CN101314045B - Sulphur butyl ether-beta-cyclodextrin clathrate compound of cinnarizine, formulated product and preparation method thereof - Google Patents

Sulphur butyl ether-beta-cyclodextrin clathrate compound of cinnarizine, formulated product and preparation method thereof Download PDF

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Publication number
CN101314045B
CN101314045B CN2008100113485A CN200810011348A CN101314045B CN 101314045 B CN101314045 B CN 101314045B CN 2008100113485 A CN2008100113485 A CN 2008100113485A CN 200810011348 A CN200810011348 A CN 200810011348A CN 101314045 B CN101314045 B CN 101314045B
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cinnarizine
beta
cyclodextrin
clathrate
preparation
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CN101314045A (en
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何仲贵
王安娜
王永军
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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Abstract

the invention belongs to the drug technical field, disclosing a sulphur butyl ether-beta- cyclodextrin(SBE-beta-CD) clathrate compound of cinnarizine, a preparation thereof and a preparation method thereof. The water soluble beta- cyclodextrin derivative SBE-beta-CD is used as a coating material to prepare the cinnarizine clathrate compound. The process comprises the following steps that: the BE-beta-CD is dissolved in proper amount of water, the pH value is adjusted by hydrochloric acid, the cinnarizine is added in the mixed solution and stirred for ultrasonic dissolution, the mixed solution obtained is added with sodium hydroxide to adjust the pH value, a clathrate solution is obtained, and the clathrate solution is subject to freeze drying or spray drying to form clathrate compound powder; the clathrate compound solution obtained is subject to degerming, pyrogen removal, sterile filling and freeze drying to obtain freeze-dry powder needles for injection; the clathrate compound solution is subject to spray drying, and the obtained powder is directly subject to sterile subpackaging or mixed with proper amount of auxiliary materials for sterile subpackaging; and the clathrate compound powder can be mixed with other auxiliary materials to prepare tablets, capsules and particles, etc. according to requirements.

Description

The sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine and preparation thereof and preparation method
Technical field:
The present invention relates to medical technical field, is sulfobutyl ether-beta-cyclodextrin inclusion compound and preparation and the preparation method of cinnarizine.The clathrate preparation comprises injection powder pin, tablet, capsule, granule etc.
Background technology:
Cinnarizine (CN) is a kind of novel hexichol piperazines calcium-ion channel antagonists, effect with blood vessel dilating smooth muscle, can significantly improve hat circulation and cerebral circulation, to the vasoconstriction medicine, such as 5-hydroxy tryptamine, epinephrine, Kallidin I, hypertensin, dopamine etc. antagonism is arranged, can alleviating vascular spasm, simultaneously anti-hemostatic tube embrittlement.Oral on blood pressure without impact, can cause the of short duration decline of blood pressure behind the quiet notes, but absorb very fast.Spasmolysis is stronger than papaverine, but than a little less than the flunarizine.This medicine is mainly used in angina pectoris and cerebrovascular disorders at present, and is not congruent such as the cerebral circulation of cerebral thrombosis, cerebral embolism, cerebral arteriosclerosis, cerebral hemorrhage convalescent period, caused by hypertension.
Cinnarizine in 1975 in Belgian Initial Public Offering, successively use in states such as English, method, meaning, days.China's pharmacopeia version in 2005 has been recorded the Tablet and Capsula agent.Its tablet, capsule (15mg, 25mg), injection (every 20mg/20mL) have been classified national essential drugs as.
But cinnarizine is almost insoluble in water, and traditional injection is after having added the organic solubilized agent, and concentration also only has 20mg/20mL, and drug safety and patient compliance are relatively poor.And it is lower that its solution type injection agent contains concentration, and heat stability is more very different than solid preparation.Therefore, be necessary very much cinnarizine is prepared into injectable powder or other solid preparations with good solubility and good stability.
(SBE-β-CD) is that (derivant of β-CD) is the product of β-CD and Isosorbide-5-Nitrae-butane sultone generation substitution reaction for the ionizing beta-schardinger dextrin-succeeded in developing by the U.S. Cydex company nineties in 20th century to sulfobutyl ether-beta-cyclodextrin.As a kind of novel water solublity pharmaceutic adjuvant, SBE-β-CD has the unrivaled advantage of other cyclodextrin derivative, and low and hemolytic is little etc. such as good water solubility, nephrotoxicity.
Because SBE-β-CD has the negative charge side chain, and cinnarizine is easily to form positively charged nitrogenous medicine.Therefore, SBE-β-CD has special affinity and enclose to cinnarizine, can increase better dissolubility and the stability of medicine, improve the bioavailability of medicine, improve the rate of release of medicine, reduce medicine to the zest of local organization, reduce the volatility of medicine, reduce toxic and side effects, cover bad smell, little etc. to Nephrotoxicity.
Chinese patent CN 1515260A has described the preparation of HP-β-CD (HPCD) the clathrate powder injection formulation of cinnarizine.Its optimum initial charge is CN: HPCD=1 by mole ratio: 7; And among the present invention, optimum initial charge is CN by mole ratio: SBE-β-CD=1: 5.As seen, SBE-β-CD has better solubilizing effect than HPCD to cinnarizine.Cinnarizine clathrate and the preparation thereof of preparation same dose, required SBE-β-CD lacks than HPCD.In addition, SBE-β-CD is owing to containing the larger sulfonic group of polarity in the molecule, and kidney is little to its Reabsorption, and homaluria is accelerated, and nephrotoxicity reduces greatly.And the hemolytic of SBE-β-CD is far smaller than HPCD (Gu Fugen etc., Chinese Journal of New Drugs, 2004,13 (1): 15-19).Therefore, the SBE-beta-CD inclusion of cinnarizine and preparation thereof have larger advantage.
Summary of the invention:
The sulfobutyl ether-beta-cyclodextrin inclusion compound that the purpose of this invention is to provide a kind of cinnarizine, dissolubility and the stability of raising cinnarizine.
Another object of the present invention is, preparation and the preparation method of the sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine is provided.The clathrate preparation comprises injection powder pin, tablet, capsule, granule etc.
The present invention is achieved through the following technical solutions:
The sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine is made of in molar ratio following raw material: cinnarizine: sulfobutyl ether-beta-cyclodextrin=1: 1-10; Best proportioning is 1: 5.When experiment showed, with 1: 5 ratio enclose, cinnarizine content is high, and the consumption of sulfobutyl ether-beta-cyclodextrin is few.
The preparation method of clathrate of the present invention is, gets SBE-β-CD by above-mentioned mol ratio, and with the suitable quantity of water dissolving, hydrochloric acid is transferred pH to 1.0-2.0; Other gets cinnarizine and adds in the above-mentioned aqueous solution, stir and ultrasonic make it dissolving after, add sodium hydroxide and transfer pH to 3.0, obtain inclusion complex in solution.Namely get the clathrate powder through lyophilization or spray drying again.
The preparation method of clathrate preparation of the present invention comprises:
(1) with the inclusion complex in solution that obtains, add appropriate amount of auxiliary materials, stirring or (reaching) are ultrasonic, make into homogeneous solution.After adding proper amount of active carbon stirring depyrogenation, filter carbon removal.Use again 0.22 μ m filtering with microporous membrane, add water for injection to ormal weight.Sterile filling is in cillin bottle, and through lyophilization, the gland of jumping a queue namely gets the injection freeze-dried powder.
(2) enclose liquid is spray-dried, the gained powder directly aseptic subpackaged or with appropriate amount of auxiliary materials (such as any or any two or more mixture such as mannitol, sorbitol, xylitol, glucose, sodium chloride) mixing after aseptic subpackaged and get final product.
(3) with the clathrate powder that obtains, add proper auxiliary materials, make the solid dosage formss such as tablet, capsule, granule.
The used pharmaceutic adjuvant of the present invention includes but are not limited to: proppant or excipient are (such as mannitol, sorbitol, xylitol etc.), isoosmotic adjusting agent (sodium chloride, citric acid acid etc.), filler is (such as starch, lactose, microcrystalline Cellulose etc.), binding agent is (such as PVP, HPMC etc.), disintegrating agent is (such as CCNa, PVPP, L-HPC etc.), lubricant is (such as magnesium stearate, Pulvis Talci, micropowder silica gel etc.), correctives (such as Fructus Citri tangerinae essence etc.) and sweeting agent are (such as sucrose, syrup, aspartame etc.).
Determining of lyophilization condition of the present invention:
The present invention adopts thermal analysis system (in temperature-rise period, the absorption of individual energy can be arranged suddenly when temperature reaches eutectic point based on the medicine that freezes) to record the clathrate eutectic point to be about-20 ℃.And obtain following comparatively ideal lyophilization condition by many experiments:
Pre-freeze mode: quick freezing
Pre-freeze temperature :-70 ℃
The pre-freeze time: 12h
Sublimation drying method: disposable sublimed method
Vacuum: 20 * 10 -3Mpa
Freeze-drying time: 24h
Baking temperature again: 25 ℃
Annotate: the present invention can adopt additive method to record the clathrate plait point; The lyophilization condition also can be done suitable the adjustment as the case may be.
Determining of spray drying condition of the present invention:
This experiment obtains following comparatively ideal spray drying condition by many experiments:
Inlet temperature: T Advance=170 ℃
Outlet temperature: T Go out=70~80 ℃
Air pressure: 0.8kg
The throwing disc rotating speed: 1.2 ten thousand turn
Flow rate of liquid: 3L/h
Annotate: the present invention adopts the spray drying condition can do as the case may be suitable the adjustment.
The discrimination method of clathrate of the present invention is as follows:
Judge whether SBE-β-CD and enclosed molecule medicine CN have formed clathrate conclusive evidence method X-ray diffraction method commonly used and differential thermal analysis method etc. by inclusion technique.
Example 1:X-ray diffraction method:
Testing conditions: graphite monochromator monochromatization CuK α radiation;
Manage electric 40KV;
Pipe flow 20mA.
Sample: the sulfobutyl ether-beta-cyclodextrin inclusion compound of the physical mixture of cinnarizine, sulfobutyl ether-beta-cyclodextrin, cinnarizine and adjuvant or incomplete clathrate, cinnarizine, carry out the X-ray diffraction analysis.
By X-ray diffracting spectrum as can be known: cinnarizine has obvious crystal diffraction peak (seeing accompanying drawing 1); Sulfobutyl ether-beta-cyclodextrin does not have obvious crystal diffraction peak (seeing accompanying drawing 2); The physical mixture of cinnarizine and adjuvant or its incomplete clathrate have obvious crystal diffraction peak and are shown as the stack (seeing accompanying drawing 3) of several independent component diffraction maximums; The sulfobutyl ether-beta-cyclodextrin inclusion compound diffracting spectrum of cinnarizine does not have obvious crystal diffraction peak (seeing accompanying drawing 4), illustrates that the cinnarizine crystal disappears, and cinnarizine exists with a kind of unformed form.
Example 2: differential thermal analysis (DSC) method:
Testing conditions: instrument: DSC-60100VAC (Japanese Shimadzu company)
Detection cell: AI
Reference: Al 2O 3
Environment: nitrogen
Initial temperature: 50 ℃
Heating rate: 10.00 (℃/min)
Control temperature: 350 ℃
Sample: the sulfobutyl ether-beta-cyclodextrin inclusion compound of the physical mixture of cinnarizine, sulfobutyl ether-beta-cyclodextrin, cinnarizine and adjuvant or incomplete clathrate, cinnarizine, carry out differential thermal analysis.
By the differential thermal analysis collection of illustrative plates as can be known: cinnarizine has obvious absworption peak (seeing accompanying drawing 5) near 119 ℃; Sulfobutyl ether-beta-cyclodextrin does not have absworption peak (seeing accompanying drawing 6); The physical mixture of cinnarizine and adjuvant or the peak of its incomplete clathrate be weak (seeing accompanying drawing 7); The sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine does not have absworption peak (seeing accompanying drawing 8), illustrates that cinnarizine and sulfobutyl ether-beta-cyclodextrin have formed clathrate really.
Determining of ingredient proportion of the present invention:
On the basis of preliminary experiment, select ingredient proportion to be respectively CN: SBE-β-CD=1: 1-10mol; Inclusion method is chosen as freeze-drying and spray drying method; Differentiate with above-mentioned X-ray diffraction method and DSC method whether made sample forms clathrate, in order to select desirable ingredient proportion and inclusion method.Experimental result such as following table.
The different host and guest's molecular proportions of table 1, different preparation method gained enclose result
Learnt by the harmony in the exterior experiment, rate of charge may be selected to be CN: SBE-β-CD=1: 1-10mol; And all can prepare the cinnarizine clathrate with two kinds of enclose modes (freeze-drying and spray drying method).But the enclose ratio is 1: during 1-4, although can form clathrate, the content of cinnarizine is low; When the enclose ratio is 1: during 5-10, cinnarizine content is higher than 98%.Therefore, best proportioning is 1: 5, and this moment, cinnarizine content was high, and the consumption of sulfobutyl ether-beta-cyclodextrin is little.
Two kinds of enclose modes of the present invention (freeze-drying and spray drying method) compare the impact of prepared cinnarizine clathrate:
For comparing two kinds of enclose modes (freeze-drying and spray drying method) to the impact of prepared cinnarizine clathrate, prepare a collection of medicinal liquid by best prescription, prepare the cinnarizine clathrate through freeze-drying and spray drying method respectively, and by content and catabolite before and after the following clathrate analytical method working sample preparation.The results are shown in Table 2.
Table 2 is two kinds of CN clathrates that the enclose mode is prepared relatively
The result: by table as seen, cinnarizine clathrate content and the catabolite prepared through two kinds of enclose modes (freeze-drying and spray drying method) have no significant change before and after preparation.Illustrate that two kinds of enclose modes (freeze-drying and spray drying method) all can be used for preparing the CN clathrate.In addition from outward appearance, character and the preparation process of cinnarizine clathrate as can be known: the sample through the freeze-drying preparation is that white loose solid and dissolubility are good, the standby sample of spray-dried legal system is the white loose powder, dissolubility, flowability are all better, but and continuous mass production.
The mensuration of clathrate dissolubility:
Get clathrate (mol ratio CN: SBE-β-CD=1: 5) and cinnarizine excessive, put in the 10mL aqueous solution, in 25 ℃ of air baths vibration 24h.Treat that dissolving reaches balance, get supernatant with 0.45 μ m filtering with microporous membrane, filtrate dilution suitable multiple is by following clathrate analytical method mensuration cinnarizine content.The dissolubility that calculates cinnarizine is 1.94 μ gmL -1, the dissolubility of clathrate is 15.73mgmL -1SBE-β-CD can make dissolubility improve 8108 times.
The foundation of clathrate analytical method:
Assay and determination of foreign matter method: get clathrate an amount of, dissolve fully and dilute into about containing cinnarizine 16 μ gmL by labelled amount with suitable quantity of water -1Solution, measure according to following chromatographic condition.
Chromatographic condition is: high performance liquid chromatography automatic sampling instrument L-7200, L-7110 pump, L-7420 UV-detector; Chromatographic column: Diamonsil (TM) diamond C 18(4.6mm * 200mm, 5 μ m); Mobile phase: acetonitrile-0.01M Ammonium biphosphate buffer-triethylamine (1000: 900: 13), regulate pH value as 4.70 take phosphoric acid; Detect wavelength: 253nm.The gained standard curve is: Y=26428X+9319.1 (r=0.9999).At 4-200 μ gmL -1In the scope, the cinnarizine peak area becomes the good linear relation with concentration; Precision Experiment and response rate experimental result are all good; Separating degree is up to specification.
Description of drawings:
Fig. 1 is cinnarizine X-ray diffracting spectrum crystal diffraction peak figure.
Fig. 2 is sulfobutyl ether-beta-cyclodextrin crystal diffraction peak collection of illustrative plates.
Fig. 3 is the crystal diffraction peak collection of illustrative plates of the physical mixture of cinnarizine and adjuvant.
Fig. 4 is the sulfobutyl ether-beta-cyclodextrin inclusion compound diffracting spectrum of cinnarizine.
Fig. 5 is the differential thermal analysis collection of illustrative plates of cinnarizine.
Fig. 6 is sulfobutyl ether-beta-cyclodextrin differential thermal analysis collection of illustrative plates.
Fig. 7 is the physical mixture of cinnarizine and adjuvant or the differential thermal analysis collection of illustrative plates of its incomplete clathrate.
Fig. 8 is the sulfobutyl ether-beta-cyclodextrin inclusion compound differential thermal analysis collection of illustrative plates of cinnarizine.
The specific embodiment:
Embodiment 1
The preparation of the sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine
The composition consumption
Cinnarizine 2.7 * 10 -2Mol
Sulfobutyl ether-beta-cyclodextrin 13.4 * 10 -2Mol
Hydrochloric acid is an amount of
Sodium hydroxide is an amount of
The sulfobutyl ether-beta-cyclodextrin of getting recipe quantity is with approximately 600mL water for injection dissolving, and hydrochloric acid is transferred pH to 1.0-2.0.The cinnarizine that other gets recipe quantity adds in the mentioned solution, and stirring and ultrasonic making it are dissolved, and add sodium hydroxide again and transfer pH to 3.0, are inclusion complex in solution.Enclose liquid namely gets white clathrate powder after lyophilization.
Annotate:
1, the amount of cinnarizine can increase and decrease according to concrete condition in the prescription, and scope is not limit.
2, CN in the prescription: it is 1 that SBE-β-CD can select mol ratio: 1-10.
Embodiment 2
The preparation of the sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine
Enclose liquid among the embodiment 1 is spray-dried, obtain white clathrate powder.
Embodiment 3
The preparation (freeze-drying) of clathrate injection powder pin
Enclose liquid among the embodiment 1 is added an amount of proppant or excipient (such as mannitol, sorbitol, xylitol), any or any two or more the mixture of isoosmotic adjusting agent (sodium chloride, citric acid acid etc.)), stirring or (reaching) are ultrasonic, make into homogeneous solution.After adding proper amount of active carbon stirring depyrogenation, filter carbon removal.Use again 0.22 μ m filtering with microporous membrane, add water for injection to 1000mL.Sterile filling is in cillin bottle, and 2mL/ props up, and through lyophilization, the gland of jumping a queue namely gets the injection freeze-dried powder.
Embodiment 4
The preparation (spray drying method) of clathrate injection powder pin
Enclose liquid among the embodiment 1 is spray-dried, the gained powder directly aseptic subpackaged or with appropriate amount of auxiliary materials (such as any or any two or more mixture such as mannitol, sorbitol, xylitol, glucose, sodium chloride) mixing after aseptic subpackaged and get final product.
Embodiment 5
The preparation of cinnarizine tablet
Prescription:
Clathrate 5%-65%
Filler 20%-80%
Binding agent 10%-20%
Disintegrating agent 0.5%-5%
Lubricant 0.3%-1.5%
Preparation technology:
Get the adjuvant mix homogeneously such as clathrate powder in embodiment 1 or 2 and an amount of filler (such as starch, lactose, microcrystalline Cellulose etc.), binding agent (such as PVP, HPMC etc.), disintegrating agent (such as CCNa, PVPP, L-HPC etc.), lubricant (such as magnesium stearate, Pulvis Talci, micropowder silica gel etc.), after crossing 80 mesh sieves, be pressed into bulk or large lamellar with suitable equipment, then it is broken into the granule granulate of suitable size, carries out tabletting and get final product.
Embodiment 6
The preparation of cinnarizine capsule
Prescription:
Clathrate 5%-65%
Filler 20%-80%
Binding agent 10%-20%
Disintegrating agent 0.5%-5%
Lubricant 0.3%-1.5%
Preparation technology:
Get the adjuvant mix homogeneously such as clathrate powder in embodiment 1 or 2 and an amount of filler (such as starch, lactose, microcrystalline Cellulose etc.), binding agent (such as PVP, HPMC etc.), disintegrating agent (such as CCNa, PVPP, L-HPC etc.), lubricant (such as magnesium stearate, Pulvis Talci, micropowder silica gel etc.), after crossing 80 mesh sieves, be filled to suitable capsule and get final product.
Embodiment 7
The preparation of cinnarizine granule
Prescription:
Clathrate 5%-65%
Filler 20%-80%
Binding agent 10%-20%
Disintegrating agent 0.5%-5%
Lubricant 0.3%-1.5%
Correctives is an amount of
Sweeting agent is an amount of
Preparation technology:
Get the adjuvant mix homogeneously such as clathrate powder in embodiment 1 or 2 and an amount of filler (such as starch, lactose, microcrystalline Cellulose etc.), binding agent (such as PVP, HPMC etc.), disintegrating agent (such as CCNa, PVPP, L-HPC etc.), lubricant (such as magnesium stearate, Pulvis Talci, micropowder silica gel etc.), correctives (such as Fructus Citri tangerinae essence etc.) and sweeting agent (such as sucrose, syrup, aspartame etc.), after crossing 80 mesh sieves, be pressed into bulk or large lamellar with suitable equipment, then it is broken into the granule granulate of suitable size, crosses sieve No. four.Carry out classification, remove the powder part, sub-dose packaging gets final product.

Claims (6)

1. the sulfobutyl ether-beta-cyclodextrin inclusion compound of a cinnarizine, it is characterized in that: used enclose material is water miscible beta-cyclodextrin derivative sulfobutyl ether-beta-cyclodextrin, the mol ratio of cinnarizine and sulfobutyl ether-beta-cyclodextrin is 1 in the clathrate: 5-10, and by the following method preparation: get sulfobutyl ether-beta-cyclodextrin, with the suitable quantity of water dissolving, hydrochloric acid is transferred pH to 1.0-2.0; Other gets cinnarizine and adds in the above-mentioned aqueous solution, stir and ultrasonic make it dissolving after, add again sodium hydroxide and transfer pH to 3.0, obtain inclusion complex in solution, namely get the clathrate powder through lyophilization or spray drying.
2. the sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine according to claim 1 is characterized in that, the mol ratio of cinnarizine and sulfobutyl ether-beta-cyclodextrin is 1: 5.
3. comprise the preparation of the sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine claimed in claim 1, it is characterized in that, with the inclusion complex in solution that obtains, add appropriate amount of auxiliary materials, degerming, depyrogenation, sterile filling through lyophilization, namely get the injection freeze-dried powder; With the clathrate powder that obtains, add proper auxiliary materials, make tablet, capsule, granule.
4. comprise the preparation of the sulfobutyl ether-beta-cyclodextrin inclusion compound of cinnarizine claimed in claim 1, it is characterized in that, inclusion complex in solution is spray-dried, the gained powder directly aseptic subpackaged or with the appropriate amount of auxiliary materials mixing after aseptic subpackaged and get final product.
5. preparation according to claim 3, it is characterized in that: described adjuvant comprises one or more in proppant, isoosmotic adjusting agent, filler, binding agent, disintegrating agent, lubricant, correctives or the sweeting agent.
6. preparation according to claim 5, it is characterized in that: described proppant is selected from mannitol, sorbitol, xylitol; Isoosmotic adjusting agent is selected from sodium chloride, the acid of structure rafter; Filler is selected from starch, lactose, microcrystalline Cellulose; Binding agent is selected from PVP, HPMC; Disintegrating agent is selected from PVPP, L-HPC; Lubricant is selected from magnesium stearate, Pulvis Talci, micropowder silica gel; Correctives is selected from Fructus Citri tangerinae essence; Sweeting agent is selected from sucrose, syrup, aspartame.
CN2008100113485A 2008-05-09 2008-05-09 Sulphur butyl ether-beta-cyclodextrin clathrate compound of cinnarizine, formulated product and preparation method thereof Expired - Fee Related CN101314045B (en)

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