PCT
`
`WORLD IN'l'ELLBCl'UAL PROPERTY ORGANIZATION
`lntemational Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`A6lK 47/48
`
`(11) International Publication Number:
`
`WO 98102186
`
`(43) International Publication Date:
`
`22 January 1998 (22.0l.98)
`
`(21) International Application Number:
`
`PCT/GB97/01872
`
`(22) International Filing Date:
`
`11 July I997 (1 1.07.97)
`
`(74) Agents: WAIN, Christopher, Paul et 111.; AA. Thomton & Co.,
`Northumberland House, 303-306 High Holbom, London
`WCIV 7LE (GB).
`
`(30) Priority Data:
`96/5889
`
`11 July 1996 (ll.07.96)
`
`ZA
`
`(71) Applicant (far all designated States except IS US): FARMARC
`NEDERLAND B.V.
`[NL/NL]; Citco Trust
`lntemational
`Management (T.I.M) B.V., World Trade Centre, Tower B,
`l7th floor, Strawinslrylaan 1725, NL-1007 JE Amsterdam
`(NL).
`
`(71) Applicant (for IS only): DYER, Alison, Margaret [GB/ZA]; 10
`Veldtuin Place, Momingside, Sandton 2057 (ZA).
`
`(72) Inventors; and
`(75) InventorsIApplicants (for US only): PENKLER, Lawrence,
`John [ZA/ZA]; 4 Verdun Road, Lorraine. Port Elizabeth
`6070 (ZA). DE KOCK, Luéta-Ann [ZA/ZA]; The Bam,
`Kragga Kamma Road, Port Elizabeth 6055 (ZA). WHIT-
`TAKER, Darryl, Vanstone [ZA/ZA]; 504 Twin Palms Beach
`Road, Humewood, Port Elizabeth 6001 (ZA).
`
`(81) Designated States: AL, AM, AT, AU, AZ, B
`BY, CA, CH, CN, CU, CZ, DE, DK, EE,
`GH, HU, IL, IS, JP, KE, KG, KP,
`LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, N0,
`PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR,
`1'1‘, UA, UG, US, UZ, VN. YU, ZW, ARIPO patent (GH,
`KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
`BY. KG, KZ, MD. RU. TJ. TM), European patent (AT, BE,
`CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE). OAPI patent (BF, BJ, CF, CG, CI, CM. GA. GN,
`ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title:
`
`INCLUSION COMPLEX CONTAINING INDOLE SELECTIVE SEROTONIN AGONIST
`
`(57) Abstract
`
`An inclusion complex comprises (a) an indole selective serotonin (5-HTID) agonist or a pharmaceutically acceptable salt thereof, such
`as for example sumatriptan, and (b) unsubstituted or substituted beta- or gamma-cyclodextfin, such as for example methyl-beta-cyclodextrin.
`Pharmaceutical compositions containing the inclusion complex and the use of the inclusion complex in the treatment of migraine and cluster
`headaches are also disclosed.
`
`
`
`   
`


`
`Lannett Holdings, Inc. LAN 1014
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States pany to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Albania
`ES
`LS
`Lesotho
`SI
`Armenia
`FI
`LT
`Lithuania
`SK
`Austria
`FR
`LU
`SN
`Luxembourg
`Australia
`GA
`LV
`Latvia
`SZ
`GB
`MC
`Monaco
`TD
`Azerbaijan
`GE
`MD
`TG
`Bosnia and Henegovina
`Republic of Moldova
`Barbadoa
`GH
`MG
`TJ
`Madagascar
`GN
`MK
`TM
`Belgium
`The former Yugoalav
`Burkina Paao
`Gll
`TI!
`Republic of Macedonia
`HU
`Mali
`1"!‘
`Bulgaria
`Benin
`IE
`UA
`Mongolia
`Brazil
`IL
`Mauritania
`UG
`Belanu
`IS
`Malawi
`US
`Canada
`IT
`Mexico
`UZ
`JP
`VN
`Central African Republic
`Niger
`KE
`Congo
`Netherlands
`YU
`Swilnerland
`KG
`ZW
`Norway
`Cote d’Ivoire
`KP
`New Zealand
`Cameroon
`Poland
`China
`Portugal
`Cuba
`Romania
`Ctech Republic
`Ruaaian Federation
`Sudan
`Gennany
`Denmark
`Sweden
`Estonia
`Singapore
`
`Spain
`Finland
`France
`Gabon
`Unixed Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`JIM"
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic oi‘ Korea
`Republic of Korea
`Kazakalan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tqiikiaran
`‘Ni-lrnienistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United Stare: of America
`Uzbekistan
`Viei Nam
`Yugoslavia
`Zimbabwe
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`1'!‘
`RO
`RU
`SD
`SE
`SG
`
`

`
`wo 93/02136
`
`PCT/GB97/01872
`
`L
`
`IN MP
`
`NAININ IND
`
`E
`
`ELE TIVE ER T NTNA
`
`IT
`
`BACKGROUND OF THE INVEVTION
`
`THIS invention relates to an inclusion complex of an indole selective
`
`serotonin (5-HTio) agonist and an unsubstituted or substituted beta- or
`
`gamrr1a—cyc1odextrin, and to pharmaceutical compositions containing such
`
`a complex, particularly for oral or nasal mucosal delivery, for the treatment
`
`of migraine or cluster headaches.
`
`Sumatriptan (3-(2—dimethylaminoethyl)indol—5-yl—\l—
`
`methylrnethanesulphonatnide)
`
`and
`
`other
`
`structurally
`
`related
`
`indole
`
`derivatives such as naratriptan,
`
`rizatriptan, zolmitriptan. eletriptan and
`
`almotriptan are selective serotonin (5—HT,D) agonists useful for the treatment
`
`of migraine. Sumatriptan is given orally or subcutaneously as the succinate
`
`salt for the treatment ofmigraine. Sumatriptan is rapidly absorbed following
`
`oral administration and undergoes extensive pre—s3/stemic metabolism.
`
`

`
`W0 98/02186
`
`7
`
`PCT/GB97I0l872
`
`resulting in a low bioavailability ofabout 14%. The bioavailability following
`
`subcutaneous administration is 96%. For the acute treatment of migraine.
`
`sumatriptan may be given in an initial dose of 100mg by mouth and a
`
`clinical response can be expected between 0.5 to 2 hours. Alternatively,
`
`sumatriptan may be given by subcutaneous injection in a single dose of 6 mg
`
`with a clinical response in 10 - 15 minutes.
`
`Apart from the low bioavailability following oral administration of anti-
`
`migraine compounds such as sumatriptan.
`
`the classical oral
`
`route of
`
`administration has limitations in the treatment of migraine due to nausea and
`
`vomiting associated with migraine attacks. Many patients are averse to self
`
`administration
`
`by
`
`subcutaneous
`
`injection.
`
`limiting
`
`this
`
`route
`
`of
`
`administration.
`
`The oral and nasal cavities have several advantages as sites for systemic drug
`
`delivery, particularly avoidance of presystemic metabolism. However,
`
`the
`
`low permeability of the membranes that line the oral and nasal cavities result
`
`in a low flux of drug. There is therefore a need to enhance drug penetration
`
`to improve bioavailability following oral or nasal mucosal drug delivery.
`
`There are several methods known in the art to deliver drugs to the oral and
`
`nasal mucosae. These include buccal and sublingual
`
`tablets or lozenges,
`
`adhesive patches, gels, solutions or sprays (powder, liquid or aerosol) for the
`
`oral cavity and solutions or sprays (powder, liquid or aerosol) for the nasal
`
`cavity.
`
`The absorption of drugs from mueosal membranes may be enhanced by (i)
`
`increasing drug solubility, (ii) pH modification to favour the unionized form
`
`of the drug,
`
`(iii) addition of mucoadhesive agents to improve Contact
`
`between the delivery system and the membrane and (iv) incorporation of so-
`
`called penetration enhancers.
`
`

`
`wo 93/02136
`
`3
`
`PCT/GB97/01872
`
`There are a number of penetration enhancers known to influence the
`
`permeability of drugs across epithelial membranes [for a recent review see
`
`Walker. RB and Smith. E.W. Advanced Drug Delivery Reviews 1996. 18.
`
`295-301].
`
`Cyclodextrins and their derivatives have found extensive
`
`application as
`
`solubilizers and stabilizers due to their ability to form inclusion complexes
`
`with a wide variety of compounds [see (J. Szejtli. C'yc1odcxn~in Teclmologi»,
`
`Kluwer Academic Press) and (J. Szejtli & K-11 Fromming, C'_t'clndc.rrrz'n.s‘ in
`
`Pharmacy, Kluwer Academic Press)]. Cyclodextrins have been used to
`
`enhance intestinal absorption ofdrugs primarily through increasing solubility.
`
`Recently, cyclodextrins have been shown to have positive and negative
`
`effects on transdermal penetration of drugs
`
`[see (Loftsson. T.
`
`et
`
`al
`
`International Journal of Pharmaceutics 1995.
`
`1 15. 255-258), (Vollmer. U. et
`
`al. International Journal of Pharmaceutics 1993, 99. 51-58), (Legendre. J.Y.
`
`et al. European Journal of Pharmaceutical Sciences 1995, 3. 311-322) and
`
`(Vollmer, U. et al Journal of Pharmacy and Pharmacology 1994. 46, 19-22)].
`
`Cyclodextrins may improve nasal absorption of drugs [see (Merkus. F.W. et
`
`al. Pharmaceutical Research 1991, 8. 588-592) and (Shao. Z. et
`
`al
`
`Pharmaceutical Research 1992, 9,
`
`1 157-1 163)] and enhance absorption from
`
`sublingual administration of drug/cyclodextrin complexes. Cyclodextrins
`
`also protect nasal mucosal damage by penetration enhancers
`
`[see Jabbal-
`
`Gill, 1. et al. European Journal of Pharmaceutical Sciences 1994, 1(5). 229-
`
`236]
`
`Cyclodextrins
`
`are water
`
`soluble
`
`cone—shaped
`
`cyclic oligosaccharides
`
`containing 6, 7 or 8 glucopyranose units. The interior or “cavity” ofthe cone
`
`is hydrophobic whilst the exterior is hydrophilic. The size of the cavity
`
`increases with increasing number of glucose units. Several cyclodextrin
`
`derivatives such as alkyl. hydroxyalkyl and sulfoalkyl ethers have been
`
`prepared with improved solubility [see (1. Szejtli & K—l~1 Fromming.
`
`Cyclodextrins in Pharmacy, Kluwer Academic Press) and (Stella. V.J. et al
`
`

`
`WO 98/02186
`
`4
`
`PCT/GB97/01872
`
`Pharmaceutical Research 1995, 12 (9) S205)]. Suitably sized hydrophobic
`
`“guest” molecules may enter the “host” cavity to form a classical host-guest
`
`"inclusion compound" or “inclusion complex" with either the entire guest
`
`molecule included or only a portion thereof. The driving mechanism for
`
`cyclodextrin inclusion complexation is the affinity of the hydrophobic guest
`molecule for the cavity of the cyclodextrin host molecule with displacement
`
`'_
`
`of cavity water molecules to a thermodynamically more stable state. The
`
`term "complex stability" or stability of a given inclusion complex refers to
`
`the association/dissociation equilibrium of host and guest
`
`in solution.
`
`intermolecular bonding
`Complex stability depends on the number of
`interactions between the host and guest. Van der waals
`forces and
`
`hydrophobic interactions are the main interactions stabilizing inclusion
`
`complexes (Bergeron. RJ. et al. Journal oft/ac .+lmeri'ccm Chemical Society
`
`1977. 99, 5146). Depending on the nature and position ofhydrogen bonding
`
`Tunctionalities on a given guest. there may be hydrogen bonding between the
`
`guest and hydroxyl groups of the cyclodextrin or other hydrogen bonding
`
`groups in the case of cyclodextrin derivatives. Ionic interactions between the
`
`host and guest are also possible in the case of ionic cyclodextrins such as
`
`stilphobutyl ethers (Stella, V.J. et al Pharmaceutical Research 1995. 12 (9)
`
`S205).
`
`Cyclodextrin inclusion complexes may be prepared on the basis of liquid
`
`state, solid state or semi-solid state reaction between the components (J.
`Szejtli, Cyclodextrin Technology, Kluwcr Academic Press). The first
`is
`
`accomplished by dissolving the cyclodextrin and guest in a suitable solvent
`
`or mixture of solvents and subsequently isolating the solid state complex by
`
`crystallization, evaporation, spray drying or freeze drying. in the solid state
`
`method, the two components may be screened to uniform particle size and
`
`thoroughly mixed whereafter they are ground in a high energy mill with
`
`optional heating, screened and homogenized. In the semi-solid state, the two
`
`components are kneaded in the presence of small amounts of a suitable
`
`solvent, and the complex so—formed,
`
`is dried. screened and homogenized.
`
`

`
`wo 93/02135
`
`5
`
`PCT/GB97/01872
`
`The liquid state reaction generally provides optimum conditions
`
`for
`
`completeness of reaction. Depending on solvent conditions,
`
`the dissolved
`
`inclusion complex exists in equilibrium between uricomplexed host and guest
`
`and complexed host/guest.
`
`SUMMARY OF THE INVENTION
`
`According to a first aspect of the invention there is provided an inclusion
`
`complex of (a) an indole selective serotonin (5—l-lT,D) agonist or
`
`a
`
`pharmaceutically acceptable salt
`
`thereof and (b)
`
`an unsubstituted or
`
`substituted beta- or gamma- cyclodextrin.
`
`By an indole selective serotonin (5-HT,D) agonist there is meant a compound
`
`which includes the indole structure, which structure will generally be
`
`substituted, and which has selective serotonin (5-HT,D) agonist activity.
`
`The indole selective serotonin (5-HT,D) agonist is preferably selected from
`
`compounds having the formula:
`
`Y
`
`wherein X and Y represent suitable substitutions, more preferably from the
`
`group consisting of sumatriptan, naratriptan,
`
`rizatriptan, zolmitriptan,
`
`eletriptan and almotriptan or a pharmaceutically acceptable salt
`
`thereof.
`
`Thus, compound (a) may be used in the form of the free base or in the form
`
`of a pharmaceutically acceptable salt such as a hydrochloride, succinate,
`
`citrate, fumarate, sulphate, benzoate, or maleate salt.
`
`The inclusion complex preferably has a stoichiometry of (a) to (b) of 1:1
`
`

`
`W0 98/02186
`
`mol/mol.
`
`PCT/GB97/01872
`
`The inclusion complex is preferably an inclusion complex of sumatriptan
`
`free base and methyl-beta-cyclodextrin or of sumatriptan succinate and
`
`methyl—beta-cyclodextrin which
`
`has
`
`substantially the X—ray powder
`
`diffraction pattern of Figure 4 or Figure 5.
`
`According to a
`
`second aspect of the invention there is provided a
`
`pharmaceutical composition which comprises as an active ingredient an
`
`inclusion complex of(a) an indole selective serotonin (5-HTID) agonist or a
`
`pharmaceutically acceptable salt
`
`thereof and (b) an unsubstituted or
`
`substituted beta~ or gamma—cyclodextrin.
`
`The pharmaceutical composition is preferably for use in the treatment of
`
`migraine and cluster headaches.
`
`The pharmaceutical composition is preferably adapted for oral or nasal
`
`mucosal delivery.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The invention will now be described in more detail, by way of example
`
`only, with reference to the accompanying drawings in which:
`
`Figurel
`
`shows a differential scanning calorimetry thermogram of
`
`sumatriptan succinate with the onset melting temperature of
`
`166°C and sharp endothermic melting peak at l67,9°C;
`
`Figure 2
`
`shows a differential seaming calorimetry thermogram of a
`
`1:1 kneaded complex of sumatriptan succinate and methyl-
`
`beta-cyclodextrin obtained from Example 1;
`
`

`
`W0 98/02186
`
`7
`
`PCTlGB97I01872
`
`Figure 3
`
`shows a differential scanning calorimetry thermogram of
`
`a
`
`1:1 kneaded complex of sumatriptan succinate and methyl-
`
`beta—cyclodextrin
`
`containing
`
`1 molar
`
`equivalent
`
`of
`
`tromethamine obtained from Example 3;
`
`Figure 4
`
`shows an X-ray powder diffraction pattern of the lzl kneaded
`
`complex
`
`of
`
`sumatriptan
`
`succinate
`
`and methyl-beta-
`
`cyclodextrin obtained from Example 1;
`
`Figure 5
`
`shows an X-ray powder diffraction pattern of the lzl kneaded
`
`complex
`
`of
`
`sumatriptan
`
`succinate
`
`and methyl-beta-
`
`cyclodextrin containing one molar equivalent oftromethamine
`
`obtained from Example 2: and
`
`Figure 6
`
`shows a cut—away perspective of the geometry optimized
`
`molecular mechanical model of an inclusion complex of
`
`sumatriptan (pale grey) in beta-cyclodextrin (dark grey).
`
`DESCRIPTION OF EMBODIMENTS
`
`The crux of the invention is an inclusion complex of (a) an indole selective
`
`serotonin (5—HT,D) agonist or a pharmaceutically acceptable salt thereof and
`
`( b) an unsubstituted or substituted beta- or gamma-cyclodextrin.
`
`Examples of suitable compounds (a) are sumatriptan, naratriptan, rizatriptan,
`
`zolmitriptan, eletriptan and almotriptan. The compound may be used in the
`
`form of the free base or in the form of a pharmaceutically acceptable salt
`
`such as a hydrochloride, succinate, citrate, fumarate, sulphate, benzoate, or
`
`maleate salt or the like.
`
`The second component of the inclusion complex is an unsubstituted or
`
`

`
`W0 93/02136
`
`PCT/GB97/01872
`
`substituted beta- or gamma-cyclodextrin.
`
`8
`
`Highly water
`
`soluble cyclodextrins
`
`such as 2-liydroxypropylated or
`
`methylated or sulphoalkylated derivatives of beta—cyclode.\'trin are the
`
`preferred cyclode.\'trins of the
`
`invention. Gamma—c_vclodextrin or 2-
`
`hydroxypropylated or methylated or sulphoalkylated derivatives of gamma-
`
`cyclodextrin may also be used in the same manner as the corresponding
`
`preferred beta—cyclodextrin derivatives. The degree of substitution of the
`
`cyclodextrin derivatives may vary between 1
`
`to 20 substituents per
`
`cyclodextrin molecule but more preferably between 3 to 15 substituents per
`
`cyclodextrin molecule. When the cyclodextrin is 2-hydroxypropyl—beta—
`
`cyclodextrin,
`
`the preferred degree of substitution is between 3.0 and 5.1
`
`hydroxypropyl groups per cyelodextrin molecule. When the cyclodextrin is
`
`methyl-beta-cyclodextrin. the preferred degree of substitution is between 1.8
`
`and 2 methyl groups per glucose unit.
`
`The inclusion complex of the invention may be prepared from aqueous
`
`solutions.
`
`slurries or pastes of the indole derivative and cyclodextrin
`
`according to conventional methods. The molar ratio of indole derivative to
`
`cyclodextrin may vary between 121 to 1:10 but more preferably between 1:1
`
`to 1:5. Solutions are prepared by dissolving the cyclodextrin in a sufficient
`
`quantity of purified deionised water which may be optionally buffered
`
`between pH 7,4 to 8,5. The indole derivative is added to the solution with
`
`stirring until dissolved. The solution may be used in the preparation of liquid
`
`delivery systems such as drops, sprays or aerosols. Where a solid inclusion
`
`complex is desired, the solution or slurry may be dried by spray drying or
`
`freeze drying.
`
`Alternatively, the indole derivative and cyclodextrin are mixed. The powder
`
`mixture is wetted with water. optionally containing a buffer pH 7.4 - 8.5.
`
`while mixing vigorously until a paste is formed. The paste is mixed for 0.25
`
`to 2 hours and dried in an oven or in vacuo at elevated temperature. The
`
`

`
`WO 98/02186
`
`PCT/GB97/01872
`
`9
`
`dried complex is crushed and sieved to the desired particle size.
`
`A pharmaceutically acceptable buffer, capable of buffering in the pH range
`
`7.4 - 8,5 may be used in the formation ofthe inclusion complex. particularly
`
`when the indole derivative is present as a salt. Preferred buffers include
`
`tromethamine,
`
`triethanolamine, diethanolamine. phosphate buffer, sodium
`
`bicarbonate, and sodium carbonate. The concentration ofthe buffer may vary
`
`from 0.5 to 5 molar equivalents relative to the indole.
`
`The second aspect of the invention is a pharmaceutical composition which
`
`comprises as an active ingredient an inclusion complex as described above.
`
`The pharmaceutical composition ofthe invention is of particular application
`
`in the treatment of migraine and cluster headaches.
`
`Further,
`
`the pharmaceutical composition of the invention is preferably
`
`adapted for oral or nasal mucosal delivery.
`
`The administration of an anti-migraine drug through the mucosal tissue of
`
`the nose or mouth avoids the problems associated with administration of
`
`indole serotonin agonists by injection (i.e. patient aversion and painful
`
`administration) and oral administration (i.e. slow onset of action. low bio-
`
`availability and poor compliance due to nausea and vomiting associated with
`
`migraines).
`
`Absorption ofthe drug from the pharmaceutical composition ofthe invention
`
`is rapid such that the drug reaches the systemic circulation almost as fast as
`
`through injection and appreciably faster than oral administration, which is
`
`highly advantageous for the rapid relief of migraine attack or cluster
`
`headache.
`
`Further, the unpleasant taste and irritant properties of the active principle are
`
`

`
`WO 98102186
`
`10
`
`PCT/GB97/01872
`
`reduced by presenting the drug to the nasal or oral mucosal membranes in
`
`the form of a cyclodextrin inclusion complex.
`
`The present invention achieves these advantages by molecular encapsulation
`
`of the anti-migraine indole drug in a cyclodextrin, so forming a molecular
`
`inclusion complex which may be used in the solid form for the preparation
`
`of sublingual or buccal tablets, buccal patches or nasal inhalation powders
`
`(insufflations). The inclusion complex may be used in the liquid state for the
`
`preparation of metered dose sprays. drops or pressurized aerosols for nasal
`
`or oral administration. The complex according to the invention may be
`
`incorporated into a shearform matrix designed for immediate release as
`
`described in Fuisz Technologies Ltd patents (Eur. Pat. Appl. EP 95—650038
`
`and PCT Int. Appl. WO 95/34293).
`
`According to the invention, the indole nucleus of selective serotonin (5-HT,,,)
`
`agonists has been found to be readily included in the cavity of beta-
`
`cyclodextrins such as hydroxypropyl-beta-cyclodextrin and methyl-beta-
`
`eyclodextrin to form molecular inclusion complexes with a l:l mol/mol
`
`stoichiometry. Inclusion complexes of a variety of indole-based serotonin
`
`agonists may therefore be prepared according to methods known in the art
`
`such as spray drying, freeze drying and kneading, as described above. The
`
`complexes according to the invention may also be incorporated into
`
`microspheres by methods appreciated in the art. The complexes according
`
`to the invention are stable, amorphous and highly water soluble.
`
`Penetration enhancers may be used to promote the passage of the indole
`
`derivative across the mucosal membranes. Typical permeation enhancers
`
`include fatty acids and their salts such as sodium caprate, sodium caprylate
`
`and sodium oleate,
`
`sodium laurate,
`
`and bile
`
`salts
`
`such as
`
`sodium
`
`glycodeoxycholate,
`
`sodium glycocholate,
`
`sodium cholate and sodium
`
`taurodeoxycholate. Other penetration enhancers may include tensides, ionic
`
`surfactants such as sodium lauryl sulphate, or non—ionic surfactants such as
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`polyethylene glycol 660 hydroxystearate or polyoxyethylene lauryl ethers.
`
`fusidates such as sodium taurodihydrofusidate. Other specific enhancers
`
`include azone and chitosan. Combinations of permeation enhancers such as
`
`polyoxyethylene 8 lauryl ether and sodium glycocholate or mixed micelles
`
`such as sodium caprate and sodium glycocholate may also be used. The
`
`penetration enhancers may also be used in combination with beta or gamma-
`
`cyclodextrins or their methyl, hydroxypropyl or sulphoalkyl derivatives.
`
`Typical concentrations of permeation enhancers are between 0.1 "/0 to 5%.
`
`more preferably between 0,25% to 3% by weight of the composition.
`
`As stated above, the serotonin (5—HT,D) agonist may be used in the form ot‘
`
`the free base or a pharmaceutically acceptable salt. When acidic penetration
`
`enhancing excipients are used such as bile acids or
`
`fatty acids or
`
`pharmaceutically acceptable salts of bile acids or fatty acids, salt formation
`
`between the basic component of the serotonin (5-HT,[,) agonists and the
`
`acidic component of the bile or fatty acid may occur.
`
`Buffering agents may be incorporated into the pharmaceutical composition
`
`of the invention to control the microenvironmental pl-I surrounding the drug
`
`delivery system in the alkaline range, so as to maximize the percentage of
`
`the unionized form of the drug. Drugs in the unionized form cross mucosa]
`
`membranes more readily than the corresponding unionized form.
`
`Liquid compositions suitable for nasal or oral administration may contain a
`
`suitable quantity of viscosity modifying agents such as hypromellose or
`
`carbopol 934P and preservative agents such as chlorhexidine gluconate or
`
`thiomersal.
`
`Oral compositions may contain suitable tlavouring and sweetening agents
`
`such as cherry, mint,
`
`spearmint, vanilla. aspartame,
`
`sucrose, xylitol.
`
`saccharin and the like.
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`Typical
`
`sublingual or buccal
`
`tablets may include lubricants
`
`such as
`
`magnesium stearate, calcium stearate and sodium stearyl
`
`fumarate to
`
`facilitate tablet compression, diluents such as
`
`lactose.
`
`inicrocrystalline
`
`cellulose, maize starch and the like and mucoadhesive agents such as
`
`chitosan. carbopol 934?. and hydroxypropylcellulose and the like.
`
`Typical disintegrants to enhance sublingual tablet disintegration may include
`
`sodium carboxymethylcellulose, sodium starch glycolate. polyplastloiie XL.
`and dried starch.
`
`The following examples illustrate the present invention.
`
`EXAMPLE 1
`
`Sumatriptan succinate (lg) and methyl—beta—cyclodextrin (34 l 8) are mixed in
`
`a mortar‘ Purified deionised water (Zml) is added in aliquots with mixing to
`
`form a uniform paste. Mixing is continued for 0.5 hours and the paste is
`
`transferred to a vacuum oven and dried at 40°C and 5 millibar. The dried
`
`complex is crushed with a pestle and passed through a 60 mesh (250 micron)
`
`sieve. The complex contains 23,0 “/0 m/m (mass/mass) sumatriptan succinate
`
`as determined by HPLC.
`
`EXAMPLE 2
`
`Tromethamine (O,293g) was dissolved in 5 ml purified deionised water.
`
`Sumatriptan succinate (lg) and methyl-beta-cyclodextrin (3,18g) are mixed
`
`in a mortar. The tromethamine solution is added in aliquots with mixing to
`
`form a uniform paste. Mixing is continued for 0,5 hours and the paste is
`
`transferred to a vacuum oven and dried at 40°C and 5 millibar. The dried
`
`complex is crushed with a pestle and passed through a 60 mesh (250 micron)
`
`sieve. The complex contains 21,7 % m/m sumatriptan succinate as
`
`determined by HPLC.
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`EXAMPLE 3
`
`The unit composition of a sublingual tablet containing the equivalent of 20
`
`mg sumatriptan base is as follows:
`
`Sumatriptan/methyl—beta-cyclodextrin complex (from Example 2)
`
`Lactose NF
`
`Magnesium stearate
`
`»
`1301112
`
`20mg
`
`lmg
`
`The complex is blended with the lactose. The lubricant is screened in and
`
`the mixture is blended and formed into sublingual tablets by compression at
`
`10 — 30N.
`
`EXAMPLE 4
`
`The unit composition of a sublingual tablet containing the equivalent of 20
`
`mg sumatriptan base is as follows:
`
`Sumatriptan/methyl-beta—cyelodextrin complex (from Example 1')
`
`122mg
`
`Xylitol
`
`Sodium caprate
`
`Magnesium stearate
`
`28mg
`
`3_75mg
`
`lmg
`
`The complex is blended with the xylitol and sodium caprate. The lubricant
`
`is screened in and the mixture is blended and formed into sublingual tablets
`
`by compression at 10 — 30N.
`
`EXAMPLE 5
`
`Hydroxypropyl—beta-cyclodextrin (3,39g) is dissolved in purified deionised
`
`water (8ml) buffered to pH 7,4 with phosphate buffer. Sumatriptan succinate
`
`(lg) is added to the solution with stirring. The solution is stirred for 20
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`minutes and then sodium caprate (25mg) and chlorhexidine gluconate
`
`(0,01%) is added. The volume is adjusted to 10 ml by addition of phosphate
`
`buffer pH 7,4 and the tonicity of the final solution is adjusted with sodium
`
`chloride to 300 mOsrn/kg. The solution is filtered and filled into a metered
`
`dose nasal spray bottle. Each 0,] ml metered dose contains
`
`10 mg
`
`sumatriptan succinate suitable for nasal administration.
`
`Referring now to the drawings, Figure 1
`
`shows a differential scanning
`
`calorimetry thermogram of sumatriptan succinate with the onset melting
`
`temperature of 166°C and sharp endothermic melting peak at 167,9°C. The
`
`thermogram was recorded on a Perkin-Elmer DSC7 calorimeter with a
`
`heating rate of 5°C per minute. A sample mass of 1.36 mg was used.
`
`Figure 2 shows a differential scanning calorimetry thermogram of a 1:1
`
`kneaded complex of sumatriptan succinate and methy1—beta-cyclodextrin
`
`obtained from Example
`
`1.
`
`The characteristic melting endotherm of
`
`sumatriptan succinate shown in Figure 1
`
`is absent, providing evidence of
`
`inclusion complexation between sumatriptan and methyl-beta-cyclodextrin.
`
`Characteristic decomposition of methyl-beta-cyclodextrin is seen from
`
`175°C. Experimental conditions where as described in Example 1, except
`
`that a sample mass of 11,1 mg was used to provide a sumatriptan succinate
`
`response equivalent to Example 1.
`
`Figure 3 shows a differential scanning calorimetry thermogram of a 1:1
`
`kneaded complex of sumatriptan succinate and methyl—beta—c)/clodextrin
`
`containing 1 molar equivalent of tromethamine obtained from Example 2.
`
`The characteristic melting endothermy of sumatriptan succinate shown in
`
`Figure 1
`
`is absent. An endotherm corresponding to the free base at 89°C is
`
`also
`
`absent providing evidence of
`
`inclusion complexation between
`
`sumatriptan and methyl—beta-cyclodextrin. Characteristic decomposition of
`
`methyl-beta—cyclodextrin is seen from 175°C. Experimental conditions were
`
`as described in Example 1 except that a sample mass of 12.42 mg was used
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`to provide a sumatriptan succinate response equivalent to Example 1.
`
`Figure 4 shows an X-ray powder diffraction pattern of the 1:1 kneaded
`
`complex of sumatriptan succinate and methyl-beta—cyc1odextrin obtained
`
`from Example 1. The absence of resolved sharp peaks characteristic of
`
`crystalline sumatriptan succinate indicates inclusion complexation with
`
`resultant
`
`loss of crystallinity.
`
`The
`
`resulting diffraction pattern is
`
`characteristic of an amorphous solid.
`
`Figure 5 shows an X-ray powder diffraction pattern of the 1:1 kneaded
`
`complex of sumatriptan succinate and Inethyl-beta—cyclodextrin containing
`
`1 molar equivalent oftromethamine obtained from Example 2. The absence
`
`of resolved sharp peaks characteristic of crystalline sumatriptan succinate and
`
`tromethamine indicates
`
`inclusion complexation with resultant
`
`loss
`
`01‘
`
`crystallinity.
`
`The resulting diffraction pattern is characteristic of an
`
`amorphous solid.
`
`Figure 6 shows a cut-away perspective ofthe geometry optimised molecular
`
`mechanical model of an inclusion complex of sumatriptan (pale grey) in
`
`beta-cyclodextrin (dark grey). The indole nucleus fills the cavity with the
`
`pendant dimethylaminoethyl (bottom) and methanesulphonamide (top) side
`
`chains extending out of the cavity.
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`CLAIMS
`
`PCT/GB97/01872
`
`1
`
`2
`
`3
`
`An inclusion complex of (a) an indole selective serotonin (5-HT,D)
`
`agonist or a pharmaceutically acceptable salt thereof and
`
`(b) an unsubstituted or substituted beta-or gamma—cyclodextrin.
`
`An inclusion complex according to claim 1 wherein (a)
`
`is
`
`sumatriptan or a pharmaceutically acceptable salt thereof.
`
`An inclusion complex according to claim 1 wherein (21)
`
`is selected
`
`from the group consisting of naratriptan, rizatriptan, zolmitriptan.
`
`eletriptan and almotriptan and the pharmaceutically acceptable salts
`
`thereof.
`
`4
`
`An inclusion complex according to any one of claims
`
`1
`
`*1
`to 3
`
`wherein (b)
`
`is
`
`selected from the group consisting of 2-
`
`hydroxypropyl-beta-cyclodextrin, a methylated—beta-cyclodextrin,
`
`and a sulphoalkylated beta-cyclodextrin.
`
`5
`
`An inclusion complex according to any one of claims l
`
`to 4
`
`wherein (b) has
`
`a degree of substitution between 1
`
`to 20
`
`substituents per cyclodextrin molecule.
`
`6
`
`7
`
`An inclusion complex according to claim 5 wherein (b) has a degree
`
`of substitution between 3
`
`to 15 substituents per cyclodextrin
`
`molecule.
`
`An inclusion complex according to any one of claims
`
`1
`
`to 3
`
`wherein (b) is 2-hydroxypropyl beta—cyclodextrin with a degree of
`
`substitution between 3,9 and 5,1 hydroxypropyl groups per
`
`cyclodextrin molecule.
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`PCT/GB97I0l872
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`8
`
`An inclusion complex according to any one of claims 1 to 3 where
`
`(b)
`
`is methyl—beta—cyclodextrin with a degree of substitution
`
`between 1.8 and 2 methyl groups per glucose unit.
`
`9
`
`An inclusion complex of sumatriptan free base and meth_vl—beta—
`
`cyclodextrin.
`
`10
`
`An inclusion complex of sumatriptan succinate and methyl-beta-
`
`cyclodextrin.
`
`11
`
`An inclusion complex of sumatriptan succinate and meth_v1-beta-
`
`cyclodextrin having substantially the X—ray powder diffraction
`
`pattern of Figure 4 or Figure 5.
`
`12
`
`An inclusion complex according to any one of claims 1
`
`to 11
`
`wherein the inclusion complex has a stoichiometry of (a) to (b) of
`
`1:1 mol/mol.
`
`13
`
`A pharmaceutical composition comprises as an active ingredient an
`
`inclusion complex of (a) an indole selective serotonin (5—HT,D)
`
`agonist or a pharmaceutically acceptable salt thereof and (b) an
`
`unsubstituted or substituted beta- or gamma-cyclodextrin.
`
`14
`
`A pharmaceutical composition according to claim 13 wherein the
`
`inclusion complex is as defined in any one of claims 2 to 12.
`
`15
`
`A pharmaceutical composition according to claim 13 or claim l4 for
`
`use in the treatment of migraine or cluster headaches.
`
`16
`
`A pharmaceutical composition according to any one of claims 13 to
`
`15 formulated for oral or nasal mucosal delivery.
`
`

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`1 8
`
`17
`
`The use of an inclusion complex of (a) an indole selective serotonin
`
`(5-HT,D) agonist or a pharrnaceutically acceptable salt thereof and
`
`(b) an unsubstituted or substituted beta— or gamma—cyclodextrin in
`
`the manufacture of a medicament
`
`for use in the treatment of
`
`migraine or cluster headaches.
`
`18
`
`The use according to claim 17 wherein the inclusion complex is as
`
`defined in any one of claims 2 to 12.
`
`

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`1/6
`
`FIGURE 1
`
`m9%WwTo.EflommHMSREIu:mo3:<_‘o.oe.._n|..
`
`
`
`
`
`1oémMW.n__.
`
`
`mmL4
`
`mxQ9%
`
`xmmmode
`
`E9%
`
`S
`
`23%TW
`ummcoWo.mm
`
`
`
`
`
`o.oomo.m:cam“o.mN«o.o2o.mno.om
`
`o.mm
`
`o.om
`
`0.3
`
`
`

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`
`2/6
`
`FIGURE