CN1225018A - Inclusion complex containing indole selective serotonin agonist - Google Patents
Inclusion complex containing indole selective serotonin agonist Download PDFInfo
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- CN1225018A CN1225018A CN97196294A CN97196294A CN1225018A CN 1225018 A CN1225018 A CN 1225018A CN 97196294 A CN97196294 A CN 97196294A CN 97196294 A CN97196294 A CN 97196294A CN 1225018 A CN1225018 A CN 1225018A
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- cyclodextrin
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- schardinger dextrin
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Abstract
The invention discloses a inclusion complex containing (a) indole selective serotonin (5-HTID) agonist or acceptale salts thereof in pharmacy, e.g Sumatriptan, and (b) unsubstituted or substituted beta- or gamma-Cyclodextrin, e.g methyl-beta--Cyclodextrin. Also disclosed pharmacy composite of inclusion complex and function in treatment of hemicrania and hemicranialike.
Description
Technical background of the present invention
The present invention relates to a kind of by a kind of indole selective serotonin (5-HT
ID) agonist and a kind of unsubstituted or β of replacing-or inclusion complex of forming of gamma-cyclodextrin, also relate to and contain this coordination compound, be specially adapted to oral cavity or nasal mucosa medicine administration, can treat the pharmaceutical compositions of migraine or class headache (cluster headaches).
Indole derivatives such as naratriptan, rizatriptan, zolmitriptan, eletriptan and the almotriptan of sumatriptan (3-(2-dimethyl aminoethyl) indole-5-base-N-methyl Methanesulfomide (methylmethanesulphonamide)) and other structurally associated are used for the treatment of migrainous selective serotonin (5-HT
ID) agonist.Identical with succinate, sumatriptan is oral or subcutaneous administration when being used for the treatment of migraine.Sumatriptan produces about 14% low bioavailability at oral medication and through absorbing rapidly behind the presystemic metabolism widely.The bioavailability of subcutaneous medication is 96%.For migrainous quick treatment, can give the sumatriptan that predose is 100mg by per os, can produce clinical effectiveness at 0.5-2 hour.In addition, sumatriptan also can pass through the subcutaneous injection administration, and single dose is 6mg, produced clinical effectiveness at 10-15 minute.
The oral medication of anti-migraine compounds such as sumatriptan is except that having low bioavailability, and owing to the nausea and vomiting of following migraine to produce, traditional oral administration route has limitation in the treatment migraine.And many patients are unwilling by subcutaneous injection oneself medication, and this has just limited this route of administration.
Oral cavity and nasal cavity discharge the position as systemic medication some superioritys, particularly can avoid presystemic metabolism.Yet the low permeability of oral cavity and nasal cavity inner membrance causes the low throughput of medicine.Therefore the permeability that needs to increase medicine is to improve the bioavailability behind oral cavity or the nasal membrane drug release.
This area has several known methods drug release can be arrived mouth or nasal mucosa.These methods comprise cheek and sublingual tablet or are used for lozenge, tablet, gel, solution or the spray in oral cavity (powder, liquid or aerosol) and are used for the solution or the spray (powder, liquid or aerosol) of nasal cavity.
Can promote the absorption of medicine by following several respects: (ⅰ) increase drug solubility from mucosa, (ⅱ) regulate the unionized form that pH is beneficial to medicine, (ⅲ) adding the mucosa binding agent transports contacting of system and film and (ⅳ) adds so-called permeation-promoter to promote medicine.
Known have many can influence the infiltrative permeation-promoter of medicine by epithelial cell membrane (nearest summary is seen Walker, R.B and Smith, the up-to-date drug release summary of E.W. (AdvancedDrug Delivery Reviews) 1996,18,295-301).
Have now found that since cyclodextrin and derivant thereof can with multiple compound formation inclusion complex, they can be widely used as solubilizing agent and stabilizing agent (is seen (J.Szejtli, " cyclodextrin technology " Kluwer academic press (Academic Press) and (J.Szeitli and K-HFromming, " cyclodextrin in the pharmaceutics ", the Kluwer academic press)).Cyclodextrin is mainly by increasing the intestinal absorption that dissolubility promotes medicine.Recently, found that cyclodextrin penetrates for the percutaneous of medicine and has positivity and negative effects [is seen (Loftsson.T. etc., international journal of Practical Pharmacy 1995,115,255-258), (Vollmer, U. etc., international journal of Practical Pharmacy 1993,99,51-58), (Legendre, J.Y. etc., European pharmaceutical science magazine 1995,3,311-322) with (Vollmer, U. etc., pharmaceutics and pharmacology's magazine 1994,46,19-22)].Cyclodextrin can increase the snuffing of medicine receive [see (and Merkus, F.W. etc., study of pharmacy, 1991,8,588-592) and (Shao, Z. etc., study of pharmacy 1992,9,1157-1163)], and increase of the absorption of medicine/cyclodextrin inclusion complexes through sublingual administration.Cyclodextrin also can protect nasal mucosa avoid the destruction of permeation-promoter [see Jabbal-Gill, I. etc.,, European pharmaceutical science magazine 1994,1 (5), 229-236].
Cyclodextrin is to contain 6,7 or 8 unitary water miscible tapered annular oligosaccharide of glucopyranose.Cone inner or " intracavity " be hydrophobic and outside be hydrophilic.The size in chamber increases with the increase of the quantity of glucose unit.Prepared the cyclodextrin derivative that some have the dissolubility of increase, [see (J.Szeitli and K-H Fromming as alkyl, hydroxyalkyl and sulfoalkyl ether derivant, " cyclodextrin in the pharmaceutics ", the Kluwer academic press) and (Stella, V.J. etc., study of pharmacy 1995,12 (9) S205)].The intracavity that hydrophobicity " object " molecule of suitable size can enter " main body " forms a kind of traditional main body-object " inclusion compound " or " inclusion complex ", comprising whole guest molecule or have only its part.To be the hydrophobicity guest molecule reach more stable status of thermodynamics for the affinity of cyclodextrin host molecule with the hydrone of displacement intracavity to the driving mechanism that cyclodextrin comprises complexation.The stability of term " complex stability " or a kind of inclusion complex that provides refers to the complexation between the subject and object/separation balance in solution.Complex stability depends on the number of bonding action between host molecule and the guest molecule.Van der Waals force and hydrophobic interaction are the significant feature power (Bergeron, R.J. etc., american Journal of the Chemical Society, 1977,99,5146) that makes inclusion complex stable.According to the character and the position of the hydrogen bonding degree of functionality of given object, between the group of other hydrogen bonding of the oh group of guest molecule and cyclodextrin or cyclodextrin derivative, has hydrogen bonding.For ion-type cyclodextrin such as sulfobutyl ether, also has ionic interaction (Stella, V.J. etc., study of pharmacy, 1995,12 (9) S205) between the subject and object molecule.
Can on the basis of the liquid state between component, solid-state or semi-solid-state reaction, prepare cyclodextrin inclusion complexes (J.Szeitli, " cyclodextrin technology ", Kiuwer academic press).At first cyclodextrin and guest molecule are dissolved in The suitable solvent or the mixed solvent, then by crystallization, evaporation, spray drying or freeze-drying method separate solid coordination compound.In solid-state approach, can be with two components screenings so that its particle size unanimity, and fully mix, subsequently under the heating condition of selecting with high energy mill levigation, screening and homogenize.In the semisolid method, under the situation that a small amount of suitable solvent exists, two components are mediated, and with the coordination compound, drying, screening and the homogenize that form.Liquid reaction generally provides and makes reaction carry out optimum condition completely.According to solvent condition, dissolved inclusion complex is present in the subject and object and the balance between the main body/object that has cooperated of not cooperation.
Brief summary of the invention
The present invention at first provides a kind of inclusion complex, and it is by (a) a kind of indole selective serotonin (5-HT
ID) agonist or a kind of its pharmaceutically acceptable salt and (b) a kind of replacement or unsubstituted β-or gamma-cyclodextrin form.
Indole selective serotonin (5-HT
ID) agonist is meant a kind of chemical compound that comprises indole structure, this structure generally is substituted, and has selective serotonin (5-HT
ID) activity of agonist.
Indole selective serotonin (5-HT
ID) agonist preferably has the chemical compound of following formula:
Wherein X and Y represent suitable substituent, preferred sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan or its pharmaceutically acceptable salt group.Therefore, can use the free alkali of chemical compound (a) or the form of its pharmaceutically acceptable salt, the form of example hydrochloric acid salt, succinate, citrate, fumarate, sulfate, benzoate or maleate.
Inclusion complex preferred (a) and stoichiometry (b) are 1: 1mol/mol.
The inclusion complex of the preferred sumatriptan free alkali of this inclusion complex and methyl-beta-schardinger dextrin-or the inclusion complex of sumatriptan succinate and methyl-beta-schardinger dextrin-, in fact they have Fig. 4 or X-ray powder diffraction style shown in Figure 5.
The present invention also provides a kind of pharmaceutical compositions, and it contains a kind of indole selective serotonin (5-HT by (a)
ID) agonist or a kind of its pharmaceutically acceptable salt and (b) a kind of replacement or unsubstituted β-or inclusion complex that gamma-cyclodextrin is formed as active component.
Pharmaceutical compositions of the present invention is preferred for treating migraine and class headache.
Pharmaceutical compositions of the present invention preferably adopts the mode of oral cavity or nasal mucosa medicine administration.
To brief description of the drawings
Now only the present invention is made a more detailed description with the mode of embodiment, wherein with reference to the following drawings:
Fig. 1 shows the differential scanning calorimetric temperature curve of sumatriptan succinate, and its initial fusion temperature is 166 ℃, and heat absorption fusion spike is at 167.9 ℃;
Fig. 2 shows the sumatriptan succinate and the differential scanning calorimetric temperature curve of methyl-beta-schardinger dextrin-by the coordination compound of the formation of kneading in 1: 1 that obtains from embodiment 1;
Fig. 3 shows from embodiment 2 sumatriptan succinate that obtains and the methyl-beta-schardinger dextrin-that the contains 1mol equivalent trimethylol aminomethane differential scanning calorimetric temperature curve by the coordination compound of the formation of kneading in 1: 1;
Fig. 4 shows the sumatriptan succinate and the X-ray powder diffraction style of methyl-beta-schardinger dextrin-by the coordination compound of the formation of kneading in 1: 1 that obtains from embodiment 1;
Fig. 5 shows from embodiment 2 sumatriptan succinate that obtains and the methyl-beta-schardinger dextrin-that the contains 1mol equivalent trimethylol aminomethane X-ray powder diffraction style by the coordination compound of the formation of kneading in 1: 1;
Fig. 6 shows how much cutaway views of the best molecular mechanics model of the inclusion complex that sumatriptan (light ash) forms in beta-schardinger dextrin-(dark-grey).
Explanation to embodiment
Key of the present invention provides a kind of by (a) indole selective serotonin (5-HTID) activator or its pharmaceutically acceptable salt and (b) replace or unsubstituted β-or γ-The inclusion complex that cyclodextrin forms.
The example of suitable compound (a) be sumatriptan, naratriptan, rizatriptan, Zolmitriptan, eletriptan and almotriptan. Can use compound free alkali or The form of its pharmaceutically acceptable salt, example hydrochloric acid salt, succinate, citrate, rich horse The form of hydrochlorate, sulfate, benzoate or maleate.
The second component of inclusion complex is a kind of unsubstituted or β of replacing-or gamma-cyclodextrin.
The 2-hydroxyl propylate of the cyclodextrin of highly-water-soluble such as beta-schardinger dextrin-or methoxide or sulfo group Alkyl derivative is the preferred cyclodextrin of the present invention. The 2-hydroxyl of gamma-cyclodextrin or gamma-cyclodextrin Base propylate or methoxide or sulfo group alkyl derivative also can be in the same manner as corresponding Preferred beta-cyclodextrin derivative. The substitution value of cyclodextrine derivatives can be 1-20 replacement Change between base/cyclodextrin molecular, but preferred 3-15 substituting group/cyclodextrin molecular. Work as ring When dextrin was 2-HP-BETA-CD, preferred substitution value was 3.9 and 5.1 hydroxypropyls Group/cyclodextrin molecular. When cyclodextrin is methyl-beta-schardinger dextrin-, on the preferred substitution value 1.8-2 methyl/glucose unit.
Can be according to the aqueous solution, slurries or the paste of conventional process with indole derivatives and cyclodextrin Prepare cyclodextrin inclusion complexes of the present invention. The molecular proportion of indole derivatives and cyclodextrin can Between 1: 1 to 1: 10, change, but more preferably 1: 1 to 1: 5. With cyclodextrin Be dissolved in pH and be in the capacity deionized purified water of any buffering of 7.4-8.5 and prepare solution. Will Indole derivatives joins in the solution, stirs until dissolving. This solution can be used for preparing liquid to be released Place system such as drops, spray or aerosol. When needing the solid inclusion complex, can pass through Spray-drying or freeze-drying are with solution or slurry dried.
On the other hand, indole derivatives and cyclodextrin are mixed. Water (any pH7.4-8.5 that contains The water of buffer solution) mixture of powders is moistening, firmly mix until form a paste. With paste Mixed 0.25-2 hour, it is dry that it is heated up in baking oven or under vacuum condition. With drying Inclusion complex pulverize and be sieved into required granular size.
Preparation can use during inclusion complex pharmaceutically acceptable, can be at pH7.4-8.5 Play the buffer of cushioning effect in the scope, especially when indole derivatives occurs with the form of salt, make Use this buffer. Preferred buffer comprises trimethylol aminomethane, triethanolamine, diethanol Amine, phosphate, sodium acid carbonate and sodium carbonate. The concentration of this buffer can be equivalent to indoles 0.5-5 in the scope of molar equivalent.
A second aspect of the present invention provides and a kind ofly contains above-mentioned inclusion complex and become as activity The pharmaceutical compositions that divides.
Pharmaceutical compositions of the present invention has special answering aspect treatment antimigraine and the class headache With.
And pharmaceutical compositions of the present invention is preferred for oral cavity or nasal administration.
The discomfort that discomfort that the migraine agent is organized administration can avoid indole serotonin agonist injecting drug use to bring by nose or oral mucous membrane (be patient feels sick, medication pain) and oral medication bring (be onset slow, hang down bioavailability and because of migraine with the poor adaptability that causes of nausea and vomiting).
The absorption of pharmaceutical compositions Chinese medicine of the present invention is fast, so that the circulation of medicine arrival body is almost the same fast with injection, and obviously faster than oral medication, this outbreak to quick releasing migraine or class headache is highly beneficial.
And, place nose or oral mucosa can reduce the bad taste and the zest of active component medicine with the form of cyclodextrin inclusion complexes.
The present invention realizes that the approach of these beneficial effects is, migraine indole medicine is carried out molecule in cyclodextrin seal, form a kind of molecule inclusion and cooperate, this coordination compound can be used to prepare the Sublingual or powder (insufflation) is gone in cheek tablet, cheek paste or snuffing with solid-state form.Can use the liquid form of this inclusion complex to prepare quantitative spray, drop or be used for nasal cavity or the pressurised aerosol of oral cavity medicine.Can join inclusion complex of the present invention in the substrate of the shearing shaping that designs for instant-free, the limited patent of Fuisz technology (Technologies Ltdpatents) has been put down in writing this substrate (European patent application EP 95-650038 and PCT International Application No. WO 95/34293).
According to the present invention, found selectivity 5-hydroxy tryptamine (5-HT
ID) indole nucleus of agonist is easy to be comprised in that to form stoichiometry in the cavity of beta-schardinger dextrin-such as HP-and methyl-beta-schardinger dextrin-be 1: the molecule inclusion coordination compound of 1mol/mol.Therefore can prepare the various serotonin agonists that contain based on indole according to methods known in the art such as above-mentioned spray drying, lyophilization and the method for kneading.Also can coordination compound of the present invention be added in the microsphere according to this area method commonly used.Coordination compound of the present invention is the coordination compound of stable, amorphism and tool highly-water-soluble.
Can use permeation-promoter to promote that indole derivatives passes through mucosa.Typical permeation-promoter comprises fatty acid and salt thereof, as Capric acid sodium salt, sodium caprylate and enuatrol, and sodium laurate and cholate such as Sodium glycodeoxycholate., sodium glycocholate, sodium cholate and sodium taurodeoxycholate.Other permeation-promoter can comprise surfactant, ionic surfactant such as sodium lauryl sulfate; or nonionic surfactant such as Polyethylene Glycol 660 hydroxyl stearates or polyoxyethylene lauryl ether, fusidate (fusidate) is as cattle sulphur dihydro fucidin (sodiumtaurodihydrofusidate).Other special promoter comprises azone and chitosan.Also can use the combination of associating permeation-promoter such as polyoxyethylene 8 lauryl ethers and sodium glycocholate or the mixed micelle of forming as Capric acid sodium salt and sodium glycocholate (micelles).Permeation-promoter also can with β-or gamma-cyclodextrin and methyl, hydroxypropyl or sulfoalkyl derivant unite use.The common concentration of permeation-promoter is the 0.1%-5% that accounts for composition weight, more preferably 0.2 5%-3%.
As mentioned above, can use 5-hydroxy tryptamine (5-HT with the form of free alkali or its pharmaceutically acceptable salt
ID) agonist.When acid permeation-promoter excipient is the form of cholic acid or fatty acid or its both pharmaceutically acceptable salt, 5-hydroxy tryptamine (5-HT
ID) can generate salt between the alkaline components of agonist and the acid ingredient of cholic acid or fatty acid.
Can in pharmaceutical compositions of the present invention, add buffer agent so that around the drug delivery system pH of microenvironment be controlled in the alkaline range, the percent of medicine nonionic form is reached at utmost.The medicine (unionized form) of the corresponding nonionic form of the medicine of nonionic form (drug in the unionized form) is easier to pass through mucosa.
The fluid composition that is suitable for nose or oral cavity medicine can contain the viscosifier of appropriate amount, as hydroxypropyl emthylcellulose (hypromellose) or carbopol 934P and antiseptic such as SY 1007 or thiomersalate.
Orally administered composition can contain suitable correctives and sweeting agent, as Fructus Pruni pseudocerasi, Herba Menthae, Herba Menthae Rotundifoliae, Rhizoma et radix valerianae, aspartame, sucrose, xylitol, glucide and similar substance.
Typical Sublingual or the cheek tablet can contain lubricant such as magnesium stearate, calcium stearate and sodium stearyl fumarate are beneficial to tabletting, can contain diluent such as lactose, microcrystalline Cellulose, corn starch and analog, can also contain mucoadhesive such as chitosan, carbopol934P and hydroxypropyl cellulose and analog.
The typical disintegrating agent of sublingual tablet disintegrate that promotes can comprise sodium carboxymethyl cellulose, starch sodium cholate (sodium starch glycolate), polyplasdone XL and dry starch.
With following embodiment the present invention is illustrated.
Embodiment 1
Sumatriptan succinate (1g) and methyl-beta-schardinger dextrin-(3.18) are mixed in mortar.Five equilibrium adds the deionized water (2ml) of purification and mixes to form uniform paste.Mix to continue 0.5 hour, paste is moved into vacuum drying oven, drying under the condition of 40 ℃ and 5 millibars.Exsiccant coordination compound is pulverized with pestle, crossed 60 mesh sieves (250 microns).Record coordination compound with high performance liquid chromatogram (HPLC) method and contain 23.0%m/m (mass/mass) sumatriptan succinate.
Embodiment 2
(0.293g) is dissolved in the deionized water of 5ml purification with trimethylol aminomethane.Sumatriptan succinate (1g) and methyl-beta-schardinger dextrin-(3.18g) are mixed in mortar.Five equilibrium adds the deionized water (2ml) of purification and mixes to form uniform paste.Mix to continue 0.5 hour, paste is moved into vacuum drying oven, drying under the condition of 40 ℃ and 5 millibars.Exsiccant coordination compound is pulverized with pestle, crossed 60 mesh sieves (250 microns).Record coordination compound with high performance liquid chromatogram (HPLC) method and contain 21.7%m/m (mass/mass) sumatriptan succinate.
Unit combination thing composed as follows that contains the sublingual tablet that is equivalent to 20mg sumatriptan alkali:
Sumatriptan/methyl-beta-cyclodextrin complex (making) 130mg by example 2
Lactose NF 20mg
Magnesium stearate 1mg
Coordination compound is mixed with lactose.The lubricant back of sieving is added (screened in), mix, and make sublingual tablet at the condition lower sheeting of 10-30N.
Unit combination thing composed as follows that contains the sublingual tablet that is equivalent to 20mg sumatriptan alkali:
Sumatriptan/methyl-beta-cyclodextrin complex (making) 122mg by embodiment 1
Xylitol 28mg
Capric acid sodium salt 3.75mg
Magnesium stearate 1mg
Coordination compound is mixed with xylitol and Capric acid sodium salt.The lubricant back of sieving is added (screened in), mix the condition lower sheeting that is incorporated in 10-30N and make sublingual tablet.
Embodiment 5
HP-(3.39g) is dissolved in phosphate buffer is adjusted in the deionized water (8ml) of the purification of pH7.4.In solution, add sumatriptan succinate (1g) and stirring.With solution stirring 20 minutes, add Capric acid sodium salt (25mg) and SY 1007 (0.01%) then therein.By the phosphate buffer that adds pH7.4 volume is adjusted to 10ml, the tension force (tonicity) of final solution is adjusted to 300mOsm/kg with sodium chloride.Solution is filtered, in the metering nose spray bottle of packing into.Every 0.1ml dosing contains the sumatriptan succinate that 10mg is suitable for nasal cavity applied medicine.
With reference now to accompanying drawing,, Fig. 1 represents the differential scanning calorimetric temperature curve of sumatriptan succinate, and its initial fusion temperature is 166 ℃, and heat absorption fusion spike is at 167.9 ℃.Temperature curve is recorded on the Perkin-Elmer DSC7 calorie meter, and its firing rate is 5 ℃/minute.The specimen in use quality is 1.36mg.
Fig. 2 represents knead at 1: the 1 differential scanning calorimetric differential thermogram of the coordination compound that forms of the sumatriptan succinate that obtains from embodiment 1 and methyl-beta-schardinger dextrin-.This figure lacks the characteristic fusion heat absorption of the sumatriptan succinate among Fig. 1, and this has confirmed to have formed inclusion complex between sumatriptan and methyl-beta-schardinger dextrin-.Characteristic at 175 ℃ of visible methyl-beta-schardinger dextrin-s is decomposed.Experiment condition is compared with example 1, and difference is that service property (quality) is that the sample of 11.1mg is to produce the sumatriptan succinate reaction suitable with embodiment 1.
Fig. 3 represents from the differential scanning calorimetric differential thermogram of 1: 1 coordination compound of kneading of embodiment 2 sumatriptan succinate that obtains and the methyl that contains 1mol equivalent trimethylol aminomethane-beta-schardinger dextrin-formation.This figure lacks the characteristic fusion heat absorption of the sumatriptan succinate among Fig. 1.Also lack 89 ℃ of heat absorptions corresponding with free alkali, this shows between sumatriptan and methyl-beta-schardinger dextrin-and has formed inclusion complex.Characteristic at 175 ℃ of visible methyl-beta-schardinger dextrin-s is decomposed.Experiment condition is compared with example 1, and difference is that service property (quality) is that the sample of 12.42mg is to produce the sumatriptan succinate reaction suitable with embodiment 1.
Fig. 4 represents the X-ray powder diffraction style of 1: 1 coordination compound of kneading that the sumatriptan succinate that obtains from embodiment 1 and methyl-beta-schardinger dextrin-form.Lack the dissolved spike feature of crystallization sumatriptan succinate, show to have lost crystallinity after forming coordination compound.The diffraction pattern that produces is the solid feature of amorphism.
Fig. 5 represents from the X-ray powder diffraction style of 1: 1 coordination compound of kneading of embodiment 2 sumatriptan succinate that obtains and the methyl that contains 1mol equivalent trimethylol aminomethane-beta-schardinger dextrin-formation.Lack crystallization sumatriptan succinate and ammonia fourth three dissolved spike features, show to have lost crystallinity after forming coordination compound.The diffraction pattern that produces is the solid feature of amorphism.
Fig. 6 represents how much cutaway views of the best molecular mechanics model of the inclusion complex that sumatriptan (light ash) forms in beta-schardinger dextrin-(dark-grey).Indole nucleus stretches into the intracavity of cyclodextrin with lateral (pendant) diformazan aminoethyl (bottom), and Methanesulfomide (top) side chain stretches out in outside the chamber.
Claims (18)
1. an inclusion complex is characterized in that a kind of indole selective serotonin (5-HT by (a)
ID) agonist or its pharmaceutically acceptable salt and (b) a kind of unsubstituted or β of replacing-or gamma-cyclodextrin form.
2. a coordination compound according to claim 1 is characterized in that (a) is sumatriptan or its pharmaceutically acceptable salt.
3. an inclusion complex according to claim 1 is characterized in that (a) is selected from naratriptan, rizatriptan, zolmitriptan, eletriptan and almotriptan and pharmaceutically acceptable salt thereof.
4. one kind according to the described inclusion complex of arbitrary claim among the claim 1-3, it is characterized in that (b) is selected from the beta-schardinger dextrin-of 2-HP-, methylated beta-schardinger dextrin-and sulfoalkylization.
5. one kind according to the described inclusion complex of arbitrary claim among the claim 1-4, and the substitution value that it is characterized in that (b) is 1-20 substituent group/cyclodextrin molecular.
6. inclusion complex according to claim 5, the substitution value that it is characterized in that (b) is 3-15 substituent group/cyclodextrin molecular.
7. one kind according to the described inclusion complex of arbitrary claim among the claim 1-3, it is characterized in that (b) is that substitution value is the 2-HP-of 3.9-5.1 hydroxypropyl group/cyclodextrin molecular.
8. one kind according to the described inclusion complex of arbitrary claim among the claim 1-3, it is characterized in that (b) is that substitution value is the methyl-beta-schardinger dextrin-of 1.8-2 methyl group/glucose unit.
9. inclusion complex of forming by sumatriptan free alkali and methyl-beta-schardinger dextrin-.
10. inclusion complex of forming by sumatriptan succinate and methyl-beta-schardinger dextrin-.
11. an inclusion complex of being made up of sumatriptan succinate and methyl-beta-schardinger dextrin-, in fact its feature has X-ray powder diffraction style shown in Fig. 4 or 5 at it.
12. one kind according to the described inclusion complex of arbitrary claim among the claim 1-11, it is characterized in that this inclusion complex has (a): (b) be 1: the stoichiometry of lmol/mol.
13. a pharmaceutical compositions is characterized in that containing a kind of indole selective serotonin (5-HT by (a)
ID) agonist or its pharmaceutically acceptable salt and (b) a kind of unsubstituted or β of replacing-or inclusion complex that gamma-cyclodextrin is formed as active component.
14. a pharmaceutical compositions according to claim 13 is characterized in that inclusion complex wherein is as the defined inclusion complex of arbitrary claim among the claim 2-12.
15. one kind according to claim 13 or 14 described pharmaceutical compositions, it is characterized in that being used for the treatment of the headache of migraine or class.
16. one kind according to the described pharmaceutical compositions of arbitrary claim among the claim 13-15, it is characterized in that this preparation of compositions become mouthful or the dosage form of nasal mucosa medicine administration.
17. one kind by (a) a kind of diindyl selectivity 5-hydroxy tryptamine (5-HT that draws
ID) agonist or its pharmaceutically acceptable salt and (b) a kind of unsubstituted or β of replacing-or the purposes of inclusion complex in the medicament of preparation treatment migraine or class headache of forming of gamma-cyclodextrin.
18. purposes according to claim 17 is characterized in that inclusion complex wherein is as the defined inclusion complex of claim 2-12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97196294A CN1225018A (en) | 1996-07-11 | 1997-07-11 | Inclusion complex containing indole selective serotonin agonist |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA96/5889 | 1996-07-11 | ||
| CN97196294A CN1225018A (en) | 1996-07-11 | 1997-07-11 | Inclusion complex containing indole selective serotonin agonist |
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| Publication Number | Publication Date |
|---|---|
| CN1225018A true CN1225018A (en) | 1999-08-04 |
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| CN97196294A Pending CN1225018A (en) | 1996-07-11 | 1997-07-11 | Inclusion complex containing indole selective serotonin agonist |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004035046A1 (en) * | 2002-10-16 | 2004-04-29 | Shanghai Institute Of Pharmaceutical Industry | Powder inhalant of sumatriptan and the method of preparation thereof |
-
1997
- 1997-07-11 CN CN97196294A patent/CN1225018A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004035046A1 (en) * | 2002-10-16 | 2004-04-29 | Shanghai Institute Of Pharmaceutical Industry | Powder inhalant of sumatriptan and the method of preparation thereof |
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