordingly, the present invention relates to the use of eletriptan, or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the prevention of migraine recurrence.

Furthermore, the present invention relates to a method for preventing migraine recurrence comprising administering to a patient an effective amount of eletriptan, or a pharmaceutically acceptable salt or composition thereof.

Pharmaceutically acceptable salts of eletriptan include the acid addition and base salts thereof.

Suitable acid addition salts are formed with acids which form non-toxic salts, examples of such salts being hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate.

Suitable base salts are formed with bases which form non-toxic salts, examples of such salts being sodium, potassium, calcium, magnesium and zinc salts.

For reviews of suitable salts, see Berge et al, J.Pharm.Sci., 1977, 66, 1-19.

Preferred eletriptan salts for use in the present invention are the hydrobromide and sulphate salts, including the hemisulphate salt.

Polymorphs, solvates and radiolabeled derivatives of eletriptan or their pharmaceutically acceptable salts are also included within the scope of the invention.

Pharmaceutically acceptable solvates of eletriptan and pharmaceutically acceptable salts thereof include hydrates thereof.

Pharmaceutically acceptable salts of eletriptan can be readily prepared by mixing a solution of eletriptan with the desired acid or base, as the case may be. The salt may precipitate out of solution and may be collected by filtration or may be recovered by evaporation of the solvent.

Eletriptan or a salt thereof may be administered alone, but is typically administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, eletriptan or its salts can be administered orally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate or sustained release administration.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine, disintegrants such as starch, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, such tablets may contain lubricating agents such as magnesium stearate, glyceryl behenate and talc.

Solid compositions of a similar type, such as fillings filled in gelatin capsules, may also be employed. For such capsules, preferred excipients include lactose or milk sugar and high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, eletriptan or a salt thereof may be combined with various sweetening or flavouring agents, colouring matter or dyes, emulsifying and/or suspending agents, diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

Eletriptan or a salt thereof may also be administered by parenteral injection, e.g., intravenous, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, intramuscular, or subcutaneous injection, or it may be administered by infusion techniques. Eletriptan is preferably administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3-9) if necessary. Suitable parenteral formulations can be readily prepared under sterile conditions by standard pharmaceutical techniques well known to those skilled in the art.

For oral and parenteral administration to human patients, the daily dosage level of eletriptan or a salt thereof is typically 0.1-4mg/kg (administered in single or divided doses).

Thus, tablets or capsules of eletriptan or a salt thereof may contain 5-240mg, preferably 5-100mg of the active compound, and as the case may be, one or two or more at a time. In any event, the physician will determine the actual dosage which will be most suitable for a particular patient and will depend on the age, weight and response of the particular patient. The above dosages are exemplary average dosages. Of course, in individual cases, higher or lower dosage ranges may be required, and such dosage ranges are within the scope of the invention.

Eletriptan or a salt thereof may also be administered intranasally, or by inhalation, and may conveniently be administered in the form of a dry powder inhaler or aerosol from a pressurised container or nebuliser, using a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A trademark) or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA 227EA trademark), carbon dioxide or other suitable gas. For pressurized aerosols, the dosage unit may be determined by providing a valve to deliver a metered dose. The pressurised container or nebuliser may contain a solution or suspension of the active compound, for example a mixture using ethanol and a propellant as solvents, and may also contain a lubricant such as sorbitan trioleate. Capsules or cartridges containing a powdered mixture of eletriptan, or a salt thereof, and a suitable powder base such as lactose or starch, for use in an inhaler or insufflator may be formulated. Alternatively, eletriptan or a salt thereof may be administered intranasally by delivery from an unpressurized unit or multi-dose pump-type device. Preferred formulations for intranasal administration include those containing eletriptan or a salt thereof and caffeine or cyclodextrin.

Alternatively, eletriptan or a salt thereof may be administered in the form of a suppository or pessary, or may be administered topically in the form of a lotion, solution, cream, ointment, or dusting powder. Eletriptan or its salts can also be administered transdermally by the use of a skin patch.

For topical application to the skin, eletriptan or a salt thereof may be formulated as a suitable ointment containing the active compound suspended or dissolved in a mixture of, for example, one or more of the following: mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene-polyoxypropylene complex, emulsifying wax and water. Alternatively, eletriptan or a salt thereof may be formulated in a suitable lotion or cream suspended or dissolved in a mixture of, for example, one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Preferred formulations of eletriptan or A salt thereof are disclosed in WO-A-92/06973, WO-A-96/06842 and WO-A-99/01135. Particularly preferred formulations of eletriptan, or a salt thereof, for use in preventing migraine recurrence include dual release, sustained release, controlled release, delayed release, or pulsed release formulations.

The sustained release dosage form is designed to release eletriptan into the gastrointestinal tract of a patient for a sustained period of time following administration of the dosage form to the patient. Suitable dosage forms include:

(a) wherein eletriptan or a pharmaceutically acceptable salt thereof is embedded in a matrix and eletriptan or a salt thereof is released from the matrix by diffusion or erosion,

(b) a dosage form wherein eletriptan, or a pharmaceutically acceptable salt thereof, is disposed within or on a multiparticulate core coated with a rate controlling membrane,

(c) wherein eletriptan, or a pharmaceutically acceptable salt thereof, is in a dosage form comprising a drug permeable coating and the drug is released therefrom by drilling,

(d) wherein the eletriptan, or a pharmaceutically acceptable salt thereof, is released via a semi-permeable membrane which allows the drug to diffuse through the membrane or through liquid-filled pores within the membrane, and

(e) dosage forms wherein eletriptan is present in the form of an ion exchange complex and the ion exchange complex is effective to provide controlled release of the active compound in "salt" form (e.g. by use of a suitable anion exchange resin such as sodium polystyrene sulfonate).

It will be appreciated by those skilled in the art that certain of the above means for achieving sustained release may be used in combination, for example to form a matrix comprising the active compound within a plurality of particles and/or to coat the matrix with a permeable coating having pores.

The pulsed release formulation is designed to release the active compound in a pulsed manner over a sustained period of time following administration of the dosage form to a patient. Such release may be in the form of immediate release or sustained release. Delayed release may be achieved by releasing the drug at a specific site in the gastrointestinal tract or by releasing the drug after a predetermined time. The pulsatile release formulations may be in the form of tablets or multiparticulates or a combination of both. Suitable dosage forms include:

(a) osmotic potential triggered release dosage forms (see e.g. US 3952741),

(b) compression coated bi-layer tablets (see for example US 5464633),

(c) capsules containing an erodable plug (see for example US 5474784),

(d) s-shaped release pellets (see, e.g., US 5112621), and

(e) formulations coated with or containing a pH-dependent polymer including shellac, phthalate derivatives, polyacrylic acid derivatives, and crotonic acid copolymers.

Dual release formulations may combine an immediate release form of the active compound with a sustained release form of the active compound. For example, a bilayer tablet may be formed wherein one layer comprises eletriptan in immediate release form and the other layer comprises eletriptan embedded within a matrix and releasable from the matrix by diffusion or erosion. Dual release formulations may also combine an immediate release form of the active compound with a pulsed release form of the active compound. For example, a capsule containing an erodable plug may first release the active compound and after a predetermined period of time, the other active compound is released in immediate or sustained release form.

Preferred dual drug release forms include

(a) Immediate release followed by controlled release;

(b) immediate release followed by zero order release;

(c) immediate release followed by S-type release; and

(d) double pulse release.

Delayed release formulations are designed to release the active compound at a predetermined time after administration. The release from the delayed release formulation may be immediate release or sustained release.

Controlled release formulations allow control of the release rate or time or both of the active compound and include sustained release, pulsatile release, dual release and delayed release formulations.

It has now surprisingly been found that 5HT can be administered in a dual release, sustained release, delayed release, controlled release, or pulsatile release formulation_1B/1DThe receptor agonist or a pharmaceutically acceptable salt thereof is capable of preventing migraine recurrence.

Usable 5HT_1B/1DOther examples of receptor agonists include sumatriptan, naratriptan, rizatriptan, zolmitriptan, omapatritan, and forovatriptan.

Dual release, sustained release, delayed release, controlled release, and pulsatile release formulations that can be used are such formulations as described above for eletriptan.

Accordingly, the present invention also provides:

a) dual-, sustained-, delayed-, controlled-, or pulsed-release pharmaceutical composition for the prevention of migraine recurrence comprising 5HT_1B/1DA receptor agonist or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or carrierA body;

b)5HT_1B/1Duse of a receptor agonist or a pharmaceutically acceptable salt thereof or a composition thereof for the manufacture of a dual-, sustained-, delayed-, controlled-or pulsed-release pharmaceutical composition for the prevention of migraine recurrence; and

c) a method for preventing migraine recurrence comprising administering to a patient an effective amount of a composition comprising 5HT_1B/1DA dual release, sustained release, delayed release, controlled release, or pulsed release pharmaceutical composition of a receptor agonist or a pharmaceutically acceptable salt thereof.

Pharmacological data

Patients suffering from an acute migraine attack are orally administered 40 or 80mg eletriptan (as the hydrobromide salt) in the form of a tablet. After the first administration, if migraine recurrence occurs within 8 hours after the first administration, or if no migraine recurrence occurs as close to 8 hours as possible after the first administration, all patients who exhibit migraine relief within 2 hours are administered a further dose (of the same intensity as the first dose) of eletriptan (in the form of the hydrobromide), or a placebo.

The above protocol is repeated if the patient suffers a second acute migraine attack at least 48 hours after the first migraine attack.

The results obtained for the migraine Recurrence Rates (RR) after the first and second migraine attacks are listed in the table below.

Dosing procedure	40 mg-placebo	40mg-40mg	80 mg-placebo	80mg-80mg
					RR% of the first episode	16.6	7.0	12.5	6.2
RR% of the second episode	10.2	3.3	11.2	6.1

These data in the above table indicate that eletriptan prevents migraine recurrence because, after successful treatment of the first migraine, the number of patients with migraine recurrence is at least halved when eletriptan is administered again compared to placebo.

Claims (7)

1. Use of eletriptan, or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the prevention of migraine recurrence.

2. Use according to claim 1, wherein the salt is the hydrobromide salt.

3. Use according to claim 1, wherein the salt is a hemisulphate salt.

4. Use according to claim 1, wherein the medicament comprises eletriptan hemisulphate and caffeine.

5. Use according to claim 1, wherein the medicament comprises eletriptan, or a pharmaceutically acceptable salt thereof, and a cyclodextrin.

6. The use according to claim 1, wherein the medicament is a dual-, sustained-, controlled-, delayed-, or pulsed-release formulation of eletriptan or a pharmaceutically acceptable salt thereof.

7. Use according to claim 6, wherein the medicament is a dual release formulation of eletriptan, or a pharmaceutically acceptable salt thereof.