(12) United States Patent
`Dearn et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,750,237 B1
`Jun. 15, 2004
`
`US006750237B1
`
`(54) PHARMACEUTICAL FORMULATIONS
`CONTAINING ZOLMITRIPTAN
`
`(75)
`
`Inventors: Alan Roy Dearn, Ware (GB); Sarah
`Louise VVilliamson, Ware (GB); Simon
`John Summers, Ware (GB); Trevor
`John Cnomheri Ware (GR)
`
`(73) Assignee: AstraZeneca AB, London (GB)
`( * ) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 0 days.
`10/129,773
`
`(21) Appl. N0.:
`
`Int. Cl.7 ...................... .. A01N 43/76; C07D 419/00
`(51)
`(52) vs. C].
`...................................... .. 514/376; 548/122
`(58) Field of Search ......................... .. 514/376; 548/122
`
`(56)
`
`E],
`
`W0
`W0
`W0
`
`_
`References Clted
`1
`I
`k
`FOREICN PATENT DOFUMENTS
`
`*
`
`4
`
`:1
`
`636623
`
`3
`WO9802186
`WO 98/02187
`5 5
`W0 98/34 9
`
`2/1995
`
`1/1998
`1/1998
`8/1998
`
`(22) PCT Filed:
`
`Nov. 28, 2000
`
`* Cm‘ by examiner
`
`PCT/GB00/04528
`
`(86) PCT No‘:
`§ 371 (C)(1)’
`(2),
`Date: Aug. 28,
`(87) PCT Pub’ No’: W001/39772
`PCT pub. Date; Jun_ 7, 2001
`Foreign Application Priority Data
`(30)
`Dec. 3, 1999
`(GB) ........................................... .. 9928578
`
`Primary Examiner—Alton N. Pryor
`(74) Attorney, Agent, or Firm—Ropes & Gray LLP
`
`A pharmaceutical formulation of the 5HT1-agonist,
`zolmitriptan, for use in intranasal administration. The for-
`mulation is useful in treatin mi raine and related disorders.
`g
`g
`16 Claims, No Drawings
`
`   
`


`
`Lannett Holdings, Inc. LAN 1001
`
`

`
`US 6,750,237 B1
`
`1
`PHARMACEUTICAL FORMULATIONS
`CONTAINING ZOLMITRIPTAN
`
`RELATED APPLICATIONS
`
`This application is a national stage filing under 35 U.S.C.
`371 of PCT application PCT/GB00/04528, filed Nov. 28,
`2000, which claims priority from Great Britain Application
`No. 9928578.5, filed Dec. 3, 1999, the specifications of each
`of which are incorporated by reference herein.
`This application is a 371 of PCT/GB00/04528 filed Nov.
`28, 2000.
`invention relates to new pharmaceutical
`The present
`formulations, their preparation and their use in treatment of
`disease In particular the present invention relates to phar-
`maceutical formulations of the anti—migraine drug zolmi—
`triptan for nasal application.
`Zolmitriptan has the chemical name (S)-4-{{3-[2-
`(dimethylaminoethyl]-1H-indol-5-yl]methyl]-2-
`oxazolidinone. Zolmitriptan is a selective 5HT1-receptor
`agonist. The 5HT1-receptor mediates vasoconstriction and
`thus modifies blood flow to the carotid vascular bed. 5HT1-
`
`receptor agonists are beneficial in the treatment (including
`prophylaxis) of disease conditions wherein vasoconstriction
`in the carotid vascular bed is indicated,
`for example
`migraine, cluster headache and headache associated with
`vascular disorders, hereinafter referred to collectively as
`‘migraine’. Zolmitriptan has been developed for the acute
`treatment of migraine in the form of a 2.5 mg and 5 mg tablet
`intended to be taken up to a maximum of 15 mg per day.
`Although zolmitriptan is a successful drug of considerable
`benefit to migraine sufferers, there is a continuing need for
`alternative methods for the direct treatment of migraine and
`the prophylactic treatment of migraine.
`In particular,
`patients suffering from migraine or the onset of migraine
`need fast relief of their suffering.
`Zolmitriptan is a member of a class of drugs known as
`triptans,
`for example sum atriptan, naratriptan and
`rizatriptan, which are prescribed for the treatment of
`migraine. The leader in terms of sales is sumatriptan which
`has been marketed as an oral formulation. A subcutaneous
`formulation was also developed; this was more efficacious
`(P. Tfelt-Hansen, Cephalalgia 1998, Vol. 18(8), page 532-8)
`and gave a faster onset of action but was not so acceptable
`to the patient. An intranasal spray was also developed. This
`was more user-friendly than the subcutaneous injection but
`was reported to be less effective in reducing the symptoms
`of migraine attacks (C Dablof, Cephalalgia 1998; 18(5);
`278-282). Also, many patients reported an unpleasant bitter
`taste after using the nasal spray.
`The present inventors sought a formulation of Zolmitrip-
`tan that achieved fast relief whilst maintaining high efficacy.
`They also sought a formulation that, for the wide variety of
`patients that suffer from migraines, had a more acceptable
`route of administration than a subcutaneous injection.
`Clearly, the thought of a subcutaneous injection may dis-
`suade many patients from taking appropriate and necessary
`treatment. Furthermore, the inventors sought a formulation
`that was convenient, effective and acceptable to the patient
`and did not cause any unnecessary irritancy or side—effects.
`U.S. Pat. No. 5,466,699 discloses a class of chemical
`compounds for the treatment and prophylaxis of migraine.
`U.S. Pat. No. 5,466,699 discloses that this class of CD11]-
`pounds may be formulated for oral, sublingual, buccal,
`parenteral (for example subcutaneous,
`intramuscular or
`intraveneous), rectal, topical and intranasal administration
`
`2
`and examples of such possible formulations, including an
`example of an intranasal formulation, are disclosed. The
`intranasal
`formulation consists of an active ingredient,
`methyl hydroxybenzoate (0.2%), propyl hydroxybenzoate
`(0.02%), citrate buffer and sufficient hydrochloric acid to
`take the pH to 7.
`The present inventors devised an intranasal formulation of
`Zolmitriptan that provided effective and improved fast relief
`for migraine sufferers. Although, the inventors do not wish
`to be bound by theory, it is thought that this is at least partly
`due to the direct mucosal absorption of a significant pro-
`portion of Zolmitriptan administered by the intranasal route.
`Furthermore, studies with an intranasal formulation of
`Zolmitriptan having a pH of above 7.0, at a pH of 7.4,
`showed the stability of that formulation would not be
`acceptable over extended periods of time.
`The present inventors provided an improved rapid onset
`of action with a stable intranasal formulation of Zolmitriptan
`having a pH of below 7.0. In addition, this formulation was
`acceptable to the general patient population and did not
`cause unnecessary irritancy or side effects.
`Accordingly the present inventors provide a pharmaceu-
`tical formulation suitable for
`intranasal administration
`which comprises Zolmitriptan and a pharmaceutically
`acceptable carrier wherein the pH of the formulation is less
`than 7.0.
`
`The Zolmitriptan formulation for intranasal administration
`is generally prepared as an aqueous formulation and typi-
`cally is buffered. Suitable buffering agents include citric
`acid, phosphates such as disodium phosphate (for example
`the dodecahydrate, heptahydrate, dihydrate and anhydrous
`forms) or sodium phosphate and mixtures thereof (for
`example McIlvaine’s buffer which is a mixture of citric acid
`and disodium phosphate).
`In a particular aspect the pH of the pharmaceutical for-
`mulation of Zolmitriptan is below 6.0, for example in the
`range 3.5 to 5.5, and in particular in the range 4.5 to 5.5. In
`a particular aspect the pH of the formulation is about 5.0.
`In addition to the buffer, the Zolmitriptan formulation may
`contain other
`ingredients typically found in intranasal
`formulations, such as antioxidants for example sodium
`metabisulphite, taste-masking agents such as menthol and
`sweetening agents for example dextrose, glycerol, saccharin
`and sorbitol.
`
`In another aspect the present invention provides an aque-
`ous solution of Zolmitriptan in a buffer at a pH of less than
`7.0 in particular at a pH below 6.0, for example in the range
`3.5 to 5.5 and in particular in the range 4.5 to 5.5, for
`example at about 5.0. In particular the present invention
`provides an aqueous solution of Zolmitriptan in a buffer of
`citric acid and phosphate at a pH of less than 7.0,
`in
`particular at a pH below 6.0, for example in the range 3.5 to
`5.5 and in particular in the range 4.5 to 5.5, for example at
`about 5.0.
`
`The pharmaceutical formulation of the present invention
`may be co—administered (simultaneously or sequentially)
`with one or more pharmaceutical agents of value in treating
`migraine or related disease conditions.
`The pharmaceutical formulations of the invention will
`normally be administered to humans so that, for example a
`unit dose of about 0.5 mg to 15 mg (for example 0.5 mg, 1.0
`mg, 2.5 mg, 5.0 mg and 10 mg) of Zolmitriptan is delivered
`to the patient in need thereof. The concentration and volume
`of the formulation may vary as known in the intranasal art,
`typically a volume of 50 to 250 ,ul is administered, for
`
`5
`
`10
`
`15
`
`'
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`
`US 6,750,237 B1
`
`3
`example 50 ,ul or 100 gal (in one spray or in two 50 gal
`sprays-13 one for each nostril), The precise dose delivered
`depends on various factors known in the art including the
`weight, age and sex of the patient being treated and on the
`particular migraine disease condition being treated. Such a
`unit dose may be taken at any stage in the onset of, or during
`the course of, a migraine attack. Such a unit dose may be
`taken as needed, typically from 1 to 3 times a day.
`The pharmaceutical formulations of this invention may be
`prepared by dissolving zolmitriptan in an acidic medium, for
`example aqueous citric acid, thereby forming the citrate salt
`of zolmitriptan, and taking the pII to the desired value by
`adding a suitable agent for example a phosphate. The
`resultant buffered solution is typically manufactured to
`ensure that it contains a low bioburden or to ensure that it is
`sterile. Typically the solution is sterilised for example by
`passing through a sterile filter (for example 0.2 gm) or by
`autoclaving. Preferably, the solution is purged with nitrogen,
`and overlaid with nitrogen in the primary pack, to minimise
`the possibility of degradation. Alternatively, another inert
`gas, such as argon, could be used. Therefore in another
`aspect the present invention provides a sterile pharmaceu-
`tical formulation suitable for
`intranasal administration
`which comprises zolmitriptan and a pharmaceutically
`acceptable carrier wherein the pH of the formulation is less
`than 7.0.
`
`The pharmaceutical formulations of the invention are
`typically filled into a suitable administration device capable
`of delivering a unit dose amount of zolmitriptan to the
`patient in need thereof. Such administration devices include
`those available commercially and the device disclosed in
`UK Registered Design 2071555. Therefore in a another
`aspect, the present invention provides an intranasal admin-
`istration device containing zolmitriptan and a pharmaceuti-
`cally acceptable carrier wherein the pH of the formulation is
`less than 7.0.
`
`The filled intranasal administration device may be pack-
`aged to provide protection from light. Accordingly in yet a
`further aspect, the present invention provides an intranasal
`administration device containing zolmitriptan and a pl1ar-
`maceutically acceptable carrier
`in light-protecting
`packaging, for example in foil pouches. In an alternative
`aspect the device itself is a dark colour to provide protection
`from light, for example, a dark blue colour.
`Therefore in a further aspect the present invention pro-
`vides a pharmaceutical formulation suitable for intranasal
`administration which comprises zolmitriptan and a pharma-
`ceutically acceptable carrier wherein the pH of the formu-
`lation is less than 7.0 for use in a method of therapeutic
`treatment of the human or animal body.
`In yet a further aspect the present invention provides a
`method of treating a disease condition wherein agonism of
`5HT1-receptors is beneficial which comprises administering
`an effective amount of a pharmaceutical formulation suitable
`for intranasal administration which comprises zolmitriptan
`and a pharmaceutically acceptable carrier wherein the pH of
`the formulation is less than 7.0. The present invention also
`provides the use of zolmitriptan and a pharmaceutically
`acceptable carrier in the manufacture of a pharmaceutical
`formulation suitable for intranasal administration wherein
`
`the pH of the formulation is less than 7.0.
`Zolmitriptan used in the formulations of the present
`invention may be prepared according to the disclosures of
`WO 91/18897 and WO 97/06162.
`EXAMPLES 1-4
`
`4
`pH 5.0 and water of injection is added to the desired volume.
`In this manner solutions with concentrations of zolmitriptan
`of 5 mg/mL, 10 mg/mL, 25 mg/mL and 50 mg/mL are
`prepared. The solution is filtered through a sterilizing grade
`filter (0.2 pm), and filled into USP/Ph Eur Type 1 glass vials
`(nominal spray volume 100 ,uL) which are closed with
`chlorobutyl stoppers.
`
`10
`
`15
`
`Nasal Spray Nominal
`Strength
`Solution Concentration
`Zolmitriptan
`Citric acid, anhydrous
`USP/Ph Eur
`Disodium phosphate
`dodecahydrate USP/'
`Ph Eur*
`Water for Injections
`USP/Ph Eur
`
`TABLE 1
`
`0.5 mg
`
`1 mg
`
`2.5 mg
`
`5 mg
`
`5 mg/ml
`0.5
`1.11
`
`qs to
`pH 5.0
`
`10 mg/ml
`1.0
`1.29
`
`25 mg/ml
`2.5
`1.79
`
`50 mg/ml
`5.0
`2.60
`
`qs to
`pH 5.0
`
`qs to
`pH 5.0
`
`qs to
`pH 5.0
`
`to 0.1 ml
`
`to 0.1 ml
`
`to 0.1 ml
`
`to 0.1 ml
`
`'
`
`*Added as a 0.4 M solution of Disodium Phosphate Dodecahydrate Ph
`Eur/USP diluted with purified water USP/Ph Eur.
`
`The vials are assembled into the unit dose nasal spray
`device disclosed in UK Registered Design 2071555. This
`device comprises a vial holder, an actuation device and a
`protection cap. The assembled device may be used to deliver
`unit doses of zolmitriptan of 0.5 mg, 1.0 mg, 2.5 mg or 5.0
`mg in a single administration. The filled nasal spray device
`is packaged into a plastic tray and placed inside a carton to
`provide protection from the light.
`EXAMPLES 5-8
`
`Zolmitriptan is dissolved in an aqueous solution of citric
`acid, 0.4M disodium phosphate is added to pH 5 .0 and water
`of injection is added to the desired volume. In this manner
`solutions with concentrations of zolmitriptan of 5 mg/mL,
`10 mg/mL, 25 mg/mL and 50 mg/mL are prepared. The
`solution is filtered and filled into USP/Ph Eur Type 1 glass
`vials (nominal spray volume 100 ;AL) which are closed with
`chlorobutyl stoppers.
`
`TABLE 1
`
`Nasal Spray Nominal
`Strength
`Solution Concentration
`Zolmitriptan
`Citric acid, anhydrous
`USP/Ph Eur
`Disodium phosphate
`USP/Ph Eur*
`Purified Water USP/Ph
`Eur
`
`0.5 mg
`
`1 mg
`
`2.5 mg
`
`5 mg
`
`5 mg/ml
`0.5
`1.11
`
`10 mg/ml
`1.0
`1.29
`
`25 mg/ml
`2.5
`1.79
`
`qs to
`pH 5.0
`to 0.1 ml
`
`qs to
`pH 5.0
`to 0.1 ml
`
`qs to
`pH 5.0
`to 0.1 ml
`
`50 mg/ml
`5.0
`2.60
`
`qs to
`pH 5.0
`to 0.1 ml
`
`*Added as a 0.4 M solution of Disodium Phosphate Ph Eur/USP diluted
`with purified Water for injection.
`
`The vials are autoclaved at 121° C. for 15 minutes. They
`are then assembled into the unit dose nasal spray device
`disclosed in UK Registered Design 2071555. This device
`comprises a vial holder, an actuation device and a protection
`cap. The assembled device may be used to deliver unit doses
`of zolmitriptan of 0.5 mg, 1.0 mg, 2.5 mg or 5.0 mg in a
`single administration. The filled nasal spray device is pack-
`aged into a plastic tray and placed inside a carton to provide
`protection from the light.
`EXAMPLES 9
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Zolmitriptan is dissolved in an aqueous solution of citric
`acid, 0.4M disodium phosphate dodecahydrate is added to
`
`The patient removes the packaging from the nasal spray
`device, and then removes the protection cap. The patient
`
`

`
`US 6,750,237 B1
`
`5
`then inserts the nozzle of the device into a nostril and
`actuates it to administer a single dose.
`What is claimed is:
`
`1. A pharmaceutical formulation suitable for intranasal
`administration which comprises zolmitriptan and a pharma-
`ceutically acceptable carrier wherein the pH of the ormu-
`lation is in the range 4.5 to 5.5.
`2. A pharmaceutical formulation according to c
`wherein the pH of the formulation is 5.
`3. A pharmaceutical formulation according to c
`wherein the formulation is buffered.
`4. A pharmaceutical formulation
`wherein the formulation is buffered.
`
`aim 1
`
`aim 1
`
`according to c aim 2
`
`5. A pharmaceutical formulation
`which is sterile.
`6. A pharmaceutical formulation
`which is sterile.
`
`according to c aim 1
`
`according to c aim 2
`
`7. A pharmaceutical formulation
`which is sterile.
`
`according to c aim 3
`
`8. A pharmaceutical formulation according to c
`which is sterile.
`9. A pharmaceutical formulation suitable for intranasal
`administration which comprises zolmitriptan and a pl1arma-
`ceutically acceptable carrier wherein the pH of the ‘ormu-
`
`aim 4
`
`6
`lation is less than 7.0, wherein the formulation is buffered by
`a mixture of citric acid and disodium phosphate.
`10. A pharmaceutical formulation according to claim 9
`which is sterile.
`
`11. A pharmaceutical formulation suitable for intranasal
`administration which comprises zolmitriptan and a pharma-
`ceutically acceptable carrier wherein the pH of the formu-
`lation is in the range 4.5 to 5.5, wherein the formulation is
`buffered by a mixture of citric acid and disodium phosphate.
`12. A pharmaceutical formulation according to claim 11
`which is sterile.
`
`13. An intranasal administration device containing a phar-
`maceutical formulation as defined in any one of claims 1, 2,
`9 or 11.
`14. The intranasal administration device of claim 13,
`wherein the pharmaceutical formulation is packaged to
`protect the formulation fron1 light.
`15. An aqueous solution of zolmitriptan in a buffer at a pH
`in the range of 4.5 to 5.5.
`16. The aqueous solution of claim 15, wherein the pH is
`
`5.
`
`5
`
`10
`
`15
`
`20