CN101953832A - Oral drug composite of beta-cyclodextrin edaravone inclusion and preparation method thereof - Google Patents

Oral drug composite of beta-cyclodextrin edaravone inclusion and preparation method thereof Download PDF

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CN101953832A
CN101953832A CN2010102500225A CN201010250022A CN101953832A CN 101953832 A CN101953832 A CN 101953832A CN 2010102500225 A CN2010102500225 A CN 2010102500225A CN 201010250022 A CN201010250022 A CN 201010250022A CN 101953832 A CN101953832 A CN 101953832A
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edaravone
schardinger dextrin
cyclodextrin
dextrin
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CN101953832B (en
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任勇
曾建
余书勤
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NANJING BAITE BIOTECHNOLOGICAL ENGINEERING Co Ltd
Nanjing Normal University
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Nanjing Normal University
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Abstract

The invention relates to an oral drug composite of beta-cyclodextrin edaravone inclusion, comprising the compositions in parts by weight: 1 part of edaravone and 6-100 parts of cyclodextrin. Based on the optimization scheme, the mass ratio of the edaravone and the cyclodextrin is 1:6-50, wherein the mass ratio of beta-cyclodextrin to the cyclodextrin is 1:6-20, and the mass ratio of mixed cyclodextrin containing the beta-cyclodextrin is 1:8-50. A preparation method comprises the following steps of mixing the beta-cyclodextrin or the mixed cyclodextrin containing the beta-cyclodextrin with 1-5 times mass of water, adding the edaravone with the selected mass ratio or adding a solution prepared from the edaravone and 10 times soluble organic solvent, grinding or stirring, vaporizing and eliminating water at the temperature no higher than 60 DEG C, and decompression drying to obtain a white powdery inclusion complex. A contrast test is carried out on the invention and edaravone injection on sale, the absolute bioavailability of an inclusion complex preparation thereof can reach above 55 percent; and compared with a common edaravone suspension preparation (attached drawing 6), the relative bioavailability of the invention reaches up to about 1000 percent.

Description

Combination of oral medication of beta-cyclodextrin inclusion compound Edaravone and preparation method thereof
Technical field
The present invention relates to a kind of pharmaceutical composition, be specifically related to a kind of for oral Edaravone pharmaceutical composition and this preparation of drug combination method.
Technical background
Edaravone (Edaravone), trade name: must deposit chemical name: 3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one (3-methyl-1-phenyl-2-pyrazolin-5-one), molecular formula: C 10H 10N 2O, molecular weight: 174.2; Structural research shows, the Edaravone molecule of virtue heterocyclic has different configuration (I.Braz.Chem.Soc. under the different solvents condition, 2008,19 (6): 1207～1214), Edaravone is 1 among the stronger DMSO of polarity, 2-dihydropyrazolone formula structure (a, accompanying drawing 1), and be single 2 in the hydrophobicity chloroformic solution, 4-dihydropyrazolone formula configuration (b, accompanying drawing 1); The difference of two kinds of ketone form structure a and b is that the nuclear magnetic resoance spectrum of its a has=the CH-proton peak in δ=5.36 places, and b is then at δ=3.39 appearance-CH of place 2-proton peak.
Edaravone is the treatment cerebral infarction medicine of first free radical scavenger type, by the calendar year 2001 exploitation listing of Mitsubishi drugmaker.Domestic enterprise is in the granted production of in December, 2003.This product can be removed free radical, suppresses lipid peroxidation, thereby suppresses the oxidative damage of brain cell, vascular endothelial cell and neurocyte.Pharmacological research shows that rat gives Edaravone at ischemia/ischemia-reperfusion posterior vein, can stop the progress of cerebral edema and cerebral infarction, alleviates the nervous symptoms of following, and suppresses delayed neuronal death.Edaravone is clinical in the injection system medication at present, and injection system adopts propylene glycol dissolving Edaravone, adds various stabilizing agents and antioxidant again and makes, and the product of solution form needs to provide clinical use to fill nitrogen ampoule manner of packing; Edaravone is oral to be difficult to absorb does not have oral formulations at present, and the patient uses inconvenience, and the research report of non-ejection preparation product is rarer.
Cyclodextrin (Cyclodextrin, be called for short CD) be that glucosyl group is with 1, the cyclic oligosaccharide of 4 glycosidic bond bondings, has the hydrophilic and hydrophobic characteristic of inner chamber (Cavity) of outer rim (Rim), cyclodextrin can form the clathrate of specific " host-guest " effect with various micromolecule objects (Guest) as main body (Host) molecule, strengthen the dissolubility and the stability of guest molecule, thereby be used widely at field of medicaments.(Int J Pharm.2009 May 8 such as Sato T.; 372 (1-2): 33-8) HP-/Edaravone (mass ratio 20: 1) is mixed with for test agent solution with citrate buffer (pH4.5), 50 ℃ of lucifuges are deposited and its heat stability were investigated discovery in 14 days, the Edaravone relative amount is reduced to 93.7% in the solution, and the solution Edaravone relative amount that adds sodium sulfite (SHS), cysteine (Cys) or the benzotriazole (BTA) of 0.1～0.6 mass ratio can keep stablizing constant.The sample solution of stable content adds the Edaravone metabolic poison again and has Transdermal absorption effect preferably.Further to HP-/Edaravone (mass ratio 20: 1) solution (citrate buffer of pH4.5) carry out that animal is oral, the pharmacokinetics test (Pharmacology.2010 of oral mucosa and rectally; 85 (2): 88-94), the result shows, add sodium sulfite (SHS) in the sample solution and cysteine (Cys) can significantly improve the Edaravone bioavailability, three kinds of administering modes are best with oral mucosa spray delivery effect, and compare with waiting dosage intravenously administrable AUC: mouthspray: intravenous injection is 140.4: 119.6; The oral administration bioavailability is minimum, even add heavy dose of sodium sulfite and cysteine (raising bioavailability), its oral administration biaavailability also only is 26.6% of mouthspray administration.
Sato T. etc. are test specimen with HP-/Edaravone solution of pH4.5, do not verify can whether HP-/Edaravone exist effective clathration, form stable clathrate in the solution, do not make the convenient solid clathrates of using, carrying easily yet, need to add the just certain oral absorption of tool of multiple auxiliary agent in its solution, therefore, the use of its HP-does not obtain the effect with actual application value.
Summary of the invention
The combination of oral medication that the purpose of this invention is to provide a kind of beta-cyclodextrin inclusion compound Edaravone, it is a kind of orally active Edaravone product, it is the neutral aqueous solution enclose Edaravone that adopts cyclodextrin, strong, the well behaved solid clathrates of pharmaceutics of preparation stability, need not to add other absorption enhancers or auxiliary agent, such preparation has oral effective, convenient characteristics of using.It is the new clinical practice of a kind of convenient effective Edaravone.The present invention also will provide the preparation method of this combination of oral medication.
Technical scheme of the present invention is: a kind of combination of oral medication of beta-cyclodextrin inclusion compound Edaravone, it is characterized in that the mass ratio of said composition consists of,
1 part of Edaravone
6～100 parts of cyclodextrin
Above-described cyclodextrin can be: beta-schardinger dextrin-(β-CD) or beta-schardinger dextrin-and HP-(HP-β-CD) or sulphur butyl-beta-schardinger dextrin-(the hybrid ring dextrin of SBE-β-CD) or beta-schardinger dextrin-and HP-and any ratio of sulphur butyl-beta-schardinger dextrin-.
The prioritization scheme of above-described pharmaceutical composition is: the mass ratio of Edaravone and cyclodextrin is: 1: 6～50, and wherein adopting the used mass ratio of beta-schardinger dextrin-is 1: 6～20, adopting the mass ratio of hybrid ring dextrin is 1: 8～50.
The optimal case of above-described pharmaceutical composition is: the mass ratio of Edaravone and cyclodextrin is: 1: 8～25.0, wherein adopting the used mass ratio of beta-schardinger dextrin-is 1: 8, the mass ratio of beta-schardinger dextrin-/HP-hybrid ring dextrin is 1: 10, and the mass ratio of beta-schardinger dextrin-/sulphur butyl-beta-schardinger dextrin-hybrid ring dextrin is 1: 25.
The further qualification of above-mentioned composition, described oral Edaravone pharmaceutical composition are the compositionss for preparing one of by the following method:
Method 1:
With beta-schardinger dextrin-, or the water that the hybrid ring dextrin adds 1～5 times of quality mixes, and adds the Edaravone of selected mass ratio again, fully grinds or stirs 1～2 hour, then, removes moisture content not being higher than to steam under 60 ℃ of temperature, and drying under reduced pressure obtains white powdery clathrate again.
Its further prioritization scheme is: with beta-schardinger dextrin-, or the water of hybrid ring dextrin and 1～4 times of quality is mixed and made into solution or suspension, stir the Edaravone that slowly adds selected mass ratio down, fully ground or stir 1 hour, then, steam under 50 ℃ of temperature and remove moisture content, reduced pressure at room temperature obtains white powdery clathrate again.
Method 2:
With beta-schardinger dextrin-, or the hybrid ring dextrin adds the water mixing of 1～5 times of quality, add the Edaravone of selected mass ratio and the solution of 10 times of solubility organic solvents (ethanol, acetone) preparation again, fully ground or stir 1～2 hour, then, remove organic solvent and moisture content not being higher than under 60 ℃ of temperature to steam, drying under reduced pressure obtains white powdery clathrate again.
Its further prioritization scheme is: with beta-schardinger dextrin-, or the water of hybrid ring dextrin and 1～4 times of quality is mixed and made into solution or suspension, stir the slow down Edaravone of selected mass ratio and the solution of 10 times of ethanol preparations of adding, fully ground or stir 1 hour, then, steam under 50 ℃ of temperature and remove ethanol and moisture content, reduced pressure at room temperature obtains white powdery clathrate again.
Employed water in the preparation process of above-mentioned composition according to the i.e. pure water of neutral (pH=7) of the Acidity of Aikalinity deviation of raw material, also can use 0.05～0.1molL -1The buffer salt weak solution of concentration.Its buffer salt is NH commonly used 4Ac or H 3PO 4-NaOH, the buffer solution that preparation becomes pH scope 6.1～7.9 uses.
Solid clathrates compatibility common medicinal supplementary material be prepared into can be oral dosage form such as preparations such as tablet, capsule, granule or dispersible tablet.Above-mentioned solid clathrates is made solid preparation, and the adjuvant that needs to add can be selected for use from following material: beta-schardinger dextrin-, microcrystalline Cellulose, starch, citric acid, Pulvis Talci, carboxymethylstach sodium, stearic acid, pregelatinized Starch, lactose, mannitol, polyvinylpolypyrrolidone, Pulvis Talci, PEG4000 (Macrogol 4000), low-substituted hydroxypropyl cellulose, micropowder silica gel, carboxymethylstach sodium, PEG6000 (polyethylene glycol 6000).
Solid clathrates of the present invention and preparation thereof are key problem in technology.With commercially available Edaravone injection contrast test, the absolute bioavailability of its clathrate preparation can reach more than 55%, compares (accompanying drawing 6) with the common suspension preparation of Edaravone, and its relative bioavailability is up to about 1000% (10 times).Even the Edaravone preparation of non-inclusion technique preparation has better dissolubility, also be difficult to reach technique effect of the present invention.
The technology of the present invention characteristics below are described.
The enclose feasibility: Edaravone is soluble in ethanol and the not high (2.623mgml of dissolubility in the water -1).In the aqueous solution, Edaravone has between the 230nm-260nm ultra-violet (UV) band more by force and to absorb, add the various cyclodextrin of self no uv absorption after, the medicine absorbance presents regular enhancing with the increase of cyclodextrin concentration, show in the aqueous solution that there are tangible clathration in cyclodextrin and Edaravone.By the variation of cyclodextrin concentration and medicine absorbance, can record apparent enclose constant, the results are shown in Table the 1 (0.1molL of condition determination: pH=4.52 or pH=6.86 -1Phosphate buffer, 240nm).
Table 1: the apparent enclose constant K a (240nm, 15 ± 5 ℃) of Edaravone
Figure BDA0000024301610000041
Test shows, cyclodextrin inclusion compound Edaravone effect is relevant with the acidity of medium, bigger apparent enclose constant is arranged in the neutral aqueous solution, various cyclodextrin all can form stable clathrate with Edaravone, this to stability of improving Edaravone, improve Edaravone pharmaceutics character very favourable.Under the acid condition (pH=4.52), Edaravone is easily protonated, and molecular polarity strengthens, and causes enclose ability drop (Ka reduces obviously), therefore, is unfavorable for producing stable clathrate.
Investigate the influence of cyclodextrin to the Edaravone dissolubility with the phase solubility method, the result shows that saturated beta-schardinger dextrin-makes the Edaravone dissolubility increase by 1.4 times; 10%～20% HP-solution increases by 2.8～7.2 times; 10%～30% sulphur butyl-beta-schardinger dextrin-solution increases by 3.3～11.8 times.The hybrid ring dextrin can make the Edaravone dissolubility increase more than 2 times, is better than single beta-schardinger dextrin-, but reduces with beta-schardinger dextrin-content, and cost also increases sharply.
Research Edaravone nuclear magnetic resoance spectrum 1HNMR finds by (accompanying drawing 2) in the strong polar aqueous solvent that Edaravone does not have=the CH-characteristic peak, shows that Edaravone does not exist with a configuration in the water; Also have significant difference with nuclear magnetic resoance spectrum (accompanying drawing 3) in the organic solvent chloroform and do not have-CH 2-characteristic peak, its fragrant proton form indistinguishable multiplet (δ=7.26～7.47) in water, methyl is split into strong and weak two unimodal (accompanying drawing 2) that does not wait simultaneously; Its 13The CNMR spectrum does not promptly have-CH 2-(δ=42.81) do not have the characteristic peak of C=O (δ=170.26) yet, and the configuration that shows Edaravone in the water promptly is different from a and also is different from b, and Edaravone exists with new (enol form) configuration in the aqueous solution, and this configuration has not yet to see bibliographical information.
The series of loops cyclodextrin inclusion compound nuclear magnetic resoance spectrum of mensuration Edaravone ( 1HNMR), find enclose front and back Edaravone in the aqueous solution 1HNMR composes existing significant difference, Benexate Hydrochloride 1HNMR spectrum is seen accompanying drawing 4: the Edaravone fragrance proton multiplet (δ=7.26～7.47) behind the enclose produces division, also form the configuration peak in keeping aqueous solvent with chloroform solvent in Edaravone 1δ 7.67 (the dd that the HNMR spectrum is similar, 2H), 7.42 (dd, 2H) with 7.26 (m, three groups of independence peaks 1H), two unimodal and low field displacement (moving to δ=2.15～2.11 by δ=2.14～2.07) of generation appear in its methyl proton, illustrate that clathrate contains original new configuration in configuration b and the aqueous solvent; In the clathrate in the ring of beta-schardinger dextrin-3-H and 5-H proton high field displacement all appears, illustrate that Edaravone and beta-cyclodextrin inclusion compound are complete in the aqueous solution, and clathrate has the rock-steady structure that aromatic structure enters cyclodextrin cavity deep layer (displacement of 5-H proton).The division of fragrance proton peak reaches the variation relation explanation with the methyl peak shift, clathrate exists phenyl ring to be introduced into two kinds of structures that are introduced into heterocycle simultaneously, wherein Edaravone has the feature of configuration b in the structure that is introduced into of heterocycle, its methyl gos deep in the cyclodextrin, screen effect obviously has bigger low field displacement (δ=2.07 are to δ=2.11), the phenyl ring proton divides, and becomes three groups of peaks; And the structure that phenyl ring is introduced into has kept original configuration in the water, go deep into the low field displacement of phenyl ring proton obvious (δ=7.39～7.37 are to δ=7.43～7.42) in the cyclodextrin, and being in the cyclodextrin outer rim, methyl is subjected to less shielding, therefore, less low field displacement (δ=2.14 are to δ=2.15) appears; Two of methyl peak are unimodal to be respectively (configuration b) methyl of configuration conversion behind the methyl of retention of configuration in the water and the enclose, its area integral is than the ratio that is two kinds of configurations, and wherein configuration b content reaches 38% (the configuration b content of HP-and sulphur butyl-Benexate Hydrochloride is respectively 44% and 37%) in the Benexate Hydrochloride.The Edaravone " clathrate " of (pH=4.5) preparation under the acid condition, its 1The HNMR spectrum is then similar to Edaravone in the water, has kept the configuration in the water substantially.The existence of configuration b illustrates under this condition in the clathrate of neutrallty condition preparation, cyclodextrin is the enclose Edaravone effectively, the environment of similar organic solvent also is provided simultaneously, make Edaravone produce the configuration of low pole, the existence of its configuration b may be the major reason that cyclodextrin significantly improves the Edaravone bioavailability.
Verify that with the differential thermal analysis contrast test result shows, adopts preparation method of the present invention can make the Edaravone clathrate of various cyclodextrin, wherein only is that the measurement result of example is seen accompanying drawing 5 with the Benexate Hydrochloride.
The sample stability test
Serial Edaravone/cyclodextrin clathrate (enclose ratio: β-CD is that 1: 8, HP-β-CD are that 1: 15, SBE-β-CD are 1: 22) is placed respectively with the Edaravone raw material and carries out ten days stability experiments under 40 ℃ of heat and the 4500 ± 500LX light.Respectively at sampling in the 5th and 10 day, HPLC content detection.Relative amount (in 0 day 100%) testing result sees Table 2.
Table 2: the relative percentage composition of Edaravone in the sample
Figure BDA0000024301610000051
Figure BDA0000024301610000052
Figure BDA0000024301610000061
The HPLC condition: the ODS-C18 chromatographic column (5 μ m, 250mm * 4.6mm); Methanol: pH=3.5 potassium dihydrogen phosphate (0.05molL -1)=50: 50 mobile phase; 1.0mlm -1Flow velocity; 25 ℃ of column temperatures; Detect wavelength: 240nm; Minute: 17min.
Table 2 shows, the Edaravone crude drug content of non-enclose decline obvious (all less thaies 95%) under light, the heat condition; And Edaravone content is relatively stable in the clathrate.Illustrate that cyclodextrin inclusion compound is improved significantly the stability of Edaravone.In addition, the clathrate of contrast condition of different pH preparation, the neutral water condition not only helps the cyclodextrin inclusion compound Edaravone, and the clathrate stability of preparation also obviously is enhanced; And the clathrate Edaravone less stable of acid condition preparation.
The bioavailability test:
1, be subjected to the reagent thing: Edaravone/cyclodextrin clathrate (enclose is than the same), Edaravone CMC-Na suspension, Edaravone tween 80 (10%) solution and injection " must be deposited " (commercially available), and totally six supply test agent.
2, zoopery: experimental animal SD rat is divided into six groups, carries out test according to the design that requires of " the non-CLINICAL PHARMACOKINETIS STUDY ON technological guidance's principle of chemicals ([H] GPT5-1) ", and the HPLC method is measured blood drug level, and the result sees Table 3 and accompanying drawing 6 respectively
Table 3: the pharmacokinetic parameter of laboratory sample
* there were significant differences with Edaravone ordinary preparation (0), P＜0.05.
The result of the test demonstration, in the Edaravone ordinary preparation, the minimum (AUC of CMC-Na suspension oral administration biaavailability 0-8h10.56 ± 1.9), the 10% tween 80 solution bioavailability (AUC that increases 0-8h57.41 ± 36.7), the Edaravone of proof dissolved state has certain oral absorption effect (absolute bioavailability about 31%), but the solution state Edaravone easily decomposes, poor stability, and the auxiliary agent side effect is strong, and preparation is difficult for preserving, uses and carry inconvenience, industrialization difficulty height; Cyclodextrin/Edaravone clathrate oral result is good, with its bioavailability of inject contrast more than 55%, be respectively 9.8～11 times and 1.8～2.1 times with Edaravone ordinary preparation (CMC-Na suspension and 10% tween 80 pharmaceutical solutions) relative bioavailability relatively, the oral result of various cyclodextrin clathrate is approaching relatively, difference is less, it is not only relevant with the dissolubility increase to show that the Edaravone bioavailability improves, and closer with the cyclodextrin inclusion compound characteristic relation, show that cyclodextrin clathrate possesses good potential applicability in clinical practice.
Advantage of the present invention:
1. the Edaravone clathrate is oral effectively, and higher bioavailability is arranged, for the patient provides new more convenient route of administration and method.
2. the Edaravone enclose of the present invention's preparation is complete, and impurity content and solvent residual amount are low, and do not have antioxidant, absorption enhancer and other complicated auxiliary agents, have guaranteed product quality and drug safety.
3. the solid clathrates stable in properties is easy to preserve transportation, and pharmaceutics is well-behaved, is suitable for various peroral dosage forms, and it is all convenient that use is carried.
4. preparation method is simple, easy and simple to handle, cost is low and non-environmental-pollution.
Description of drawings
Fig. 1: a of the Edaravone under the different solvents condition and b configuration;
Fig. 2: the nuclear magnetic resoance spectrum of Edaravone in aqueous solvent: 1H-NMR (D 2O): δ 7.47-7.26 (m, 5H); 3.58 (s, 2H ,-CH 2-); 2.14-2.08 (ss, 3H, CH 3)
Fig. 3: the nuclear magnetic resoance spectrum of Edaravone in chloroform solvent: 1H-NMR (CDCl 3): δ 7.83-7.81 (dd, 2H); 7.37-7.33 (dd, 2H); 7.16-7.12 (dd, 1H); 3.39 (s, 2H ,-CH 2-); 2.16 (s, 3H, CH 3)
The nuclear magnetic resoance spectrum of Fig. 4 beta-schardinger dextrin-/Edaravone clathrate (mass ratio 8: 1, mol ratio 1.2: 1): 1H-NMR (D 2O, Edaravone part correlation peak): δ 7.67 (dd, 2H); 7.43 (m, 5H); 7.42 (dd, 2H); 7.26 (m, 1H); 2.15-2.11 (ss, 3H, CH 3)
The DTA figure contrast of Fig. 5 Edaravone (a), Edaravone and beta-schardinger dextrin-physical mixture (b), beta-schardinger dextrin-(c), Benexate Hydrochloride (d).
Curve chart during the animal pharmaceuticals metabolic test medicine of Fig. 6 Edaravone CMC-Na suspension preparation and three kinds of cyclodextrin clathrate preparations.
The specific embodiment
Embodiment 1, and beta-schardinger dextrin-80 grams mix with 400 ml pure waters, make into suspension (pH=6.9), add the Powdered Edaravone of 10 grams, mixing, the abundant grinding were stirred 1 hour, and reducing pressure down in 50 ℃ dewaters, and then spend the night in reduced pressure at room temperature, must about 90 gram white solid inclusion compound.
Embodiment 2, and is substantially the same manner as Example 1, but adopts 10 gram beta-schardinger dextrin-s to add the 0.1molL of 240 gram sulphur butyl-beta-schardinger dextrin-s and 400 milliliters of pH=6.1 -1NH 4The Ac buffer mixes, and makes about 260 gram white solid inclusion compound.
Embodiment 3, and is substantially the same manner as Example 1, but adopts 10 gram beta-schardinger dextrin-s to add the 0.05molL of 90 gram HP-and 400 milliliters of pH=7.5 -1Phosphate buffer mixes, and makes about 110 gram white solid inclusion compound.
Embodiment 4, and is substantially the same manner as Example 1, but adopts 70 gram beta-schardinger dextrin-s and the hybrid ring dextrin of 10 gram HP-and the 0.1molL of 400 milliliters of pH=7.9 -1Phosphate buffer mixes, and makes about 90 gram white solid inclusion compound.
Embodiment 5, and is substantially the same manner as Example 1, but adopts the hybrid ring dextrin of 70 gram beta-schardinger dextrin-s and 10 gram sulphur butyl-beta-schardinger dextrin-s, makes about 90 gram white solid inclusion compound.
Embodiment 6, and is substantially the same manner as Example 1, but adopts the hybrid ring dextrin of 100 gram beta-schardinger dextrin-s, 20 gram HP-and 20 gram sulphur butyl-beta-schardinger dextrin-s, makes about 150 gram white solid inclusion compound.
Embodiment 7, and is substantially the same manner as Example 1, but adopts the hybrid ring dextrin of 90 gram beta-schardinger dextrin-s, 5 gram HP-and 5 gram sulphur butyl-beta-schardinger dextrin-s, makes about 110 gram white solid inclusion compound.
Embodiment 8, and is substantially the same manner as Example 1, but adopts the hybrid ring dextrin of 30 gram beta-schardinger dextrin-s and 30 gram HP-and 30 gram sulphur butyl-beta-schardinger dextrin-s, makes about 100 gram white solid inclusion compound.
Embodiment 9, and is substantially the same manner as Example 1, but adopts the 0.05molL of 80 milliliters of pH=7.1 -1Phosphate buffer mixes, and makes about 90 gram white solid inclusion compound.
Embodiment 10, and is substantially the same manner as Example 1, but adopts 150 ml pure waters, makes about 90 gram white solid inclusion compound.
Embodiment 11, and is substantially the same manner as Example 1, but adopts 200 ml pure waters, makes about 90 gram white solid inclusion compound.
Embodiment 12, and is substantially the same manner as Example 1, but adopts 60 gram beta-schardinger dextrin-and 60 ml pure waters, makes about 70 gram white solid inclusion compound.
Embodiment 13, and is substantially the same manner as Example 1, but adopts 160 gram beta-schardinger dextrin-and 150 ml pure waters, makes about 170 gram white solid inclusion compound.
Embodiment 14, and is substantially the same manner as Example 1, but adopts 500 gram beta-schardinger dextrin-and 700 ml pure waters, makes about 510 gram white solid inclusion compound.
Embodiment 15, and is substantially the same manner as Example 1, but adopts 1000 gram beta-schardinger dextrin-and 1000 ml pure waters, makes about 1100 gram white solid inclusion compound.
Embodiment 16, and is substantially the same manner as Example 1, but adopts 79 gram beta-schardinger dextrin-s and 1 gram HP-and 100 ml pure waters, makes about 90 gram white solid inclusion compound.
Embodiment 17, and is substantially the same manner as Example 1, but adopts 250 gram beta-schardinger dextrin-s and 10 gram HP-and 260 ml pure waters, makes about 270 gram white solid inclusion compound.
Embodiment 18, and is substantially the same manner as Example 1, but adopts 110 gram beta-schardinger dextrin-s and 10 gram sulphur butyl-beta-schardinger dextrin-and 150 ml pure waters, makes about 130 gram white solid inclusion compound.
Embodiment 19, and is substantially the same manner as Example 1, but adopts 490 gram beta-schardinger dextrin-s and 10 gram sulphur butyl-beta-schardinger dextrin-and 750 ml pure waters, makes about 510 gram white solid inclusion compound.
Embodiment 20, are mixed with solution for standby with 100 milliliters of dissolve with ethanols, 10 gram Edaravones.Beta-schardinger dextrin-75 grams mix with 400 ml pure waters, make into suspension (pH=7.5); Stir the Edaravone solution that slowly adds dissolve with ethanol down, fully ground or stir 1.5 hours, steam under 50 ℃ of temperature and remove ethanol and moisture content, drying under reduced pressure makes about 85 gram white solid inclusion compound under room temperature again.
Embodiment 21, and is substantially the same manner as Example 20, but adopts the acetone solution Edaravone, makes about 85 gram white solid inclusion compound.
Embodiment 22, get clathrate 90.0 grams of embodiment 1 preparation, it is standby to cross 100 mesh sieves, take by weighing microcrystalline Cellulose 72.0 grams, starch 20.0 grams, carboxymethylstach sodium 16.0 grams, magnesium stearate 2.0 gram mixing, crossing 60 mesh sieves fully mixes, getting 2/3 amount pharmaceutic adjuvant behind the mixing mixes with solid clathrates, cross 80 mesh sieves, then with 70% ethanol moistening system soft material, crossing 14 mesh sieves granulates, add other 1/3 amount pharmaceutic adjuvant behind 50 ℃ of dryings, the granulate, fully measure Edaravone content behind the mixing, require tabletting to make the Edaravone containing plate according to dosage.
Embodiment 23, get clathrate 90.0 grams of embodiment 4 preparations, mix with 32.0 gram PEG4000,26.0 gram carboxymethylstach sodium, cross the abundant mixing of 80 mesh sieves, fully mix in mixer for 15 milliliters with 10% hyprolose alcoholic solution, 50 ℃ of dryings 2 hours are sieved and are made 250 microns powder of granularity again, measure Edaravone content, requiring to pack into according to dosage promptly makes the Edaravone capsule in the capsulae vacuus.
Embodiment 24; get clathrate 90.0 grams of embodiment 9 preparations; mix with pregelatinized Starch 30 grams, lactose 30 grams, mannitol 30 grams and carboxymethylstach sodium 20 grams; cross the abundant mixing of 80 mesh sieves; again with 70% ethanol system soft material; make granule with granulation machine 14 mesh sieves, measure Edaravone content, require packing promptly to make the Edaravone granule according to dosage.
Embodiment 25, get clathrate 90.0 grams of embodiment 8 preparations, mix 50 ℃ of dryings of wet granulation 2 hours with carboxymethylstach sodium 8 grams, microcrystalline Cellulose (MCC) 80 grams, mannitol 12 grams, micropowder silica gel 10 grams, measure content, according to dosage require to suppress the Edaravone dispersible tablet.

Claims (10)

1. the combination of oral medication of a beta-cyclodextrin inclusion compound Edaravone is characterized in that, the mass ratio of said composition consists of,
1 part of Edaravone
6～100 parts of cyclodextrin.
2. the combination of oral medication of beta-cyclodextrin inclusion compound Edaravone according to claim 1, it is characterized in that described cyclodextrin is selected from: the hybrid ring dextrin that contains beta-schardinger dextrin-of the hybrid ring dextrin that contains beta-schardinger dextrin-of beta-schardinger dextrin-or beta-schardinger dextrin-and HP-or any ratio of sulphur butyl-beta-schardinger dextrin-or beta-schardinger dextrin-and HP-and any ratio of sulphur butyl-beta-schardinger dextrin-.
3. the combination of oral medication of beta-cyclodextrin inclusion compound Edaravone according to claim 1 is characterized in that, the mass ratio of described pharmaceutical composition consists of and is: the mass ratio of Edaravone and cyclodextrin is: 1: 6～50.
4. the combination of oral medication of beta-cyclodextrin inclusion compound Edaravone according to claim 3, it is characterized in that, when wherein adopting beta-schardinger dextrin-separately, Edaravone is 1: 6～20 with the The quality of ss-cyclodextrin ratio, when employing contained the hybrid ring dextrin of beta-schardinger dextrin-, Edaravone was 1: 8～50 with the mass ratio that contains the dark cyclization dextrin of beta-schardinger dextrin-.
5. the combination of oral medication of beta-cyclodextrin inclusion compound Edaravone according to claim 1, it is characterized in that, the mass ratio of described pharmaceutical composition is for to be: the mass ratio of Edaravone and cyclodextrin is: 1: 8～25.0, when wherein adopting beta-schardinger dextrin-, Edaravone is 1: 8 with the The quality of ss-cyclodextrin ratio; The mass ratio of the hybrid ring dextrin of Edaravone and beta-schardinger dextrin-and HP-is 1: 10, and the mass ratio of the hybrid ring dextrin of Edaravone and beta-schardinger dextrin-and sulphur butyl-beta-schardinger dextrin-is 1: 25.
6. according to the combination of oral medication of the described beta-cyclodextrin inclusion compound Edaravone of one of claim 1-5, it is characterized in that described combination of oral medication is the compositions for preparing one of by the following method:
Beta-schardinger dextrin-or beta-schardinger dextrin-are mixed with the water that the hybrid ring dextrin of HP-and any ratio of sulphur butyl-beta-schardinger dextrin-adds 1～5 times of quality with the hybrid ring dextrin that contains beta-schardinger dextrin-or the beta-schardinger dextrin-of HP-or any ratio of sulphur butyl-beta-schardinger dextrin-, the Edaravone that adds selected mass ratio again, or the solution of adding Edaravone and 10 times of solubility organic solvent preparations, fully ground or stir 1～2 hour, then, remove moisture content not being higher than under 60 ℃ of temperature to steam, drying under reduced pressure obtains white powdery clathrate again.
7. the preparation method of the combination of oral medication of the described beta-cyclodextrin inclusion compound Edaravone of claim 1 is characterized in that step is as follows:
With the hybrid ring dextrin of beta-schardinger dextrin-or beta-schardinger dextrin-and HP-or any ratio of sulphur butyl-beta-schardinger dextrin-or beta-schardinger dextrin-hybrid ring dextrin with HP-and any ratio of sulphur butyl-beta-schardinger dextrin-, the water that adds 1～5 times of quality mixes, the Edaravone that adds selected mass ratio again, or the solution of adding Edaravone and 10 times of solubility organic solvent preparations, fully ground or stir 1～2 hour, then, remove moisture content not being higher than under 60 ℃ of temperature to steam, drying under reduced pressure obtains white powdery clathrate again.
8. the preparation method of the combination of oral medication of beta-cyclodextrin inclusion compound Edaravone according to claim 7, it is characterized in that, the concrete operation method of each step is: with beta-schardinger dextrin-, or the hybrid ring dextrin of beta-schardinger dextrin-and HP-or any ratio of sulphur butyl-beta-schardinger dextrin-, or beta-schardinger dextrin-is mixed and made into solution or suspension with the hybrid ring dextrin of HP-and any ratio of sulphur butyl-beta-schardinger dextrin-and the water of 1～4 times of quality, stir the Edaravone that slowly adds selected mass ratio down, fully ground or stir 1 hour, then, steam under 50 ℃ of temperature and remove moisture content, reduced pressure at room temperature obtains white powdery clathrate again.
9. according to the preparation method of the combination of oral medication of claim 7 or 8 described beta-cyclodextrin inclusion compound Edaravones, it is characterized in that described solubility organic solvent is selected from: ethanol or acetone.
10. according to the preparation method of the combination of oral medication of claim 7 or 8 described beta-cyclodextrin inclusion compound Edaravones, it is characterized in that employed water in the preparation process is meant the neutral pure water of pH=7, or 0.05～0.1molL -1The buffer salt weak solution of concentration, described buffer salt solution are NH 4Ac or H 3PO 4-NaOH, preparation becomes the buffer solution of pH scope 6.1～7.9.
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Cited By (12)

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Publication number Priority date Publication date Assignee Title
WO2012019381A1 (en) * 2010-08-10 2012-02-16 南京师范大学 Oral pharmaceutical composition containing inclusion of edaravone and cyclodextrin and preparation method thereof
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WO2018133957A1 (en) 2017-01-17 2018-07-26 Treeway Tw001 B.V. Medical treatment comprising enteral administration of edaravone
WO2018134243A1 (en) 2017-01-17 2018-07-26 Treeway Tw001 B.V. Treatment comprising oral or gastric administration of edaravone
WO2019008144A1 (en) 2017-07-06 2019-01-10 Treeway Tw001 B.V. Use of edaravone in oral treatment of oxidative-stress mediated neurodegenerative disorders
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CN113768879A (en) * 2016-03-16 2021-12-10 苏州澳宗生物科技有限公司 Edaravone dosage form
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1440749A (en) * 2003-03-24 2003-09-10 南昌弘益科技有限公司 Edaravone injection for treating acute cerebral thrombus and its prepn

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4746856B2 (en) * 2004-08-12 2011-08-10 三笠製薬株式会社 Pyrazolone preparation
US20080104001A1 (en) * 2006-10-27 2008-05-01 Kipp James E Algorithm for estimation of binding equlibria in inclusion complexation, host compounds identified thereby and compositions of host compound and pharmaceutical
CN101953832B (en) * 2010-08-10 2012-02-15 南京师范大学 Oral drug composite of beta-cyclodextrin edaravone inclusion and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1440749A (en) * 2003-03-24 2003-09-10 南昌弘益科技有限公司 Edaravone injection for treating acute cerebral thrombus and its prepn

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
《中国药学杂志》 20050531 陆亚鹏等 阿莫西林/beta-环糊精包合作用研究 第757-759页 1-10 第40卷, 第10期 2 *

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WO2018133957A1 (en) 2017-01-17 2018-07-26 Treeway Tw001 B.V. Medical treatment comprising enteral administration of edaravone
WO2018134243A1 (en) 2017-01-17 2018-07-26 Treeway Tw001 B.V. Treatment comprising oral or gastric administration of edaravone
WO2019008144A1 (en) 2017-07-06 2019-01-10 Treeway Tw001 B.V. Use of edaravone in oral treatment of oxidative-stress mediated neurodegenerative disorders
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EP3785698A4 (en) * 2018-04-27 2022-01-19 Beijing Tiantan Hospital Capital Medical University Edaravone pharmaceutical composition
CN114099499A (en) * 2020-08-26 2022-03-01 上海博志研新药物技术有限公司 Edaravone oral sustained-release composition, preparation method and application
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