Background technology
Ibuprofen BP/EP is effective PGSI, have antipyretic, analgesia and anti-inflammatory action; Almost insoluble in water, easily molten in sodium hydroxide or sodium carbonate test solution.Oral easy absorption, through rectal absorption after medication, Tmax(represent from after taking medicine reach the peak value time used to Plasma Concentration) be about 0.92 ± 0.33h, during consumption 200mg, Plasma Concentration is 22 μ g/ml ~ 27 μ g/ml; Be 23 μ g/ml ~ 45 μ g/ml during consumption 400mg; Be 43 μ g/ml ~ 57 μ g/ml during consumption 600mg.Transformation period T after a drug
1/2be generally 1.82h.
Pseudoephedrine hydrochloride has optionally vasoconstriction effect, eliminates pharynx nasalis mucous hyperemia, swelling, alleviates the symptoms such as nasal obstruction, very easily dissolve in water, and absorbed following oral administration is fast, T
maxfor about 1h, between 0.5 ~ 2h, mean blood plasma concentration is 274 ± 33 μ g/ml, mean half-life (T
1/2) be 4.35h.
Chlorpheniramine maleate is collaborative alleviates nasal decongestion, has certain drowsiness and anticholinergic side effects, easily molten in water, and oral comparatively slow through gastrointestinal absorption, bioavailability is about 25% ~ 50%, 15 ~ 60min onset after oral, T
maxbe 3 ~ 6h, transformation period (T
1/2) be 12 ~ 15h.
In treatment flu process, above three kinds of medicines one work and can alleviate cold symptoms from different perspectives, headache, heating that especially alleviating catches a cold causes simultaneously, have a stuffy nose, have aches in the limbs and the various symptom such as swelling and pain in the throat.But due to above three kinds of medicine absorptions separately, transformation period difference, three's plasma concentration curve is made to differ larger, can not treatment concentration be reached at identical or similar time simultaneously and keep certain hour, so above three kinds of medicines respectively simultaneously, take with same number every day, the medicine of long half time then may be caused not eliminate in time, thus accumulate in vivo, cause the generation of some side effects; Transformation period short medicine then can not maintain effective blood drug concentration, does not reach result for the treatment of.
The compound medicine comprising above three kinds of active constituents of medicine at present goes on the market in the U.S., it is the ordinary preparation adopting conventional traditional preparation process obtained, this compound medicine takes three times in one day, take number of times more, and it is equally due to these three kinds of medicine absorptions separately, transformation period difference, each active constituents of medicine release is unbalanced, and drug effect is undesirable.
Application number be 200910191072.8 Chinese patent application disclose a kind of compound medicine and the preparation technology thereof that treat flu.It includes the Ibuprofen BP/EP of effective amount, pseudoephedrine hydrochloride and chlorpheniramine maleate activeconstituents, and appropriate pharmaceutical excipient, wherein: the Ibuprofen BP/EP of part significant quantity and the pseudoephedrine hydrochloride of significant quantity are made sustained release preparation; The Ibuprofen BP/EP of surplus and the chlorpheniramine maleate of significant quantity are made quick releasing formulation; Again sustained release preparation and quick releasing formulation are made various pharmaceutical preparation routinely.The present invention adopts slow release method and quick-release technology, effectively control three kinds of different pharmaceutical activeconstituentss absorbing in vivo, make the time consistency that the Plasma Concentration of these three kinds of active constituents of medicine reaches effective concentration and disappears, thus the collaborative drug effect enhancing compound medicine of the present invention, improve the bioavailability of compound medicine of the present invention.
Although aforesaid method controls three kinds of different pharmaceutical activeconstituentss absorbing in vivo effectively, make the time consistency that the Plasma Concentration of these three kinds of active constituents of medicine reaches effective concentration and disappears, but should slow release method be used, use quick-release technology again, its preparation method is complicated.In view of this, special proposition the present invention.
Summary of the invention
The first object of the present invention is to provide a kind of chlorpheniramine maleate compound.
The second object of the present invention is to provide a kind of pharmaceutical composition, containing chlorpheniramine maleate compound of the present invention in described pharmaceutical composition.
The third object of the present invention is to provide the preparation method of described pharmaceutical composition.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
Chlorpheniramine maleate compound shown in a kind of formula (I), is characterized in that, described chlorpheniramine maleate compound powder x-ray diffraction assay method measures, and the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1;
Comprise in the compound medicine of Ibuprofen BP/EP, pseudoephedrine hydrochloride and chlorpheniramine maleate three kinds of active constituents of medicine, because Ibuprofen BP/EP peak time is short, the transformation period is short, pseudoephedrine hydrochloride peak time is shorter, the transformation period is shorter, and chlorpheniramine maleate peak time is long, long half time, if above three kinds of medicines respectively simultaneously, take with same number every day, the medicine of long half time then may be caused not eliminate in time, thus accumulate in vivo, cause the generation of some side effects; Transformation period short medicine then can not maintain effective blood drug concentration, does not reach result for the treatment of.Polymorph in pharmaceuticals investigation and application is in the formulation extensive, and by changing crystal habit and the crystal formation of medicine, for the stability of medicine, solubleness and dissolution rate, bioavailability etc. have impact.The present invention is after having carried out large quantifier elimination to chlorpheniramine maleate bulk drug, a kind of crystal compound of chlorpheniramine maleate has been obtained by constantly changing crystallization condition, and pass through pharmacodynamics test, surprisingly find that peak time and the transformation period of that the quick middle chlorphenamine of ibuprofen and pseudoephedrine adopting the crystal compound of this chlorpheniramine maleate to obtain obtain obvious shortening, decrease chlorphenamine and Ibuprofen BP/EP and pseudoephedrine hydrochloride in peak time and the gap on the transformation period, the Plasma Concentration of these three kinds of active constituents of medicine is made to reach effective concentration as far as possible consistent with the time of disappearing.
In the present invention, described chlorpheniramine maleate compound is adopted and is prepared with the following method:
1) crude product solution is prepared: added by chlorpheniramine maleate crude product by chloroform and the formulated mixed solvent of ethanol, be heated to 40 ~ 60 DEG C, be stirred to dissolve, cross and filter particulate matter, obtain crude product solution, for subsequent use;
2) recrystallisation solvent is prepared: by the proportions recrystallisation solvent of acetone and ether 0.5 ~ 1.5:10 by volume, described recrystallisation solvent volume is 8 ~ 12 times of chlorpheniramine maleate crude product weight;
3) crystallization: under stirring, in the crude product solution of step 1) gained, stream adds step 2) gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip ether, the volume of dropping is 3 ~ 7 times of chlorpheniramine maleate crude product weight, and whole dropping process control solution temperature is 40 ~ 60 DEG C; Drip and finish, be cooled to 3 ~ 8 DEG C and leave standstill 2 ~ 4h, filter, washing, dry, obtain described chlorpheniramine maleate crystalline compounds.
In the present invention, chlorpheniramine maleate crude product can adopt the method for prior art to prepare, and also can be commercially available chlorpheniramine maleate.
A kind of chlorpheniramine maleate crystalline compounds that adopted preparation method of the present invention to obtain, this crystalline compounds powder x-ray diffraction assay method measures, and the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
As preferred version of the present invention, in above-mentioned preparation method, wherein, the weightmeasurement ratio of the crude product of chlorpheniramine maleate described in step 1) and described mixed solvent is 1:5 ~ 10.
In described mixed solvent, the volume ratio of chloroform and ethanol is 1:5 ~ 7.
In step 3), stream adds step 2) gained recrystallisation solvent time stirring velocity be 250 ~ 300r/min; Stirring velocity when dripping ether is 120 ~ 180r/min.
The speed that described stream adds is 10 ~ 15ml/min; The speed of described dropping is 5 ~ 8ml/min.
In the present invention alleged " weight " unit be gram or kilogram, " volume " unit corresponding is with it milliliter or liter, and namely when the weight unit of chlorpheniramine maleate crude product use is gram, in operating process, the volume unit of solvent is milliliter; When the weight unit that chlorpheniramine maleate crude product uses be kilogram, in operating process solvent volume unit for liter.
For realizing the second object of the present invention, the present invention adopts following technical scheme:
A kind of pharmaceutical composition, wherein, described pharmaceutical composition contains chlorpheniramine maleate compound of the present invention.
Described pharmaceutical composition is also containing Ibuprofen BP/EP and pseudoephedrine hydrochloride two kinds of active constituents of medicine, and wherein, in described pharmaceutical composition, the mass ratio of chlorpheniramine maleate compound and Ibuprofen BP/EP and pseudoephedrine hydrochloride is 2:200:30.
Further described pharmaceutical composition is the ibuprofen and pseudoephedrine that quick obtained by chlorpheniramine maleate compound, Ibuprofen BP/EP and pseudoephedrine hydrochloride three kinds of active constituents of medicine and pharmaceutically acceptable auxiliary material.
Further, every 1000 feed composition comprising following weight part of described ibuprofen and pseudoephedrine that quick:
As a kind of preferred version, every 1000 feed composition comprising following weight part of described ibuprofen and pseudoephedrine that quick:
In the present invention, that feed composition of quick of described ibuprofen and pseudoephedrine also comprises coating material.
Described coating material is the coating liquid that film coating pre-mix dose and purified water are made.
For realizing the third object of the present invention, the present invention adopts following technical scheme:
A preparation method for pharmaceutical composition of the present invention, wherein, described preparation method comprises the following steps:
(1) supplementary material is taken by described consumption; Ibuprofen BP/EP, pseudoephedrine hydrochloride are pulverized, makes it all by 80 mesh sieves, for subsequent use; Chlorpheniramine maleate was pulverized 100 mesh sieves, for subsequent use;
(2) tackiness agent is prepared: separately get starch appropriate, add purified water, be uniformly mixed obtained starch suspension; The polysorbate of described consumption to be joined in appropriate purified water and after boiling, under agitation to join in starch suspension, obtain starch paste, preparing 10% starch paste, let cool to 50-60 DEG C for subsequent use;
(3) Microcrystalline Cellulose getting consumption described in chlorpheniramine maleate and 2/3 is mixed to get powder mix A by equivalent dilution method;
(4) powder mix A and sodium starch glycolate, hydroxypropylcellulose, starch, pseudoephedrine hydrochloride and Ibuprofen BP/EP premix are obtained powder mix B;
(5) 10% starch paste prepared in step (2) is joined softwood processed in powder mix B; Obtained softwood to be sieved granulation, obtain wet granular;
(6) wet grain drying made is not more than 2.5% to pellet moisture, discharging must do particle; By whole for dried pellet through sieves grain, obtain that quick dry particle of ibuprofen and pseudoephedrine;
(7) by obtained dry particle and Magnesium Stearate and remaining Microcrystalline Cellulose always mixed compressing tablet afterwards and get final product.
In the present invention, described preparation method also comprises and further the ibuprofen and pseudoephedrine of gained that quick is carried out dressing.
In the present invention, described dressing is that the coating liquid adopting film coating pre-mix dose and purified water to make carries out dressing.
Compared with prior art, the present invention has obtained a kind of crystal compound being different from the chlorpheniramine maleate of prior art, and pass through pharmacodynamics test, surprisingly find that peak time and the transformation period of that the quick middle chlorphenamine of ibuprofen and pseudoephedrine adopting the crystal compound of this chlorpheniramine maleate to obtain obtain obvious shortening, reduce chlorphenamine and Ibuprofen BP/EP and pseudoephedrine hydrochloride in peak time and the gap on the transformation period, the Plasma Concentration of these three kinds of active constituents of medicine is made to reach effective concentration as far as possible consistent with the time of disappearing, thus collaborative enhance that drug effect of quick of ibuprofen and pseudoephedrine of the present invention.
Embodiment
The specific embodiment of the present invention is only limitted to further explain and the present invention is described, does not limit Composition of contents of the present invention.
The preparation of [embodiment 1] chlorpheniramine maleate compound
1) crude product solution is prepared: added by chlorpheniramine maleate crude product by chloroform and the formulated mixed solvent of ethanol, be heated to 50 DEG C, be stirred to dissolve, cross and filter particulate matter, obtain crude product solution, for subsequent use;
2) recrystallisation solvent is prepared: by the proportions recrystallisation solvent of acetone and ether 1.0:10 by volume, described recrystallisation solvent volume is 10 times of chlorpheniramine maleate crude product weight;
3) crystallization: under stirring, in the crude product solution of step 1) gained, stream adds step 2) gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip ether, the volume of dropping is 4 times of chlorpheniramine maleate crude product weight, and whole dropping process control solution temperature is 50 DEG C; Drip and finish, be cooled to 5 DEG C of standing 3h, filter, washing, dry, obtain described chlorpheniramine maleate crystalline compounds.
The chlorpheniramine maleate compound powder x-ray diffraction assay method obtained measured, the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
Be below embodiments of the invention 2-9, step is with embodiment 1, and concrete technology parameter is in table 1:
Table 1, embodiment 2-9
The chlorpheniramine maleate compound powder x-ray diffraction assay method obtained by embodiment 2-9 measures, and the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle is with embodiment 1.
That the quick preparation of [example of formulations 1] ibuprofen and pseudoephedrine
Prescription:
Element sheet:
Preparation method:
(1) supplementary material is taken by described consumption; Ibuprofen BP/EP, pseudoephedrine hydrochloride are pulverized, makes it all by 80 mesh sieves, for subsequent use; Chlorpheniramine maleate was pulverized 100 mesh sieves, for subsequent use;
(2) tackiness agent is prepared: separately get starch 12.1g, add 18.15g purified water, be uniformly mixed obtained starch suspension; 1.8g Polysorbate 80 to be joined in 102.85g purified water and after boiling, under agitation join in starch suspension, obtain starch paste, weigh, deduct actual weight with theoretical weight 134.9g, calculate the purified water of loss in process of heating up water, loss part is added to theoretical amount, obtained 10% starch paste, let cool to 50-60 DEG C for subsequent use;
(3) Microcrystalline Cellulose getting consumption described in chlorpheniramine maleate and 2/3 is mixed to get powder mix A by equivalent dilution method;
(4) powder mix A and sodium starch glycolate, hydroxypropylcellulose, starch, pseudoephedrine hydrochloride and Ibuprofen BP/EP premix are obtained powder mix B;
(5) 10% starch paste prepared in step (2) is joined softwood processed in powder mix B; Obtained softwood to be sieved granulation, obtain wet granular;
(6) wet grain drying made is not more than 2.5% to pellet moisture, discharging must do particle; By whole for dried pellet through sieves grain, obtain that quick dry particle of ibuprofen and pseudoephedrine;
(7) by obtained dry particle and Magnesium Stearate and remaining Microcrystalline Cellulose always mixed compressing tablet afterwards and get final product.
That the quick preparation of [example of formulations 2] ibuprofen and pseudoephedrine
Prescription:
Element sheet:
Coating liquid:
Film coating pre-mix dose (85G68918 type) 7.2g
Purified water 28.8g
Preparation method:
(1) supplementary material is taken by described consumption; Ibuprofen BP/EP, pseudoephedrine hydrochloride are pulverized, makes it all by 80 mesh sieves, for subsequent use; Chlorpheniramine maleate was pulverized 100 mesh sieves, for subsequent use;
(2) tackiness agent is prepared: with example of formulations 1;
(3) Microcrystalline Cellulose getting consumption described in chlorpheniramine maleate and 2/3 is mixed to get powder mix A by equivalent dilution method;
(4) powder mix A and sodium starch glycolate, hydroxypropylcellulose, starch, pseudoephedrine hydrochloride and Ibuprofen BP/EP premix are obtained powder mix B;
(5) 10% starch paste prepared in step (2) is joined softwood processed in powder mix B; Obtained softwood to be sieved granulation, obtain wet granular;
(6) wet grain drying made is not more than 2.5% to pellet moisture, discharging must do particle; By whole for dried pellet through sieves grain, obtain that quick dry particle of ibuprofen and pseudoephedrine;
(7) by obtained dry particle and Magnesium Stearate and remaining Microcrystalline Cellulose always mixed compressing tablet afterwards obtain plain sheet;
(8) carry out dressing, coating weight gain about 1% with the plain sheet of coating liquid to gained that film coating pre-mix dose and the purified water of recipe quantity are made, obtain described ibuprofen and pseudoephedrine that quick.
That the quick preparation of [example of formulations 3] ibuprofen and pseudoephedrine
Prescription:
Preparation method: with example of formulations 1.
That the quick preparation of [example of formulations 4] ibuprofen and pseudoephedrine
Prescription:
Preparation method: with example of formulations 1.
That the quick preparation of [example of formulations 5] ibuprofen and pseudoephedrine
Prescription:
Element sheet:
Coating liquid:
Film coating pre-mix dose (85G68918 type) 7.2g
Purified water 28.8g
Preparation method: with example of formulations 2.
That the quick preparation of [example of formulations 6] ibuprofen and pseudoephedrine
Prescription:
Element sheet:
Coating liquid:
Film coating pre-mix dose (85G68918 type) 7.2g
Purified water 28.8g
Preparation method: with example of formulations 2.
That the quick preparation of [example of formulations 7] ibuprofen and pseudoephedrine
Prescription:
Element sheet:
Coating liquid:
Film coating pre-mix dose (85G68918 type) 7.2g
Purified water 28.8g
Preparation method: with example of formulations 2.
That the quick preparation of [example of formulations 8] ibuprofen and pseudoephedrine
Prescription:
Element sheet:
Coating liquid:
Film coating pre-mix dose (85G68918 type) 7.2g
Purified water 28.8g
Preparation method: with example of formulations 2.
Test example 1, pharmacodynamics test
1, materials and methods
1.1 medicines and reagent
By test preparation: the ibuprofen and pseudoephedrine that quick (every sheet is containing Ibuprofen BP/EP 200mg, pseudoephedrine 30mg, chlorphenamine 2mg) adopting the method for invention formulation embodiment 2 obtained; Reference preparation: (every sheet is containing Ibuprofen BP/EP 200mg for the ibuprofen and pseudoephedrine that quick adopting the prescription of invention formulation embodiment 2 and preparation method to obtain, pseudoephedrine 30mg, chlorphenamine 2mg, difference is chlorpheniramine maleate used is commercially available bulk drug).Ibuprofen BP/EP standard substance (Nat'l Pharmaceutical & Biological Products Control Institute, lot number: 100179-200303), chlorphenamine reference substance (Nat'l Pharmaceutical & Biological Products Control Institute, lot number: 100047-200606, content: 99.7%), pseudoephedrine control product (Nat'l Pharmaceutical & Biological Products Control Institute, lot number: 171237-200505), interior mark imipramine (Hunan Dongting Pharmaceutical Co., Ltd., lot number: 071101).Chromatographic Pure Methanol, acetonitrile and tertbutyl methyl miaow (MTBE) are purchased from Guangzhou Di Ma company, and experimental water is distilled water, and all the other reagent are analytical pure.
Instrument: Shimadzu LC-20A chromatograph system, comprises CBM-20Alite central controller, LC-20AT infusion pump, CTO-20A column oven, SIL-20A automatic sampler, SPD detector and LCsolution workstation; Waters2695 type high performance liquid chromatograph, band automatic sampler and column oven, Waters, US; MassLynx4.1 software, Waters, US; AB-265S type precision balance, Japanese Mei Tele company; Eddy mixer, Shanghai Hu Xi analytical instrument factory.
Study subject
20 men's health experimenters, the age is (25.2 ± 2.0) year, and body weight is (64 ± 4) kg, and height is (172 ± 3) cm, without habits of smoking and alcohol drinking.No abnormal through disease history inquire, physical examination and laboratory examination (comprising blood, routine urinalysis, Liver and kidney function inspection) before test.Experimenter's medicine-less allergy history and pharmacological dependence history, the medical history that is a cup too low and other chronic medical histories.Do not take any medicine in 2wk, tested period unifies light diet.This test is through The Third Xiangya Hospital of Central South University's Medical Ethics Committee approval, and experimenter all signs Informed Consent Form.
1.2 testing programs and blood specimen collection
20 experimenters are divided into 2 groups at random, and dicycle intersects to be taken by test preparation 1 or reference preparation 1, and the cleaning phase is 2wk.Experimenter is fasting after 12h light diet before test, and test oral test preparation or reference preparation on an empty stomach in early morning on the same day, takes with warm water 300mL.Take medicine after 2h and can drink water, unifiedly after 4h and 10h to have meal.Experimenter before taking medicine and after taking medicine 0.25,0.5,1.0,1.5,2.0,3.0,4.0,6.0,8.0,12.0,24.0,36.0,48.0h gets blood 5mL from ulnar vein respectively, puts in calparine pipe, immediately centrifugal separation plasma, frozen for subsequent use at putting-20 DEG C.
1.2.1 the mensuration of ibuprofen concentration in blood plasma
1.2.1.1, plasma sample process
Get blood plasma 200 μ L, add methyl alcohol 400 μ L, vortex 2min, then with the centrifugal 10min of 13000 × g, get the analysis of supernatant liquor 40 μ L sample introduction.
1.2.1.2, chromatographic condition
Chromatographic column: Féraud door Synergi4uPolar-RP(250mm × 4.6mm, 4 μm), column temperature: 40 DEG C, determined wavelength: 220nm, moving phase: acetonitrile-20mmolL
-1phosphate buffered saline buffer (pH=4.0) (27:73, V/V), flow velocity: 1.0mLmin
-1.
1.2.2 the mensuration of chlorphenamine and pseudoephedrine concentration in blood plasma
1.2.2.1, plasma sample process
Get blood plasma 200 μ L, add 113 μ gL
-1imipramine (interior mark) 50 μ L, adds MTBE600 μ L after mixing, vortex concussion 2min, then with the centrifugal 10min of 13000 × g, in transfer supernatant liquor 400 μ L to new EP pipe, volatilizes, then dissolves by 200 μ L moving phases, get 20 μ L sample introductions in 40 DEG C of water-bath nitrogen.
1.2.2.2, chromatographic condition
Chromatographic column is Féraud door ThermoHypurityC18 post (50mm × 2.1mm, 5 μm), and moving phase is methyl alcohol-20mmolL
-1ammonium formate solution (formic acid containing 0.1%) (70: 30, V/V), flow velocity is 0.25mLmin
-1, column temperature is 40 DEG C, automatic sampling bottle temperature 15 DEG C.
1.2.2.3, Mass Spectrometry Conditions
Ion source is ESI, capillary voltage: 3500V, source temperature: 100 DEG C, desolventizing gas temperature: 350 DEG C, taper hole gas flow rate: 50Lh
-1, desolventizing gas flow rate: 350Lh
-1, collision air pressure: 4.0 × 10
-3pSI; Detection mode positive ion polyion reaction monitoring (MRM).Ionic reaction for quantitative analysis is respectively m/z275.2 → m/z230.2(chlorphenamine), m/z166.5 → m/z148.5(pseudoephedrine) and the interior mark of m/z281.3 → m/z85.7(, imipramine); Collision energy is respectively 20V(chlorphenamine), 15V(pseudoephedrine) and 20V(in mark, imipramine), residence time is 300ms.
2, determination of plasma concentration result
In process of the test, 20 people all complete test by scheme.These 20 health volunteers are intersected after oral test preparation and reference preparation, and the mean blood plasma concentration-time curve of Ibuprofen BP/EP, pseudoephedrine and chlorphenamine is shown in Fig. 2-a, Fig. 2-b and Fig. 2-c respectively.
As can be seen from Fig. 2-a and Fig. 2-b, compared with the reference preparation obtained with adopting commercially available chlorpheniramine maleate bulk drug, what adopt chlorpheniramine maleate of the present invention to obtain is similar with the mean blood plasma concentration-time curve of pseudoephedrine by Ibuprofen BP/EP in test preparation, and as can be seen from the mean blood plasma concentration-time curve (Fig. 2-c) of chlorphenamine, what adopt chlorpheniramine maleate of the present invention to obtain is short by the peak time of chlorphenamine in test preparation, thus the collaborative drug effect strengthening compound medicine of the present invention.
The ibuprofen and pseudoephedrine that quick slice obtained to other example of formulations of the present invention has also carried out above-mentioned test, and its result obtained is similar.