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    • 专利摘要:
    PURPOSE: An indole selective serotonin (5-HTID) agonist is prepared, which is used to release migraine and headache, also it is prepared in the form of micro-spheric capsule. CONSTITUTION: 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 cyclodextrin or gamma cyclodextrin, 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 prepared.
    公开号:KR20000022239A
    申请号:KR1019980710659
    申请日:1997-07-11
    公开日:2000-04-25
    发明作者:다릴 반스톤 휘타커；루에타-앤 드 콕；로렌스 존 펜클러
    申请人:토마스 헤인；팔마크 네덜란드 비브이 오브 시트코 트러스트 인터내셔날 매니지먼트(티.아이.엠) 비.브이.；
    IPC主号:
    专利说明:

    Inclusion Complex with Indole Selective Serotonin Agonists
    Sumatriptan (3- (2-dimethylaminoethyl) indol-5-yl-N-methylmethanesulfonamide) and other structurally related indole derivatives such as naratriptan, rizatriptan, zolmitriptan eletriptan and Almotriptan is a selective serotonin (5-HT ID ) agonist useful for the treatment of migraine headaches. Sumatriptan is given orally or subcutaneously as succinic acid salt for migraine treatment. Sumatriptan is rapidly absorbed following oral administration and undergoes extended pre-systemic metabolism, resulting in a low bioavailability of about 14%. Bioavailability following subcutaneous administration is 96%. For acute treatment of migraine headaches, sumatriptan can be given orally at an initial dose of 100 mg, and a clinical response can be expected between 0.5 and 2 hours. Alternatively, sumatriptan may be given by subcutaneous injection in a single dose of 6 mg with a clinical response within 10-15 minutes.
    The low bioavailability following oral administration of antimigraine compounds such as sumatriptan is a matter of concern, and typical oral administration methods are limited in the treatment of migraine due to the concomitant nausea and vomiting of migraine attacks. Many patients do not like to administer themselves by subcutaneous injection, thus limiting this method of administration.
    The oral cavity and nasal cavity have several advantages, in particular, as a site for systemic drug delivery, which can avoid preliminary systemic metabolism. However, a small amount of drug spills as a result of the low permeability of the membrane across the oral and nasal passages. Therefore, there is a need to enhance the penetration of the drug in order to improve the bioavailability following drug delivery of the oral and nasal mucosa.
    Several methods are known in the art for delivering drugs to the mucous membranes of the oral and nasal passages. These include oral and sublingual tablets, adhesive plasters, gels, solutions or sprays (powder, liquid or aerosol) for oral use and solutions or sprays (powder, liquid or aerosol) for nasal use.
    Absorption of the drug from mucosal tissue can be achieved by i) increasing the solubility of the drug, ii) modifying the pH to favor the non-ionized form of the drug, iii) adding a mucosal adhesive to enhance contact between the delivery system and the membrane, and iv) the so-called penetration It can be strengthened by mixing the reinforcing agent.
    There are several penetration enhancers known to affect the permeability of drugs across the epithelial membrane [Walker, R.B and Smith, E.W. "Advanced Drug Delivery Reviews" 1996, 18, 295-301.
    Cyclodextrins and their derivatives have been found to be extended as solubilizers and stabilizers because of their ability to form inclusion complexes with a wide variety of compounds [J. Szejtli, Cyclodextrin Technology, Kluwer Academic Press) and (J. Szejtli and KH Forming, cyclodextrin in pharmacy, Kluwer Academic Press). Cyclodextrins have been used to enhance the intestinal absorption of drugs primarily through increased solubility. Recently, cyclodextrins have been shown to have positive and negative effects on transdermal penetration of drugs [(Loftsson, T. et al., International Journal of Pharmaceutics 1995, 115, 255-258), (Vollmer, U. et al. , International Journal of Pharmaceutics 1993, 99, 51-58), (Legendre, JY 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 can enhance nasal absorption of drugs (see Merkus, FW et al., Pharmaceutical Research 1991, 8, 588-592) and (Shao, Z. et al., Pharmaceutical Research 1992, 9, 1157-1163). ] Can enhance absorption from sublingual administration of the drug / cyclodextrin complex. Cyclodextrins also prevent damage to nasal mucosa by penetration enhancers [Jabbal Gill, I. et al., European Journal of Pharmaceutical Sciences 1994, 1 (5), 229-236].
    Cyclodextrins are water soluble conical cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units. The inner or “lumen” of the cone is hydrophilic while the outer is hydrophobic. The size of the lumen increases as the number of glucose units increases. Several cyclodextrin derivatives such as alkyl, hydroxyalkyl and sulfoalkyl ethers have improved solubility [(J. Szejtli and KH Fromming, Cyclodextrins in Pharmacy, Kluwer Academic Press) and (Stella, VJ et al. Pharmaceutical Research 1995, 12 (9) S205). Suitable sized hydrophilic "guest" molecules can enter the "host" lumen and form a typical host-guest "inclusion compound" or "inclusion complex" along with all or part of the contained guest molecule. The driving mechanism for cyclodextrin inclusion complexation is the affinity for the lumen of the cyclodextrin host molecule of the hydrophilic guest molecule, which becomes thermodynamically more stable by substitution of the lumen water molecule. The term "complex stability" or the stability of a given inclusion complex refers to the equilibrium / decomposition equilibrium of the host and guest in solution. Complex stability depends on the number of intramolecular interactions between the host and the guest. Van der Waals forces and hydrophilic interactions are the main interactions that stabilize the inclusion complex (Bergeron, R. J. et al., Journal of the American Chemical Society 1977, 99, 5146). Depending on the nature and location of the hydrogen bonding action in a given guest, there may be hydrogen bonding between the guest and the hydroxyl group of the cyclodextrin or, in the case of a cyclodextrin derivative, between other hydrogen bonding groups. In the case of ionic cyclodextrins, such as sulfobutyl ethers, ionic interactions between hosts and guests are also possible (Stella, V.J et al. Pharmaceutical Research 1995, 12 (9) S205).
    Cyclodextrin inclusion complexes can be prepared based on liquid, solid or semisolid reactions between components (J. Szejtli, Cyclodextrin Technology, Kluwer Academic Press). The cyclodextrin and guest are first dissolved in a suitable solvent or solvent mixture and then the solid phase complex is isolated by crystallization, evaporation, spray drying or freeze drying. In the solid state method, the two components can be filtered to a uniform particle size and mixed thoroughly after grinding in a high energy mill with selective heating, sorting, and homogenization. In the semisolid state, the two components are kneaded with a small amount of a suitable solvent, and the complex thus formed is dried, selected and homogenized. Liquid state reactions generally provide the optimum state for completion of the reaction. Depending on the solvent state, dissolved inclusion complexes are present in balance between uncomplexed guest and host and complexed guest / host.
    The present invention relates to the inclusion complex of indole-selective serotonin (5-HT ID ) agonists with unsubstituted or substituted beta- or gamma-cyclodextrins, and especially for migraine or complex headache treatment for mucosal delivery of the mouth or nose containing such complexes. It relates to a pharmaceutical composition for.
    The invention will be described in more detail by way of example only with reference to the accompanying drawings, in which: FIG.
    1 shows a differential scanning calorimetry thermogram of sumatriptan succinate having a melting point at 166 ° C. and a sharp endothermic melting peak at 167.9 ° C. FIG.
    FIG. 2 shows a differential scanning calorimetry thermogram of a composite in which the sumatriptan succinate obtained in Example 1 and methyl-beta-cyclodextrin are kneaded 1: 1.
    FIG. 3 shows a differential scanning calorimetry thermogram of a composite in which 1: 1 sump of sumatriptan succinate and methyl-beta-cyclodextrin containing 1 molar equivalent of tromethamine obtained in Example 2 was kneaded.
    FIG. 4 shows the X-ray powder diffraction pattern of the composite in which the sumatriptan succinate obtained in Example 1 and methyl-beta-cyclodextrin were kneaded 1: 1.
    FIG. 5 shows an X-ray powder diffraction pattern of a composite in which 1-molecular equivalent of sumatriptan succinate and methyl-beta-cyclodextrin containing 1 molar equivalent of tromethamine obtained in Example 2 was kneaded.
    FIG. 6 shows a cutout perspective model of the optimized geometry of the molecular dynamics model of the inclusion complex of sumatriptan (light gray) in beta-cyclodextrin (dark gray).
    Detailed description of the invention
    A key aspect of the present invention is the inclusion complex of (a) an indole selective serotonin (5-HT ID ) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin.
    Suitable examples of compound (a) are sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan. The compound may be used in the form of a free base or in the form of a pharmaceutically acceptable salt such as hydrochloride, succinate, citrate, fumarate, sulfate, benzoate, or maleate salts.
    The second component of the inclusion complex is unsubstituted or substituted beta- or gamma-cyclodextrin.
    Highly water soluble cyclodextrins such as 2-hydroxypropylated or methylated or sulfoalkylated derivatives of beta-cyclodextrins are preferred cyclodextrins of the present invention. 2-hydroxypropylated or methylated or sulfoalkylated derivatives of gamma-cyclodextrin or gamma cyclodextrin can 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 and 20 substituents per cyclodextrin molecule, but more preferably between 3 and 15 substituents per cyclodextrin molecule. If the cyclodextrin is 2-hydroxypropyl-beta-cyclodextrin, the preferred degree of substitution is between 3.9 and 5.1 hydroxypropyl groups per cyclodextrin molecule. If the cyclodextrin is methyl-beta-cyclodextrin, the preferred degree of substituent is between 1.8 and 2 methyl groups per glucose unit.
    Inclusion complexes of the present invention can be prepared from aqueous solutions, slurries or doughs of indole derivatives and cyclodextrins according to conventional methods. The molar ratio of indole derivative to cyclodextrin may vary between 1: 1 and 1:10, but more preferably between 1: 1 and 1: 5. The solution is prepared by dissolving the cyclodextrin in a sufficient amount of purified deionized water that can optionally be buffered between pH 7.4 and 8.5. The solution may be formulated and used in a liquid delivery system such as a drop, spray or aerosol. If a solid inclusion complex is required, the solution or slurry may be dried by spray drying or freeze drying.
    Alternatively, the indole derivative and the cyclodextrin are mixed. The powder mixture is soaked in water optionally containing a pH 7.4-8.5 buffer and mixed vigorously until a dough is formed. The dough is mixed for 0.25-2 hours and dried in an oven or vacuum at high temperature. The dried composite is broken up and sieved to the required particle size.
    Buffers that can buffer in the pH range of pharmaceutically acceptable 7.4 to 8.5 can be used to form inclusion complexes, especially when indole derivatives are present as salts. Preferred buffers include tromethamine, triethanolamine, diethanolamine, phosphate buffer, sodium bicarbonate, and sodium carbonate.
    The second aspect of the invention is a pharmaceutical composition consisting of the inclusion complex as an active ingredient as described above.
    Pharmaceutical compositions of the invention are particularly suitable for the treatment of migraine and complex headache.
    In addition, the pharmaceutical compositions of the present invention are preferably adapted for mouth and nasal mucosal delivery.
    Administration of antimigraine drugs through mucosal tissues of the nose and mouth is poorly coordinated due to injection (ie, patient aversion and painful administration) and oral administration (ie, slow onset of response, low bioactivity, and nausea and vomiting associated with migraine headaches). Avoid problems associated with the administration of the indole serotonin agonist. Absorption of the drug from the pharmaceutical composition of the present invention almost reaches the systemic circulation as quickly as the drug is via injection, which is very beneficial for the rapid recovery of migraine onset or complex headache.
    In addition, the unpleasant taste and the irritating properties of the active ingredient are reduced by providing the drug to the nasal or mouth mucosal tissue in the form of a cyclodextrin inclusion complex.
    The present invention achieves this benefit by molecularly encapsulating antimigraine indole drugs in cyclodextrins, and the molecular inclusion complexes thus formed can be used in solid form to produce sublingual or oral tablets, oral plasters or nasal inhalant powders (blown). . Inclusion complexes can be used in the liquid state to prepare as a single dose spray, a drop or a compressed aerosol for nasal or oral administration. The complex according to the invention can be bound to a scissor form matrix designed for immediate release as described in the Pitts Technologies limited patent (European Patent Application No. 95-650038 and PCT International Application No. 95/34293).
    According to the present invention, the indole nucleus of the selective serotonin (5-HT ID ) agonist is rapidly incorporated into the lumen of beta-cyclodextrins such as hydroxypropyl-beta-citrodextrin and methyl-beta-cyclodextrin to be 1: 1 It has been found to form molecular inclusion complexes in mole / molar stoichiometry. Thus, various inclusion complexes of indole-based serotonin agonists can be prepared according to methods known in the art, such as spray drying, freeze drying and kneading as described above. Inclusion complexes according to the present invention may also be incorporated into microspheres by methods related to the present technology. The composite according to the invention is stable, amorphous and very water soluble.
    Penetration enhancers can be used to facilitate the passage of indole derivatives past mucosal tissue. Typical penetration enhancers include fatty acids and their salts such as sodium caprylate, sodium caprylate, sodium oleate, and sodium laurate, sodium glycodeoxycollide, sodium glycocholate, sodium cholate and sodium taurodeoxychol Bile salts such as raids. Other penetration enhancers include tensides, ionic surfactants such as sodium lauryl sulfate, or nonionic surfactants such as polyethylene glycol 660 hydroxystearate or polyoxyethylene lauryl ether, sodium taurodihydrofusate It includes push dates such as Other special reinforcing agents include azone and chitosan. Combinations of penetration enhancers such as polyoxyethylene 8 lauryl ether and sodium glycolate or mixed micelles such as sodium caprate and sodium glycocholate can also be used. Penetration enhancers can also be used in combination with beta or gamma cyclodextrins or methyl, hydroxypropyl or sulfoalkyl derivatives thereof. Typical concentrations of penetration enhancers are between 0.1% and 5% by weight of the composition, more preferably between 0.25 and 3% by weight.
    As mentioned above, serotonin (5-HT ID ) agonists may be used in the form of free base or pharmaceutically acceptable salts. Acid permeability enhancing excipients such as bile salts or fatty acids or pharmaceutically acceptable salts of fatty acids are used, and salts may form between the basic component of the serotonin (5-HT ID ) agonist and the acidic component of the bile salt or fatty acid. Can be.
    The buffer may be bound to the pharmaceutical composition of the present invention to adjust the microenvironmental pH around the drug delivery system in the alkaline range, maximizing the percentage of non-ionized form of the drug. The non-ionized form of the drug passes through mucosal tissue more rapidly than its corresponding non-ionized form.
    Liquid compositions suitable for nasal or oral administration may contain an appropriate amount of a viscosity modifier such as hypromellose or carbopol 934P and a preservative such as gluconate or thiomerzal.
    Oral compositions may include suitable flavoring and sweetening agents, such as cherry, mint, spearmint, vanilla, aspartame, sucrose, xylitol, saccharin, and the like.
    Typical sublingual or oral tablets include lubricants such as magnesium stearate, calcium stearate and sodium stearyl fumarate, diluents such as lactose, microcrystalline cellulose, maize stark and the like to facilitate tablet compression, and chitosan Mucoadhesives such as carbopol 934P and hydroxypropylcellulose.
    Typical disintegrants to enhance the decomposition of sublingual tablets may include sodium carboxymethylcellulose, sodium stark glycolate, polyplastone XL and dry starch.
    The present invention will be described in the following examples.
    Summary of the Invention
    According to a first aspect of the invention there is provided a process for (a) indole selective serotonin (5-HT ID ) agonists or their pharmaceutically acceptable salts and (b) unsubstituted or substituted beta- or gamma-cyclodextrins. Inclusion complexes are provided.
    An indole selective serotonin (5-HT ID ) agonist means a compound comprising an indole structure, which structure will generally be substituted, which has selective serotonin (5-HT ID ) agonist activity.
    Indole selective serotonin (5-HT ID ) agonists are preferably selected from compounds having the formula:
    Formula 1

    Wherein X and Y represent suitable substituents, more preferably selected from the group consisting of sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan or pharmaceutically acceptable salts thereof do. Thus, compound (a) can be used in the form of a free base or in the form of a pharmaceutically acceptable salt such as hydrochloride, succinate, citrate, fumarate, sulfate, benzoate, or malate salt.
    Inclusion complexes preferably have a stoichiometry of 1: 1 mole / mole of (a) to (b).
    Inclusion complexes are preferably inclusion complexes of sumatriptan free base and methyl-beta-cyclodextrin having substantially the X-ray powder diffraction pattern of FIG. 4 or FIG. 5 or inclusion complexes of sumatriptan succinate and methyl-beta-cyclodextrin.
    According to a second aspect of the invention there is provided an active ingredient comprising (a) an indole selective serotonin (5-HT ID ) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin. Pharmaceutical compositions consisting of inclusion complexes are provided.
    Pharmaceutical compositions are preferred for use in the treatment of migraine and complex headaches.
    The pharmaceutical composition is preferably adapted for oral or nasal mucosal delivery.
    Example 1
    Sumatriptan succinate (1 g) and methyl-beta-cyclodextrin (3.18 g) were mixed with mortar. Purified deionized water (2 mL) was added in portions and mixed to form a uniform dough. Mixing was continued for 0.5 hours and the dough was transferred to a vacuum oven and dried at 40 ° C., 5 millibar. The dried complex was broken with a pestle and passed through a 60 mesh (250 micron) net. The complex contained 23.0% m / m (mass / mass) sumatriptan succinate as measured by HPLC.
    Example 2
    Tromethamine (0.293 g) was dissolved in 5 ml clarified deionized water. Sumatriptan succinate (1 g) and methyl-beta-cyclodextrin (3.18 g) were mixed with mortar. The tromethamine solution was added in portions to mix to form a uniform dough. Mixing was continued for 0.5 hours and the dough was transferred to a vacuum oven and dried at 40 ° C., 5 millibar. The dried complex was broken with a pestle and passed through a 60 mesh (250 micron) net. The complex contained 21.7% m / m (mass / mass) sumatriptan succinate as measured by HPLC.
    Example 3
    The unit composition of the sublingual tablet containing 20 mg equivalent of sumatriptan base was as follows.
    130 mg sumatriptan / methyl-beta-cyclodextrin complex (complex of Example 2)
    Lactose NF 20mg
    Magnesium Stearate 1mg
    The complex was mixed with lactose. The lubricant was filtered off and the mixture was combined to form sublingual tablets by compression at 10-30N.
    Example 4
    The unit composition of the sublingual tablet containing 20 mg equivalent of sumatriptan base was as follows.
    122 mg of sumatriptan / methyl-beta-cyclodextrin complex (complex of Example 1)
    Xylitol 28mg
    Sodium Caprate 3.75mg
    Magnesium Stearate 1mg
    The complex was mixed with xylitol and sodium caprate. The lubricant was filtered off and the mixture was combined to form sublingual tablets by compression at 10-30N.
    Example 5
    Hydroxypropyl-beta-cyclodextrin (3.39 g) was dissolved in clarified deionized water (8 mL) and buffered to pH 7.4 with phosphate buffer. Sumatriptan succinate (1 g) was added to the solution while stirring. The solution was stirred for 20 minutes, followed by addition of sodium caprate (25 mg) and clohexidine gluconate (0.01%). The volume was adjusted to 10 ml by addition of phosphate buffer pH 7.4 and the elasticity of the final solution was adjusted to 300 mOsm / Kg with sodium chloride. One serving, measured at 0.1 ml each, contained 10 mg sumatriptan succinate suitable for nasal administration.
    Referring to the figures, FIG. 1 shows a differential scanning calorimetry thermogram of sumatriptan succinate having a melting point at 166 ° C. and a sharp endothermic melting peak at 167.9 ° C. FIG. Thermograms were recorded on a Perkin-Elmer DSC7 calorimeter with a heating rate of 5 ° C. per minute. A sample of 1.36 g in mass was used.
    FIG. 2 shows a differential scanning calorimetry thermogram of a composite obtained by mixing sumatriptan succinate and methyl-beta-cyclodextrin 1: 1 in Example 1. FIG. The characteristic endothermic melting of sumatriptan succinate shown in FIG. 1 was not seen, which is evidence of inclusion complexation between sumatriptan and methyl-beta-cyclodextrin. Characteristic degradation of methyl-beta-cyclodextrin is shown at 175 ° C. The experimental conditions as depicted in Example 1, except using a sample of 11.1 g in mass, provided the same reaction of sumatriptan succinate as in Example 1.
    FIG. 3 shows a differential scanning calorimetry thermogram of a composite in which 1-mole equivalent of sumatriptan succinate and methyl-beta-cyclodextrin containing 1 molar equivalent of tromethamine obtained in Example 2 was kneaded. The characteristic endothermic melting of sumatriptan succinate shown in FIG. 1 was not seen. In addition, there was no endotherm corresponding to the free base at 89 ° C., which provides evidence of inclusion complexation between sumatriptan and methyl-beta-cyclodextrin. Characteristic degradation of methyl-beta-cyclodextrin appears from 175 ° C. The experimental conditions as depicted in Example 1, except using a sample of 12.42 mg mass, provided the same reaction of sumatriptan succinate as Example 1.
    Figure 4 shows the X-ray powder diffraction type of the composite of sumatriptan succinate obtained in Example 1 and methyl-beta-cyclodextrin 1: 1 kneaded. Absence of the degraded pointed peak properties of crystalline sumatriptan succinate indicates inclusion complexes with losses resulting from crystallinity. The results of the diffraction type show the properties of amorphous solids.
    FIG. 5 shows the X-ray powder diffraction type of a composite in which 1: 1 mixture of sumatriptan succinate and methyl-beta-cyclodextrin containing 1 molar equivalent of tromethamine obtained in Example 2 was kneaded. Absence of the degraded pointed peak properties of crystalline sumatriptan succinate and tromethamine indicates inclusion complexes with losses resulting from crystallinity. The results of the diffraction type show the properties of amorphous solids.
    FIG. 6 shows the geometry of an optimized cut out perspective model of the molecular dynamics model of sumatriptan (light gray) inclusion complex in beta-seclodextrin (dark gray). The core of the indole fills the lumen with a chain next to the protruding dimethylaminoethyl (bottom) and methanesulfonamide (top) that extend out of the lumen.
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] An inclusion complex of (a) an indole selective serotonin (5-HT ID ) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin.
    [2" claim-type="Currently amended] The inclusion complex of claim 1, wherein (a) is sumatriptan or a pharmaceutically acceptable salt thereof.
    [3" claim-type="Currently amended] The inclusion complex of claim 1, wherein (a) is selected from the group consisting of naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan and pharmaceutically acceptable salts thereof.
    [4" claim-type="Currently amended] The method according to any one of claims 1 to 3, wherein (b) is selected from the group consisting of 2-hydroxypropyl-beta-cyclodextrin, methylated beta-cyclodextrin, and sulfoalkylated beta-cyclodextrin. Inclusion complex.
    [5" claim-type="Currently amended] The inclusion complex according to any one of claims 1 to 4, wherein (b) has a degree of substitution that is 1 to 20 substituents per mole of cyclodextrin.
    [6" claim-type="Currently amended] The inclusion complex of any one of claims 1 to 5, wherein (b) has a degree of substitution that is 3 to 15 substituents per mole of cyclodextrin.
    [7" claim-type="Currently amended] The inclusion complex according to any one of claims 1 to 3, wherein (b) is 2-hydroxypropyl-beta-cyclodextrin having a degree of substitution which is 3.9 to 5.1 hydroxypropyl groups per mole of cyclodextrin.
    [8" claim-type="Currently amended] The inclusion complex according to any one of claims 1 to 3, wherein (b) is methyl-beta-cyclodextrin having a degree of substitution of 1.8 to 2 methyl groups per glucose unit.
    [9" claim-type="Currently amended] Inclusion complex of sumatriptan free base with methyl-beta-cyclodextrin.
    [10" claim-type="Currently amended] Inclusion complex of sumatriptan succinate and methyl-beta-cyclodextrin.
    [11" claim-type="Currently amended] Inclusion complex of sumatriptan succinate and methyl-beta-cyclodextrin having substantially the X-ray powder diffraction pattern of FIG. 4 or 5.
    [12" claim-type="Currently amended] The inclusion complex according to any one of claims 1 to 11, wherein the inclusion complex has a stoichiometry of 1: 1 moles / mole of (a) to (b).
    [13" claim-type="Currently amended] A pharmaceutical composition comprising (a) an indole selective serotonin (5-HT ID ) agonist or a pharmaceutically acceptable salt thereof and (b) an inclusion complex of unsubstituted or substituted beta- or gamma-cyclodextrin as active ingredient.
    [14" claim-type="Currently amended] The pharmaceutical composition of claim 13, wherein the inclusion complex is as defined in any one of claims 2 to 12.
    [15" claim-type="Currently amended] The pharmaceutical composition according to claim 13 or 14 for use in the treatment of migraine or complex headache.
    [16" claim-type="Currently amended] The pharmaceutical composition according to any one of claims 13 to 15, which is formed for oral or nasal mucosal delivery.
    [17" claim-type="Currently amended] (A) an indole-selective serotonin (5-HT ID ) agonist or a pharmaceutically acceptable salt thereof and (b) unsubstituted or substituted beta- or gamma in the manufacture of a medicament for use in the treatment of migraine or complex headache. A method of using an inclusion complex of cyclodextrins.
    [18" claim-type="Currently amended] 18. The method of claim 17, wherein the inclusion complex is as defined in any one of claims 2-12.
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    同族专利:
    公开号 | 公开日
    CA2257860A1|1998-01-22|
    BR9710289A|1999-08-17|
    IL127955D0|1999-11-30|
    KR20000023708A|2000-04-25|
    US6255502B1|2001-07-03|
    JP2001508027A|2001-06-19|
    AU3455297A|1998-02-09|
    AU3455197A|1998-02-09|
    WO1998002187A1|1998-01-22|
    BR9710241A|1999-08-10|
    CN1230123A|1999-09-29|
    JP2000505090A|2000-04-25|
    CA2259418A1|1998-01-22|
    IL127956D0|1999-11-30|
    WO1998002186A1|1998-01-22|
    AU712546B2|1999-11-11|
    EP1024833A1|2000-08-09|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-07-11|Priority to ZA9605889
    1996-07-11|Priority to ZA96/5889
    1997-07-11|Application filed by 토마스 헤인, 팔마크 네덜란드 비브이 오브 시트코 트러스트 인터내셔날 매니지먼트(티.아이.엠) 비.브이.
    2000-04-25|Publication of KR20000022239A
    优先权:
    申请号 | 申请日 | 专利标题
    ZA9605889|1996-07-11|
    ZA96/5889|1996-07-11|
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