Ulllted States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,705,520
`
`
`Craig et al.
`[45] Date of Patent:
`Jan. 6, 1998
`
`US005705520A
`
`[S4] MEDICAMENTS
`
`[56]
`
`References Cited
`
`[75]
`
`Inventors: Joanne Craig; Derek Leslie Crookes;
`Stephen 'J0_hn Skittmll- 811 Of Wart
`Great Bntam
`
`FOREIGN PATENT DOCUMENTS
`543/504
`0433043
`3/1991
`European Pat. on
`2162522
`2/1933 United Kingdom ................... 548/504
`
`[73] Assignee: Glaxo Group Limited. London.
`England
`
`[21] APPL N04 551,961
`[22]
`Filed:
`May 21, 1996
`
`_
`_
`Related US‘ Applmmon Data
`[63] Continuation of Ser. No. 460,791, Jun. 2, 1995, Pat No.
`5,554,693, which is a continuation of Ser. No. 377,485. Jan.
`24. 1995, abandoned. Which is 8 Oontinllafion of Set NO.
`doned
`66933’ filed as PCT/Epgumaézi Dec‘ 10’ 1991’ ‘ban’
`'
`[30]
`Foreign Application Priority Data
`Dec. 12, 1990
`[GB]
`United Kingdom ................... 9026998
`[51]
`Int. Cl.° ......................... A61K 31/40; CO7D 209/14
`[52] U.S. Cl.
`......... ..
`514/415', 548/504
`
`[58] Field of Search .
`514/415‘, 548/504
`
`OTHER PUBLICATIONS
`Dawson. Eur. Naurol.. 31. pp. 332—338. 1991.
`CA 105
`(9):
`78831c
`3—[2-(Dimefl1ylamino)ethy1]—n—
`methyl—14—indole—5—methanesu1fonamide. Oxford. p. 632.
`1936-
`Primary Examiner——Joseph McKane
`Attorney, Agent, or Fz'rm—Bacon & Thomas
`[57]
`ABSTRACT
`
`The present invention. relates to 3-[2-(dimethyla.mino)ethyl]
`-N—n1ethyl-1H-methanesulphonamide sulphate salt(2:1) and
`pharmaceutically acceptable solvates thereof. and to phar-
`maceutical compositions containing same. ‘The compound is
`5:“;1:“1:‘1:at;fl:E“a:“:n‘;;:?::‘f'I;’l‘;5p‘;:’s°°‘“::l‘:u?:;:hc:‘:f]’£)‘::
`sitions are particularly useful as intranasal formulations.
`
`7 Claims, No Drawings
`
`   
`


`
`Lannett Holdings, Inc. LA
`
`

`
`5,705,520
`
`2
`withdrawal (for example drug withdrawal). tension head-
`ache and in particular migraine.
`We have found that the 3-[2-(dimethylamino)ethy1]-N-
`methyl-1H-indole-5-methanesulphonamide sulphate salt
`(2:1) or a physiologically acceptable solvate thereof is
`surprisingly advantageous when administered inlranasally.
`Oral compositions may be associated with certain disad-
`vantages 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 an oral composition. It is also
`highly desirable. particularly in the treatment of acute
`conditions.
`that pharmaceutical compositions have high
`bioavailability and a rapid and consistent onset of action.
`Rapid absorption can be achieved by parenteral adrninistra—
`tion but this may be unacceptable to some patients. espe-
`cially if the drug is to be self-administered.
`Intranasal
`administration represents a convenient alternative route for
`administration.
`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)ethy1]-N-methyl-1-indole-5-
`methanesulphonarnide sulphate salt (2:1) or a physiologi-
`cally acceptable solvate thereof in particular in the treatment
`of conditions associated with cephalic pain and in alleviating
`the symptoms associated therewith.
`is
`It will be appreciated that reference to treatment
`intended to include prophylaxis as well as the alleviation of
`established symptoms.
`Thus. in a preferred aspect the pharmaceutical composi-
`tion according to the invention is provided in a form adapted
`for intranasal admi.uistration.
`Intranasal formulations may generally be provided in
`liquid or in dry powder forms. Satisfactory intranasal for-
`mulations must be sufliciently stable. chemically and
`physically. to be consistently dispensed in accurate metered
`doses. even after prolonged storage with potential tempera-
`ture 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
`manna which would result
`in a loss of accurate dose
`delivery. for example by precipitation from a l.iquid formu-
`lation or by caking of a powder formulation. To maximise
`retention of an intranasal formulation within the nasal pas-
`sages 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 50-200 pl, preferably 100 pl or less.
`This may necessitate the use of high concentrations of
`medicament and highly soluble active ingredients are there-
`fore 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.
`We have found that for intranasal administration the salt
`according to the invention may advantageously be admin-
`istaed in the form of a solution.
`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
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`1
`MEDICAMENTS
`
`This application is a continuation of application Ser. No.
`08/460.791. filed Jun. 2. 1995. now U.S. Pat. No. 5.554.693.
`which is a continuation of application Ser. No. 08/377,485.
`filed Jan. 24. 1995. now abandoned. which is a continuation
`of application Ser. No. 08/066038. filed Jun. 14. 1993. now
`abandoned which is a 37 1 of PCT/EP91/02362 filed Dec. 10.
`1991.
`This invention relates to a novel salt of 3-[2-
`(dimethylamino)ethyl]-N—methyl-1H-indole-5-
`methanesulphonarnide.
`to pharmaceutical compositions
`containing it.
`in particular to compositions adapted for
`intranasal administration. and to its use in medicine.
`3-[2-(dimethy1am.ino)ethyl]-N-methyl-1H-indole-5-
`methanesulphonamide. which may be represented by the
`formula (I)
`
`H3C
`
`NS0-;CH
`
`Cl-[2CI-{zN
`
`CH3
`
`(1)
`
`CH3
`
`NIH
`
`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. Physi-
`ologically acceptable salts of the compound of formula (D
`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 pharmaceuti-
`cal compositions. in particular for intranasal administration.
`The present
`invention therefore provides 3-[2-
`(dimethylamino)ethyl]-N-methyl-1H-indole-5-
`methanesulphonamide sulphate salt (2:1). and physiologi-
`cally acceptable solvates. including hydrates. thereof.
`In an alternative aspect the invention provides a pharma-
`ceutical composition comprising 3-[2-
`(dimethylamino)
`ethyl]-N-methyl-1H-indole-5-rnethanesulphonamide sul-
`phate 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-1I-l-indole-5-
`methanesulphonamide sulphate salt (2:1) and physiologi-
`cally acceptable solvates thaeof for use in therapy.
`in
`particular in human medicine. It will be appreciated that use
`in therapy embraces but is not necessarily limited to use of
`3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-
`methanesulphonamide sulphate salt (2:1) or a physiologi-
`cally acceptable solvate thereof as an active therapeutic
`substance.
`In a further aspect there is provided the use of 3-[2-
`(dimethylarnino)ethyl]-N—methyl-ll-l—indole—5—
`methanesulphonamide sulphate salt (2:1) or a physiologi-
`cally acceptable solvate thereof in the preparation of a
`medicament for use in the treatment of conditions associated
`with cephalic pain such as cluster headache. chronic parox-
`ysmal hemicrania. headache associated with vascular
`disorders. headache associated with substances or their
`
`

`
`5.705.520
`
`3
`(for example aromatic flavouring agents such as menthol.
`eucalyptol. 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% wlw. 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 metering atomising spray pump.
`Intranasal administration may also be achieved by means
`of an aerosol formulation in which the compound is pro-
`vided in a pressurised pack with a suitable propellant such
`as
`a chlorofluorocarborr (CFC).
`for example
`dichlorodifluoromethane.
`trichlorofluoromethane or
`dichlorotetra.fluoroethane. a hydrofluorocarbon (HFC) for
`example 1.l.1.2—tetrafluoroethane or
`l.l.1.2.3.3.3—
`heptafluoropropane. carbon dioxide or other suitable gas.
`The dose of drug may be controlled by provision of a
`metaed valve.
`Preferably a pharmaceutical composition containing 3-[2-
`(dimethylamino)ethyl]-N-methyl-1H-indole-5-
`methanesulphonamide sulphate salt (2:1) adapted for intra-
`nasal 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 intranasa]
`administration will be 5 to 7. such as 5.4 to 5.6. Adjustment
`of the pH of aqueous solutions of the hernisulphate 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
`prefaably sodium hydroxide.
`Thus in a particularly preferred aspect the present inven-
`tion provides an aqueous solution of 3-[2—(dimethylamino)
`ethyl]-N-methyl-1H-indole-5-methanesulphonarnide sul-
`phate salt (2:1) adapted for intranasal administration
`wherein the pH is in the range of S 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-1H-indole-5-methanesulphonarnide 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 20 mgml" to 500 mgml“.
`most preferably 25 mgml" to 400 mgml".
`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 of
`conditions associated with cephalic pain. for example acute
`treatment of migraine. will lie in the range of 0.5 to 100 mg.
`
`4
`preferably 1 to 60 mg. most preferably 2 to 40 mg of the
`active ingredient per unit dose which could be administered
`in single or divided doses. for example. 1 to 4 times per day.
`The salt of the present invention my conveniently be
`presented in unit dose form. A convenient unit dose formu-
`lation for intranasal administration contains the active ingre-
`dient in an amount of from 0.5 mg to 100 mg. preferably in
`the range of 1 to 60 mg. most preferably 2 to 40 mg. which
`may be administered to either one or both nostrils. Most
`preferably. 2.5 mg to 25 mg of the active ingredient is
`administered in a single dose to one nostril.
`A preferred unit dose formulation my 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 rnanufactrning 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 121° C. 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 pl. for example 100 pl.
`According to one general process (A). the compound of
`the present invention or a solvate thereof may be prepared by
`reaction of 3-[2-(dimethylamino)ethyl]-N-methyl-1H-
`indole-S-methanesulphonarnide 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 inven-
`tion 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 or a solvate thereof may be prepared
`by reaction of a salt of 3-[2-(dimethylamino)ethyl]-N-
`methyl-1H-indole-5-methanesulphonarnide or a solvate
`thereof with an appropriate sulphate salt. for example a
`metal sulphate (such as sodium or silver sulphate) or a
`sulphated ion exchange resin. preferably in an aqueous
`medium.
`
`Such processes (A) and (B) form further aspects of the
`present invention.
`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)ethy1]-N-methyl-1H-
`indole-5-methanesulphonamide or a physiologically accept-
`able salt or solvate thereof. which solution has a pH in the
`range of pH 5 to pH 7.
`invention
`A further altanative aspect of the present
`provides a method for the treatment of a mammal. including
`man. sufiering from or susceptible to cephalic pain.
`in
`particular migraine. which comprises intranasal administra-
`tion of a pharmaceutical composition comprising an aqueous
`solution of 3-[2-(dimethylamino)ethyl]-N-methyl-1H-
`indole-5-methanesulphonamide or a physiologically accept-
`able 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.
`
`E(AMPLE 1
`
`10
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`65
`
`3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-5-
`methanesulphonarnide sulphate (2:1)
`Sulphuric acid solution (2.N.l69 ml) was diluted with
`water (106 ml) and added rapidly dropwise to a stirred
`
`

`
`5.705.520
`
`5
`solution of 3-[2-(dimethylamino)ethyl]-N-methyl-lH-
`indole-5—methanesulphona.rnide (100 g) in ethanol (2.3 1)
`and water (25 Iul) at reflux. The resulting solution was
`cooled to 45° C.; then seeded. cooled to 4° C. and aged 1 h.
`The reaction mixture was filtered and the filtrate washed
`with ethanol (50 ml) then dried at 40° C. in vacuo to give the
`title compound (114 g) in a solvated form. m.p. 157° C.
`(decomp.).
`Assay shows 6.16% w/w ethanol by G.C.
`H.p.l.c. 97.3% corrected. 0.84% w/W water content.
`Analysis Found C.47.75: H.632; N.ll.ll; S.13.00
`C2aH44N6O8S.O.99C2H5OH.0.35H20 requires C.48.6l;
`H.688; N.11.35; S.l2.98%.
`The following non-limiting examples illustrate pharma-
`ceutical formulations for intranasal administration according
`to invention.
`
`EXAMPLES 2 and 3
`
`Sterile Formulation
`
`6
`EXAMPLES 6 and 7
`
`Staile Formulation
`
`
`
`
`Example 6 Example 7
`
`Comound of formula (I),
`sulphate salt (2:1)
`qs to pH 5.4-5.6
`qs to pH 5.4-5.6
`Sodium Hydroxide BP
`to 1 ml
`to 1 ml
`Bulk Water for Injections Ph. Eur.
`
`
`23.2 mg
`
`465 mg
`
`The compound of formula (I). sulphate (2:1). is dissolved
`in water and the solution 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 is remeasured and adjusted if
`necessary.
`intranasal
`The solution may be packaged for
`administration. for example by filling into vials. sealing and
`sterilising the vials by autoclaving at 121° C. for not less
`than 15 minutes.
`
`20
`
`Example 2
`
`Example 3
`
`EXAMPLES 8 and 9
`
`Compound of formula (I)
`Sulphuric Acid (concentrated) BP
`Sodium Hydroxide BP
`Bulk Water for Injections Ph. Eur.
`
`20 mg
`4.23 mg
`qs to pH 5.4-5.6
`to 1 ml
`
`400 mg
`84.8 mg
`qs to pH 5.4-5.6
`to 1 ml
`
`25
`
`Preserved Formulation
`
`
`
`
` Example 8 Example 9
`
`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 is
`remeasured and adjusted if necessary.
`intranasal
`The solution may be packaged for
`administration. for example by filling into vials. sealing and
`sterilising the vials by autoclaving at 121° C. for not less
`than 15 minutes.
`
`EXAMPLES 4 and 5
`
`Preserved Formulation
`
`30
`
`35
`
`40
`
`Compound of formula (I),
`sulphate salt (2:1)
`4.0 mg
`4.0 mg
`Phenylethyl Alcohol USP
`0.2 mg
`0.2 mg
`Henzalkouiurn Chloride
`qs to pH 5.4-5.6
`qs to pH 5.4-5.6
`Sodium Hydroxide BP
`
`
`to 1 mlPurified Water 13.1’. to 1 ml
`
`23.2 mg
`
`465 mg
`
`is
`The compound of formula (I), sulphate salt (2:1).
`dissolved in water. Phenylethyl alcohol and benzalkonium
`chloride are added and the solution ma.de up to approxi-
`mately 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 is remeasured and
`adjusted if necessary.
`EXAMPLES 10 to 13
`
`Example 4
`
`Example 5
`
`45
`
`Sterile Formulation
`
`
`Compound of formula (I)
`Sulphuric Acid (concentrated) BP
`Phenylethyle Alcohol USP
`Benzalkoniium Chloride USNF
`Sodium Hydroxide BP
`Purified Water 131’.
`
`25 mg
`5.3 mg
`4 mg
`0.2 mg
`qs to pH 5.4-5.6
`to 1 ml
`
`400 mg
`34.3 mg
`4 mg
`0.2 mg
`qs 11) pH 5.4-5.6
`to 1 ml
`
`50
`
`Example 10 Example 11 Example 12
`Compound of formula (I)
`25 mg
`50 mg
`1(1) mg
`Sulphuric acid (cone) BP
`53 mg
`10.6 mg
`21.2 mg
`Bulkwaterfor
`tolml
`tolml
`tolml
`Injections Ph. Eur.
`
`
`The compound of formula (I) was dissolved in the sul-
`phuric acid previously diluted with water. Phenylethyl alco-
`hol 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 200 mgml'1 of the
`compound of formula (I).
`Formulations were administered in unit dose volumes of
`100 pl to either one or both nostrils of patients suffering from
`a moderate or severe migraine attack to deliver a dose of 1.
`5. 10. 20 or 40 mg of the compound of formula (I).
`
`EXAMPLE 13
`
`
`
`Compound of formula (I)
`Sulphuric acid (conc.) BP
`Bulk Water for
`Injections Ph. Eur.
`
`N0 mg
`42.3 mg
`to 1 ml
`
`65
`
`The compound of formula (I) was dissolved in the sul-
`phuric acid previously diluted with water. The solution was
`made up to approximately 90% of volume. 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.
`
`

`
`5,705,520
`
`7
`The formulations are filled into vials in 100 pl 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 100 ill to a single nostril of patients suffering from a
`moderate or severe migraine attack to deliver a dose of 2.5.
`5. 10 or 20 mg of the compound of formula (I).
`
`EXAMPLES 14 and 15
`
`Sterile Formulation
`
`Compound of formula (I)
`Sulphuric acid (conc.) BP
`Sodium Saccharin BP
`Bulk water for Injections Ph. Eur.
`
`Example 14
`
`Example 15
`
`20.") mg
`42.3 mg
`10 mg
`to l ml
`
`2(1) mg
`42.3 mg
`20 mg
`to 1 ml
`
`The compound of formula (I) was dissolved in the sul-
`phuric acid previously diluted with water. The solution was
`made up to approximately 90% of volume and the saccharin
`dissolved thaein. 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 100 pl 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 100 pl to a single nostril of patients suffering from a
`moderate or severe migraine attack to deliver a dose of 20
`mg of the compound of formula (I).
`
`EXAIVIPLES 16 and 17
`
`Sterile Formulations
`
`20
`
`25
`
`30
`
`35
`
`Compound of formula (I),
`Succinalc salt (1:1)
`Sodium saccharin BP
`Bulk Water for Injections Ph. Eur.
`
`Example 16
`
`Example 17
`
`70 mg
`
`—
`to 1 ml
`
`'70 mg
`
`20 mg
`to 1 ml
`
`45
`
`8
`The compound of fonnula L succinate salt (1:1) is dis-
`solved in water. The solution is made up to approximately
`90% of 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 adjusted if
`necessary.
`
`10
`
`intranasal
`The solution may be packaged for
`administration, for example by filling into vials. sealing and
`sterilising the vials by autoclaving at 121° C. for not less
`than 15 minutes.
`We claim:
`
`1. 3-[2-(dirnethylamino)ethyl]-N-methyl- 1H-indole-5-
`methanesulphonamide hemisulphate salt (2:1) or a physi-
`ologically acceptable solvate thereof.
`2. A pharmaceutical composition which comprises 3-[2-
`(dimethylamino)ethyl]-N-methyl-1H-indole-5-
`methanesulphonamide hemisulphate salt (2:1) or a physi-
`ologically acceptable solvate thereof as active ingredient
`together with a pharmaceutically acceptable carrier.
`3. A pharmaceutical composition as claimed in claim 2
`adapted for intranasal administration.
`4. A method of treating a human suffering from or
`susceptible to cephalic pain which comprises administration
`of an efiective amount of 3-[2-(di.methyla.mino)ethyl]-N-
`methyl-1H—indole-5—methanesulphonarnide hemisulphate
`salt (2:1) or a physiologically acceptable solvate thereof to
`the human in need thereof.
`
`5. A method according to claim 4 wherein the 3-[2-
`(dimethylamino)ethyl]-N-methyl-lH-indole-5-
`methanesulphonarnide hemisulphate salt (2:1) or a physi-
`ologically acceptable solvate thereof is administered
`lnlranasally.
`6. A method according to claim 4 wherein the 3-[2-
`(dimethylamino)ethyl]-N-methyl-lH-indole-5-
`methanesulphonamide hemisulphate salt (2:1) or a physi-
`ologically acceptable solvate thaeof is administered in the
`form of an aqueous solution.
`7. A method according to claim 4 wherein the cephalic
`pain is caused by migraine.
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`:
`PATENT NO.
`;
`DATED
`INVENTQFKS) ;
`
`A
`
`5,705,520
`January 6, 1998
`CRAIG et 8|.
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`Column 2, line 22, delete “-1 —indo|e-5-"" and insert therefor — -1H-indole-5- --.
`
`Column 4, line 4, delete “my” and insert therefor "may".
`
`Signed and Sealed this
`
`Eighth Day of June, 1999
`
`E.//M»/@w
`
`Q. TODD DICKINSON
`
`Attesring 0fi‘IL‘(.’I‘
`
`/lclilig (‘mrm1i.\ximI¢'r uf PuIenI.\ um} Tludmnurkx