AP230A

AP230A - 3-(2-(dimethylamino) ethyl) -n-methyl 1h-indole-5-methane sulphonamide sulphate and pharmaceutical compositions thereof.

Info

Publication number: AP230A
Application number: APAP/P/1991/000339A
Authority: AP
Inventors: Joanne Graig; Derek Leslie Crookes; Stephen John Skittrall
Original assignee: Glaxo Group Ltd
Priority date: 1990-12-12
Filing date: 1991-12-11
Publication date: 1993-01-27
Also published as: IS3790A7; PT99757B; GB9126297D0; ES2069836T3; JPH06503560A; HU211937A9; ZA919750B; GB2251614B; IE62894B1; TW205035B; NL9102071A; IT1252868B; YU191491A; TW300886B; YU48926B; PT99757A; ITRM910922A0; FR2670487B1; CN1128259A; WO1992010477A1

Abstract

3-(2-(dimethylamino)ethyl)-n-methyl-1h-indole-5-methanesulphonamide sulphate salt (2:1)and pharmaceutically acceptable solvents thereof are disclosed. The compound is of use in the preparation of pharmaceutical compositions, particularly for intranasal formulations, for use in the treatment of conditions associayed with cephalic pain, in particular migraine.

Description

MEDICAMENTS

Thia invention relates to a novel salt of 3-(2(dimethylamino)ethyl]-N-me thyl-ΙΗ-indole-5-me thanesulphon amide, to pharmaceutical compositions containing it, in particular to compositions adapted for intranasal administration, and to its use in medicine.

- (2 - (dimethylami.no) ethyl] -N-methyl-lH-indole-5methanesulphonamide, which may be represented by the formula (I)

HjC.

CH,

NSO;CH₂ ch₇ch

CH₃ (I) and its physiologically acceptable salts and solvates are disclosed in UK Patent Specification No. 2162522. The compound of formula (I) exhibits selective vasoconstrictor activity and is useful in the treatment of migraine. Physiologically acceptable salts of the compound of formula (I) specifically disclosed in UK Patent Specification No. 2162522 are the succinate, hemisuccinate, fumarate, benzoate, methanesulphonate and hydrochloride salts.

We have now surprisingly found that a particular salt of the compound of formula (I), which falls within the scope of the salts described and claimed in UK Patent Specification No. 2162522 but which is not specifically disclosed therein, is advantageous for the preparation of certain pharmaceutical compos it ions, in particular for intranasal administrat ion .

The present invention therefore provides 3-(2(d ime thylami no ) ethyl]-N-methyl-lH-indole-5-methanesulphonamide sulphate salt (2:1), and physiologically acceptable solvates, including hydrates, thereof.

In an alternative aspect the invention provides a pharmaceutical composition comprising 3-(2-(dimethylamino)ethyl]-NBAD ORIGINAL metby 1 -1H-indole-5-methanesulphonamide sulphate salt (2:1) or a physiologically acceptable solvate thereof as active ingredient together with a pharmaceutically acceptable carrier therefor.

There is also provided as a further aspect of the invention 3[2- (dimethylamino)ethyl]-N-methyl-IH-indole-5-methanesulphonamide sulphate salt (2:1) and physiologically acceptable solvates thereof for use in therapy, in particular in human medicine. It will te appreciated that use in therapy embraces but is not necessarily limited to use of 3-[2-(dimethylamino)ethyl]-N-methyl-lH-indole-5methanesulphonamide sulphate salt (2:1) or a physiologically acceptable solvate thereof as an active therapeutic substance.

In a further aspect there is provided the use of 3—[2— (dimethylamino)ethyl]-N-methyl-ΙΗ-indole-5-methanesulphonamide sulphate salt (2:1) or a physiologically acceptable solvate thereof in the preparation of a medicament for use in the treatment of conditions associated with cephalic pair, such as cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or their withdrawal (for example drug withdrawal), tension headache and in particular migraine.

We have found that the 3-[2-(dimethylamino)ethyl]-N-methyl-lHindο 1e-5-methanesu1ph οnamide sulphate salt (2:1) or a physiologically acceptable solvate thereof is surprisingly advantageous when administered intranasally.

Oral compositions may be associated with certain disadvantages in the treatment of conditions associated with cephalic pain. For example, such conditions, particularly migraine, are often accompanied by nausea which makes it difficult for a patient to take ar. oral composition. It is also highly desirable, particularly in tr.e treatment of acute conditions, that pharmaceutical compositions have high bioavai1abiiity and a rapid and consistent onset of action. Rapid absorption can be achieved by parenteral administration but this may be unacceptable to some patients, especially if the drug is to be seif-administered . Intranasal administration represents a convenient alternative route for admin ist ration .

BAD ORIGINAL ft

AP Ο Ο Ο 2 3 Ο

- 3 Accordingly, a further aspect of the invention provides a method for the treatment of a mammal, including man, comprising intranasal administration of an effective amount of 3-(2(dimethylamino)ethyl)-N-methyl-lH-indole-5-methanesulphonamide sulphate salt (2:1) or a physiologically acceptable solvate thereof in particular in the treatment of conditions associated with cephalic pain and in alleviating the symptoms associated therewith.

It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms .

Thus, in a preferred aspect the pharmaceutical composition according to the invention is provided in a form adapted for intranasal administration.

Intranasal formulations may generally te provided in liquid or in dry powder forms. Satisfactory intranasal formulations must be sufficiently stable, chemically and physically, to be consistently dispensed in accurate metered doses, even after prolonged storage with potential temperature fluctuations of between 0 and 40®C. Accordingly, the active ingredient must be compatible with the excipients used in the formulation and should not aggregate in a manner which would result in a loss of accurate dose delivery, for example by precipitation from a liquid formulation or by caking of a powder formulation. To maximise retention of an intranasal formulation within the nasal passages of a patient after administration, particularly of a liquid formulation, it is desirable to deliver the unit dosage of active ingredient within a relatively small delivery volume, for example 50-200μ1, preferably lOCpl or less. This may necessitate the use of high concentrations cf medicament and highly soluble active ingredients are therefore advantageous. Clearly, an active ingredient must also be presented in a form which is readily absorbed through the nasal mucosa but which is unassociated with any adverse effects such as irritancy.

Ke have found that for intranasal administration the salt according to the invention may advantageously be administered in the form of a solution.

BAD ORIGINAL ft

Solutions will generally be aqueous for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol, propylene glycol, polyethylene glycols such as PEG 400) .

Such solutions may additionally contain other excipients such as preservatives (for example benzalkonium chloride and phenylethylalcohol), buffering agents, isotonicity-adjusting agents (for example sodium chloride), viscosity enhancing agents, absorption enhancers, flavouring agents (for example aromatic flavouring agents such as menthol, eucaiyptol, camphor and methyl salicylate in amount of about 0.001 to 0.5% w/w) and sweetening agents (for example saccharin in an amount of about 0.01% w/w to about 10% w/w, preferably in the range of 1 to 5% w/w) .

Preferably solutions according to the invention will be sterile and free from preservatives. Sterile formulations may be prepared by methods known in the art, for example by aseptic manufacture or sterilisation of bulk products.

Solutions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case a means of dose metering is desirably provided. In the case of a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution. In the case of a spray this may be achieved for example by means of a notering atomising spray pump.

Intranasal administration may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFO, for example dichlorodif1uoromethane , trrchlorofiuoromethane or dichiorotetraflucroethane, a h ·. d r of 1 uo roca r bon (HFC) for example 1,1,1,2-tetrafluoroethane or 1, 1, 1,2,3,3,3-heptafiuoroprcpane, carbon dioxide or other suitable gas. The dose of drug may be controlled by provision of a metered va1ve.

Preferably a pharmaceutical composition containing 3-[2(cimethylamino)ethyl]-N-methyl-lH-indole-5-methanesulphonamide

BAD ORIGINAL ft

AP000230 sulphate salt (2:1) adapted for intranasal administration will be in the form of an aqueous solution.

Aqueous solutions of the salt of the present invention adapted for intranasal administration will preferably have a pH in the range 4 to 8. Most preferably the pH of aqueous solutions of the salt according to the invention for intranasal administration will be 5 to 7, such as 5.4 to 5.6. Adjustment of the pH of aqueous solutions of the hemisulphate salt of the compound of formula (I) to within the desired range is conveniently effected by addition of a base, such as an inorganic base, preferably an alkali metal hydroxide, most preferably sodium hydroxide.

Thus in a particularly preferred aspect the present invention provides an aqueous solution of 3-[2-(dimethylamino)ethyl]-N-methyllH-indoie-5-methanesulphonamide sulphate salt (2:1) adapted for intranasal administration wherein the pH is in the range of 5 to 7.

It will be appreciated that aqueous solutions of the salt of the present invention may be prepared by dissolving the salt in water. Preferably, however, such solutions are prepared by admixture of 1 molar equivalent of 3-(2-(dimethylamino)ethyl]-N-methyl-lHindole-5-methanesulphonamide and 0.5 to 0.7 molar equivalent of concentrated sulphuric acid, preferably 0.625 molar equivalent of concentrated sulphuric acid, in water.

Aqueous solutions of the salt of the present invention adapted for intranasal administration will preferably contain the salt in a concentration of 20mgml^-1 to SOOmgml*¹, most preferably 25mgml^-1 to 400mgml^-l.

It will be appreciated that the precise therapeutic dose of the salt will depend on the age and condition of the patient and the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

However, in general effective doses for the treatment cf conditions associated with cephalic pain, for example acute treatment of migraine, will lie in the range of 0.5 to ICO mg, preferably 1 to 60mg, most preferably 2 to 40mg of the active ingredient per unit dose which could be administered in single or divided doses, for example, 1 to 4 times per day.

bad ORIGINAL

- 6 The salt of the present invention may conveniently be presented in unit dose form. A convenient unit dose formulation for intranasal administration contains the active ingredient in an amount of from 0.5mg to 100 mg, preferably in the range of 1 to 60mg, most preferably 2 to 40mg, which may be administered to either one or both nostrils. Most preferably, 2.5mg to 25mg of the active ingredient is administered in a single dose to one nostril.

A preferred unit dose formulation may be provided as a single dose in a sealed unit, for example a vial of glass or plastics material which may be filled and sealed using conventional manufacturing techniques. Alternatively, a sealed vial of plastics material may be produced by form-fill-seal technology. Preferably the vial and the components of the pharmaceutical formulation filled therein are heat stable. The sealed vial may be sterilised, for example by autoclaving at 121θ0 for not less than 15 minutes, to provide a sterile unit dosage vial which can be assembled into a convenient delivery device prior to use. Preferably the unit dose volume is 50 to 200 μΐ, for example 100 μΐ.

According to one general process (A), the compound of the present invention cr a solvate thereof may be prepared by reaction of 3-[ 2 -(dimethylamino)ethyl]-N-methyl-lH-indole-5methanesulphonamide or a salt or solvate thereof with sulphuric acid. The process is desirably carried out in aqueous media, optionally in the presence of an organic solvent such as alcohol (for example ethanol or isopropanol). Preferably the compound of the present invention or a hydrate thereof is prepared by admixture of the free base and sulphuric acid in water.

According to another general process (B), the compound of the present invention cr a solvate thereof may be prepared by reaction of a salt oi 3-[2 - (dimethy1 amino)ethy1]-N-methy1-1H-indole-5methanesuIphonamide cr a solvate thereof with an appropriate sulphate salt, for example a metal sulphate (such as sodium or silver sulphate) cr a sulphated ion exchange resin, preferably in an aqueous medium.

Such processes (A) and (B) form further aspects of the present invent ion .

BAD ORIGINAL

AP Ο Ο Ο 2 3 Ο

- 7 In an alternative aspect of the present invention there is provided a pharmaceutical composition in a form adapted for intranasal administration which comprises an aqueous solution of 3(2 - (dimethylamino) ethyl ] -N-methyl-lH-indole-5-methanesulphonamide or a physiologically acceptable salt or solvate thereof, which solution has a pH in the range of pH 5 to pH 7.

A further alternative aspect of the present invention provides a method for the treatment of a mammal, including man, suffering from or susceptible to cephalic pain, in particular migraine, which comprises intranasal administration of a pharmaceutical composition comprising an aqueous solution of 3-(2-(dimethylamino)ethyl]-Nmethy1-1H-indoIe-5-methanesu1phonamide or a physiologically acceptable salt or solvate thereof wherein the pH of the solution is in the range of pH 5 to pH 7.

The following non-limiting examples further illustrate the invention .

Example 1

3-(2- (Dimethylamino) ethvl] -N-methyl-lH-indole-5-methanesulphonamide sulphate (2:1)

Sulphuric acid solution <2N,169ml) was diluted with water (106ml) and added rapidly dropwise to a stirred solution of 3-(2(dimethylamino) ethyl] -N-methyl-lH - indo le -5 - me thanesu lphonamide (IOOg) in ethanol (2.31) and water (25ml) at reflux. The resulting solution was cooled to 45θ€, then seeded, cooled to 4θϋ and aged lh. The reaction mixture was filtered and the filtrate washed with ethanol (50ml) then dried at 4 0 °C in vacuo to give the title comoound (114g) in a solvated form, m.p. 157^C (decomp.) .

Assay shows 6.161w/w ethanol by G.C.

H.p.l.c. 97.3¾ corrected, 0.84¾ w/w water content.

Analysis Found C, 47.75; H,6.32; N,11.11;

gH₄₄N₆0gS .0.99C->Hc,CH . 0 . SShUO

S, 13.00 requires C,48.61; H,6.88; N,11.35; S,12.98%.

BAD ORIGINAL

The following non-limiting examples illustrate pharmaceutical formulations for intranasal administration according to the invent ion .

Examples 2 and 3

STERILE FORMULATION

Examole 2

Example 3

Compound of formula (I) mg

Sulphuric Acid (concentrated) BP 4.23mg

00mg 8 4.8mg

Sodium Hvdroxide BP qs to pH 5.4-5.6 qs to pH 5.4-5.6

Bulk Water for Injections Ph. Eur. to 1ml to lmi

The compound of formula (I) is dissolved in the sulphuric acid previously diluted with water. The solution is made up to approximately 90% of volume. The solution pH is adjusted to 5.5 with sodium hydroxide solution and the solution finally made up to volume. The solution pH i3 remeasured and adjusted if necessary.

The solution may be packaged for intranasal administration, for example by filling into vials, sealing and sterilising the vials by autoclaving at 121θΩ for net less than 15 minutes.

Examoles 4 and 5

PRESERVES FORMULATION

Excmoie 4

Examole 5

Ccmpcund cf formula (I)	2 5 mg	400mg
Sulphuric Acid (concentrated) BP	5.3 mg	64.8 mg
Phenylethyl Alcohol USP	4 mg	4 mg
Benzalkonium Chloride US’.'F	0.2 mg	0.2mg
Sodium (hydroxide BP	qs to pH5.4-5.6 qs	to pH
Purified Water B.P.	to 1ml	to 1ml

BAD ORIGINAL

AP Ο Ο Ο 2 3 Ο

- 9 The compound of formula (I) was dissolved in the sulphuric acid previously diluted with water. Phenylethyl alcohol and benzalkonium chloride were added and the solution made up to approximately 90% of volume. The solution pH was adjusted to 5.5 with sodium hydroxide solution and the solution finally made up to volume. The solution pH was remeasured and adjusted if necessary.

In a similar manner further preserved formulations were prepared containing 5, 10, 50, 100 and 200mgml“l of the compound of formula (I) .

Formulations were administered in unit dose volumes of 100μ1 to either one cr both nostrils of patients suffering from a moderate or severe migraine attack to deliver a dose of 1, 5, 10, 20 or 4Gmg of the compound of formula (I).

Examples 6 and 7 STERILE FORMULATION

Example 6

Example 7

Compound of formula (I), sulphate salt (2:1)

Sodium Hydroxide BP

Bulk Water for Injections Ph. Eur

23.2mg qs to pH 5.4-5.6 to 1ml

65mg qs to pH 5.4-S.6 to 1ml

The compound of formula (I), sulphate (2:1), is dissolved in water and the soiution made up to approximately 90% of volume. The solution pH is adjusted to 5.5 with sodium hydroxide solution and the soiution finally made up to volume. The solution pH is remeasured and adjusted if necessary.

The soiution may be packaged for intranasal administration, for example by filling into vials, sealing and sterilising the vials by autoclaving at 121θ0 for not less than 15 minutes.

Examples 8 and 9

PRESERVED FORMULATION bad original

- 10 Example 8

Example 9

Compound of formula (I),
sulphate salt (2:1)	2 3.2mg	4 65mg
Phenylethyl Alcohol USP	4 . Omg	4 . Omg
Benzalkonium Chloride	0.2mg	0.2 mg
Sodium Hydroxide BP	qs to pH 5.4-5.6	qs to pH
Purified Water B.P.	to 1ml	to 1ml

The compound of formula (I), sulphate salt (2:1), is dissolved in water. Phenylethyl alcohol and benzalkonium chloride are added and the solution made up to approximately 90% of volume. The solution pH is adjusted to 5.5 with sodium hydroxide solution and the soiution finally made up to volume. The solution pH is

remeasured and adjusted if	necessary.
Examoles 10 to 13
STERILE FORMULATION
		Examole 10	Example 11	Example
Compound of formula	(I)	25mg	50mg	10 Omg
Sulphuric acid (cone	. ) SP	5.3mg	10.6mg	21.2mg
Bulk Water fcr		to 1ml	to 1ml	to 1ml
Injections Ph. Eur.		Examcle 13
Compound cf formula	(I)	200 mg
Sulphuric acid (cone	. ) 5?	42.3mg
Bulk Water for		to lmi

Injections Ph. Eur.

The compound of formula (I) was dissolved in the sulphuric acid previously diluted with water. The solution was made up to approximately 90% of volume. The solution pH was adjusted to pH 5.4

BAD ORIGINAL

AP Ο Ο Ο 2 3 ο

- 11 to 5.6 with sodium hydroxide BP solution and the solution finally made up to volume. The solution pH was remeasured and adjusted if necessary .

The formulations are filled into vials in ΙΟΟμΙ aliquots, the vials are sealed and are sterilised by autoclaving at 121®C for not less than 15 minutes. The sterile unit dosage vials are assembled into a convenient delivery device prior to use.

The formulations are administered in unit dose volumes of 100ml to a single nostril of patients suffering from a moderate or severe migraine attack to deliver a dose of 2.5, 5, 10 or 20mg of the compound of formula (I).

Examples 14 and 15

STERILE FORMULATION

Compound of formula (I) Sulphuric acid (cone.) BP Sodium Saccharin BP Bulk water for Injections Ph.

Exam.Dle 14	Exancl·’
200mg	200mg
42.3 mg	42.3mg
lOmg	20mg
to 1ml	to 1ml

The compound of formula (I) was dissolved in the sulphuric acid previously diluted with water. The solution was made up to approximately 90% of volume and the saccharin dissolved therein. The solution pH was adjusted to pH 5.4 to 5.6 with sodium hydroxide BP solution and the solution finally made up to volume. The solution pH was remeasured and adjusted if necessary.

The formulations are filled into vials in ΙΟΟμΙ aliquots, the vials are sealed and are sterilised by autoclaving at 12I®C for not less than 15 minutes. The sterile unit dosage vials are assembled into a convenient delivery device prior to use.

The formulations are administered in unit dose volumes of ΙΟΟμΙ to a single nostril of patients suffering from a moderate or severe migraine attack to deliver a dose of 20mg of the compound of formula (I) .

BAD ORIGINAL $

Examples 16 and 17

STERILE FORMULATIONS

Example 16 Example 17

Compound of formula (I) Succinate salt (1:1)

70mg

Sodium saccharin BP

0mg 20mg

Bulk Water for Injections Ph. Eur. to 1ml to 1ml

The compound of formula I, succinate salt (1:1) is dissolved in water. The solution is made up to approximately 90% cf volume and the saccharin dissolved therein. The solution pH is adjusted to pH 5.4 to 5.6 with sodium, hydroxide BP solution and the solution finally made up to volume. The solution pH is remeasured and ad j usted if necessary .

The solution may be packaged for intranasal admi.nist rat ion, for example by filling into vials, sealing and sterilising the vials by autoclaving at 121®C for not less than 15 minutes.

Claims

Claims

5 1. A physiologically acceptable salt of 3-[2(dimethylamino)ethyl]-N-methyl-lH-indole-5methanesulphonamide or a physiologically acceptable solvate thereof characterised in that the salt is the sulphate salt (2:1).
2. A pharmaceutical composition which comprises a physiologically acceptable salt of 3-[2(dimethylamino) ethyl] - N-methyl-lH-indole-5methanesulphonamide or a physiologically acceptable

15 solvate thereof as active ingredient together with a pharmaceutically acceptable carrier characterised in that the salt is the sulphate salt (2:1).
3. A pharmaceutical composition as claimed in Claim

20 2 adapted for intranasal administration.

»
4. A pharmaceutical composition as claimed in Claim 2 or Claim 3 wherein the salt is in the form of an aqueous solution.
5. A pharmaceutical composition as claimed in Claim 4 wherein the pH is in the range of pH 5 to pH 7.
6. A pharmaceutical composition as claimed in Claim

3 0 4 or Claim 5 which contains the salt in a concentration of 20mgml^-1 to 500mgml^_1.
7. A pharmaceutical composition as claimed in any one of Claims 2 to 6 which is formulated in unit dosage

35 form comprising 0.5 to lOOmg of active ingredient.

bad original (i «Λ
8. A pharmaceutical composition which comprises a sterile aqueous solution of a physiologically

5 acceptable salt of 3-(2-(dimethylamino)ethyl]-N-methyllH-indole-5-methanesulphonamide or a physiologically acceptable solvate thereof characterised in that the composition is adapted for intranasal administration, the salt is the sulphate salt (2:1) which is present in

10 a concentration of 20mgml^_1 to SOOmgml”¹, and that the solution has a pH in the range of pH 5 to pH 7.
9. A physiologically acceptable salt of 3-[2(dimethylamino) ethyl ] - N-methyl-lH-indole-515 methanesulphonamide or a physiologically acceptable solvate thereof for use in the treatment of conditions associated with cephalic pain, in particular migraine, characterised in that the salt is the sulphate salt (2:1).
10. Use of a physiologically acceptable salt of 3-[2(dimethylamino) ethyl)-N-methyl = lH-indole-5methanesulphonamide or a physiologically acceptable solvate thereof in the preparation of a medicament for

25 use in the treatment of conditions associated with cephalic pain, in particular migraine characterised in that the salt is the sulphate salt (2:1).
11. A process for the preparation of a

30 physiologically acceptable salt of 3-[2(dimethylamino)ethyl]-N-methyl-lH-indole-5methanesulphonamide and pharmaceutically acceptable solvates thereof characterised in that the salt is the sulphate salt (2:1); and the process comprises