CN102335178B - Oral solid pharmaceutical composition and preparation method thereof - Google Patents
Oral solid pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN102335178B CN102335178B CN 201110197317 CN201110197317A CN102335178B CN 102335178 B CN102335178 B CN 102335178B CN 201110197317 CN201110197317 CN 201110197317 CN 201110197317 A CN201110197317 A CN 201110197317A CN 102335178 B CN102335178 B CN 102335178B
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- hydrochlorothiazide
- levamlodipine
- pharmaceutical composition
- olmesartan medoxomil
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- 229960002003 hydrochlorothiazide Drugs 0.000 claims abstract description 174
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Abstract
The invention discloses a brand-new oral solid pharmaceutical composition. The pharmaceutical composition is an oral preparation prepared from hydrochlorothiazide, l-amlodipine, olmesartan medoxomil and pharmaceutically acceptable auxiliary materials, and the oral preparation comprises but is not limited to tablets or capsules. The composition comprises the following raw materials in parts by weight: 5-25 parts of hydrochlorothiazide, 2.5-5 parts of l-amlodipine, 20-40 parts of olmesartan medoxomil, 40-120 parts of microcrystalline cellulose, 30-90 parts of pregelatinized starch, 15-40 parts of low-substituted hydroxypropyl cellulose, 10-45 parts of crosslinked polyvinylpyrrolidone, 3-8 parts of silica and 1-2 parts of magnesium stearate. The pharmaceutical composition disclosed by the invention has the advantages of scientific and reasonable prescription, low auxiliary material content and high bioavailability, and is a drug of first choice for treating hypertension.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of medicinal composition and method of making the same of brand-new oral administration solid that comprises hydrochlorothiazide, olmesartan medoxomil and Levamlodipine.
Background technology
Hypertension is modal cardiovascular disease, is the great public health difficult problem in the global range.China 1991 has carried out sample census to 940,000 crowds more than 15 years old, and statistics shows: China's hypertension prevalence has reached 11.26%, and than increasing 25% in the period of the 1979-1990 10, the existing hyperpietic of China surpasses 1.3 hundred million.And the impetus of this rising is still continuing.Statistics shows that also hypertension therapeutic rate city is 17.4%, and the rural area is 5.4%; Control rate (through treatment systolic pressure＜140mmHg, diastolic pressure＜90mmHg) only 2.9%.Can find out that from above-mentioned statistics China's hypertension prevalence constantly increases, but treatment rate, control rate are low, form huge contrast.According to the WHO prediction, will account for 79% of China's cause of death to the year two thousand twenty noninfectious, wherein the cardiovascular diseases will account for the first place.In order to contain the arrival on this cardiovascular diseases peak, carry out the control of hypertension energetically, the active treatment hyperpietic, very urgent.
The bad hypertension of long-term control can produce grievous injury to target organs such as the heart, brain, kidneys; Actively main cardiovascular diseases's M & M can be significantly lowered in the blood pressure lowering treatment, and most hypertensive patients need use the depressor could be with controlling of blood pressure in ideal target blood pressure level.The evidence-based medicine EBM evidence shows, low dose of Combined application variety classes antihypertensive drugs is better and untoward reaction is less with heavy dose of a certain medicine antihypertensive effect than single.Therapeutic alliance can improve efficacy of antihypertensive treatment, in the untoward reaction that causes with different pharmaceutical, blood pressure reduces the compensation response that triggers when preventing single therapy, increases patient's toleration, improves compliance.
Levamlodipine belongs to long-acting dihydropyridine (DHP) type calcium antagonists; On the amlodipine basis, split out; Its drug effect is 2 times of racemic amlodipine, and Levamlodipine has the effect of protection EH patient renal function, not only depends on the decline of system's blood pressure.Also because the afferent glomerular arteriole of nephrectasia bead lastingly of this medicine; Improve the kidney ischemia, stop the disorder of kidney blood vessel and glomerule 26S Proteasome Structure and Function, alleviate the kidney hypertrophy; Reducing mesenteric tissue catches macromolecular substances; Suppress free radical and form, weaken the somatomedin mitosis reaction, improve the mitochondrial calcium load and reduce the nephron metabolism all useful kidney.Levamlodipine possess onset slowly, long action time, characteristics that the paddy p-ratio is high, the clinical treatment that has been widely used in cardiovascular and cerebrovascular diseases such as hypertension, angina pectoris.Levamlodipine can change the VSMC calcium ion and stride the film transfer, reduces flow of calcium ions, makes cardiac muscle and vascular smooth muscle relaxation; Regulate the picked-up of vascular endothelial cell, smooth muscle cell and macrophage to lipoprotein; Regulate cellular cholesterol for body, reduce the deposition of cholesterol, suppress the short vascular smooth muscle hypertrophy of somatomedin at arterial wall; The mononuclear cell that slows down is invaded profit and platelet aggregation; Increase erythrocyte deformability, blood viscosity lowering delays atherosclerotic formation and development.Levamlodipine mainly acts on all blood vessels; Also can act on coronary artery and renal artery, slow with the acceptor site effect, vasorelaxation action is steady; Conducting system of heart and myocardial contraction all there is not the obvious suppression effect; Can reduce cardiac load, reverse ventricular hypertrophy, and blood glucose, blood fat and serum electrolyte are had no adverse effects.
Levamlodipine is a calcium channel blocker of new generation, clinical treatment hypertension, angina pectoris and the correction Atheromatosis reason state of being mainly used in.Dihydropyridine calcium channel blocker is one of the most frequently used clinically cardiovascular drugs, is widely used in the treatment of cardiovascular disease such as hypertension, angina pectoris and arrhythmia.Along with the research to dihydropyridine calcium channel blocker deepens continuously, find that all dihydropyridine calcium channel blockers all have chiral structure except that nifedipine, and its enantiomer biological activity is usually different in recent years, in addition opposite.Amlodipine (amlodipine) is clinical dihydropyridine calcium channel blocker commonly used, has left-handed and two kinds of enantiomer of dextrorotation.Levamlodipine is the renewal product of amlodipine, obtains through chiral separation technology, and is nontoxic and hypotensive effect arranged, and R toxicity is big and do not have a hypotensive effect.Therefore, Levamlodipine maybe be more effective than amlodipine, and safety is higher.Levamlodipine possess onset slowly, long action time, characteristics that the paddy p-ratio is high, the clinical treatment that has been widely used in cardiovascular and cerebrovascular diseases such as hypertension, angina pectoris.
The benzenesulfonic acid Levamlodipine Besylate, chemical name: (s) (-) 3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate.Molecular formula: C20H25N2O5ClC6H6O3S, molecular weight: 567.1.
Olmesartan medoxomil is a kind of comparatively ideal anti-high I blood pressure medicine, and various high pressure is all had better curative effect, and its outstanding feature is that the half-life is longer, can be in one day effective controlling blood pressure, it is comparatively convenient therefore to take.Compare with other angiotensin ii receptor antagonist class medicine simultaneously.Have that dosage is little, rapid-action, hypotensive effect is stronger and lasting, obvious advantage such as incidence rate of adverse reaction is low.Clinical research shows: olmesartan medoxomil can also be taken to reach better therapeutic effect with other depressor simultaneously.In addition, Olmesartan all has better effect to arteriosclerosis, myocardial hypertrophy, heart failure, diabetes, nephropathy etc.
Hydrochlorothiazide is the diuretic that acts on tubular distal of extensive use clinically; Mechanism of action mainly suppresses the heavily absorption to sodium chloride of distal tubule leading portion and proximal tubule (acting on lighter); Thereby increase the Na+-K+ exchange of distal tubule and collecting tubule, the K+ secretion increasing.Except that the effect of diuresis row sodium, also have the outer mechanism of action of kidney to participate in blood pressure lowering.Be applicable to edema and hypertensive treatment, can effectively control moderate hypertension, adverse reaction rate is low.
Medical evidence shows, low dose of Combined application variety classes antihypertensive drugs is better and untoward reaction is less with heavy dose of a certain medicine antihypertensive effect than single.Therapeutic alliance can improve efficacy of antihypertensive treatment, in the untoward reaction that causes with different pharmaceutical, blood pressure reduces the compensation response that triggers when preventing single therapy, increases patient's toleration, improves compliance.
Levamlodipine or its salt are dihydropyridine calcium channel blocker of new generation (CCB) like Levamlodipine besylate; And olmesartan medoxomil is a kind of angiotensin receptor blocker (ARB).Both all have effects such as blood pressure lowering, expansion blood vessel, can be used for preventing and treating cardiovascular system diseases such as hypertension, coronary heart disease, heart failure.
Existing research shows that CCB and ARB share can have certain synergism, discloses the compound antihypertensive drug of a kind of amlodipine and irbesartan like patent documentation CNZL03150996.7; CN1765362A discloses a kind of compositions that comprises amlodipine and angiotensin ii receptor antagonist (ARB), and the weight proportion of wherein having mentioned amlodipine and candesartan Cilexetil is 1: 10-10: 1; WO2006/034631 discloses the compositions of a kind of amlodipine and ARB; CN200610081591.5 discloses a kind of pharmaceutical composition that comprises the treatment hypertension and cardiovascular disease of Levamlodipine officinal salt and ARB.
Most of hyperpietics need more than one antihypertensive to come controlling blood pressure, and the serious hyperpietic of minority needs 3 kinds or the next strict controlling blood pressure of more medicine.Prior art discloses hydrochlorothiazide, Levamlodipine and olmesartan medoxomil three coupling and has treated hypertensive technical scheme; Normally adopt the tablet take two or three; Like hydrochlorothiazide olmesartan medoxomil compound recipe sheet+amlodipine sheet or hydrochlorothiazide tablet+amlodipine sheet+olmesartan medoxomil sheet; And find that in the actual clinical test the above-mentioned mode one of taking is that dosage is big, especially the hyperpietic is generally the old people; Take medicine at every turn and all must take at least two or three and bring inconvenience, also serious consequence possibly occur in case missed wherein certain to the old people; The 2nd, because every kind of tablet all contains a large amount of adjuvants, different auxiliary materials produces Different Effects to the release of active constituents of medicine, is difficult to control three kinds of active component after taking and discharges with ideal speed, influences therapeutic effect.Therefore, a kind of compound medicinal formulation that contains three components of exploitation is significant.
China application 201010234033.4 discloses a kind of compound preparation that hypertension contains amlodipine and Olmesartan of treating, and described preparation includes following composition: amlodipine or amlodipine officinal salt, hydrochlorothiazide, Olmesartan or its officinal salt be Main Ingredients and Appearance, be equipped with pharmaceutically suitable carrier composition.Advantage of the present invention: be to give full play to the complementary mechanism of action of medicine according to drug combination to increase curative effect, up to standard fast, make the blood pressure compliance rate reach 80.25%, help reducing and the relevant untoward reaction of a certain dosage increase, keep the time of longer effect.But do not provide concrete embodiment in the above-mentioned application, one skilled in the art will appreciate that for certain preparation; Especially novel compound preparation, different auxiliary materials and consumption have a strong impact on the curative effect of medicine, therefore; Though above-mentioned application puts forward the three is prepared together the technical scheme of compound preparation, it does not provide the prescription of any compound preparation, does not propose in addition adjuvant is made any improvement yet; The enlightenment that those skilled in the art obtain only is that the tablet that simply will contain two of above-mentioned three kinds of active component or three is made of one; Such adjuvant content is big, has reduced drug effect on the contrary, also causes simultaneously patient's difficulty of taking medicine.
In view of this, special proposition the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of brand-new oral administration solid medicinal compositions; The oral formulations of described Pharmaceutical composition for being prepared from acceptable auxiliary on hydrochlorothiazide, Levamlodipine, olmesartan medoxomil and the pharmaceutics, described oral formulations includes, but are not limited to be tablet or capsule.Levamlodipine of the present invention includes but not limited to acid group such as benzenesulfonic acid, maleic acid, L-Aspartic Acid and the crystal that forms with Levamlodipine thereof, the crystal of preferred benzenesulfonic acid and Levamlodipine formation.
Compositions of the present invention contains following raw material by weight: hydrochlorothiazide 5-25 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 20-40 weight portion, microcrystalline Cellulose 40～120 weight portions, amylum pregelatinisatum 30～90 weight portions, low-substituted hydroxypropyl cellulose 15～40 weight portions, crospolyvinylpyrrolidone 10～45 weight portions, silicon dioxide 3-8 weight portion and magnesium stearate 1-2 weight portion.
Preferably: hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 20 weight portions, microcrystalline Cellulose 40～60 weight portions, amylum pregelatinisatum 40～60 weight portions, low-substituted hydroxypropyl cellulose 25～40 weight portions, crospolyvinylpyrrolidone 30～45 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 40 weight portions, microcrystalline Cellulose 70～120 weight portions, amylum pregelatinisatum 50～90 weight portions, low-substituted hydroxypropyl cellulose 25～40 weight portions, crospolyvinylpyrrolidone 30～45 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
More preferably: hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, olmesartan medoxomil 20 weight portions, microcrystalline Cellulose 50 weight portions, amylum pregelatinisatum 50 weight portions, low-substituted hydroxypropyl cellulose 32 weight portions, crospolyvinylpyrrolidone 38 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, olmesartan medoxomil 40 weight portions, microcrystalline Cellulose 80 weight portions, amylum pregelatinisatum 50 weight portions, low-substituted hydroxypropyl cellulose 32 weight portions, crospolyvinylpyrrolidone 38 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
Hydrochlorothiazide of the present invention is preferably the hydrochlorothiazide crystal, and characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that described hydrochlorothiazide crystal use Cu-K alpha ray measures.
Described hydrochlorothiazide crystal is prepared from through following steps:
(1) hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln of hydrochlorothiazide;
(2) under agitation in acetone soln, drip distilled water, occur muddy to solution;
(3) under ultrasonic field, in step 2 gained solution, flow the organic mixed solution that adds ethanol and ether, continue to stir;
(4) continued ultrasonic 1-3 minute, leave standstill, growing the grain filters, and filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
The acetone soln concentration of hydrochlorothiazide is 0.05-0.2g/ml in the said step 1; The mixing speed of said step 2 is 80-180r/min, and the mixing speed in the said step 3 is 20-30r/min; Flow acceleration is 10-15ml/min, and the power of said ultrasonic field is 0.4～0.6KW, and the volume ratio of ethanol and ether is 2 in said organic mixed solution: 3-7: 6, and the volume ratio of said mixed liquor and acetone is 4: 5-8: 5; The growing the grain that leaves standstill of said step 4 is at 12-18 ℃ of following growing the grain 1.5-2.5 hour.
Second purpose of the present invention is to provide a kind of method for preparing of above-mentioned composition.Described compositions is a tablet, and its preparation method comprises the steps:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, subsequent use;
3) take by weighing above-mentioned subsequent use hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the olmesartan medoxomil of recipe quantity, with the resulting mixed powder mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, promptly get described pharmaceutical composition.
The 3rd purpose of the present invention is to provide a kind of method for preparing of above-mentioned composition capsule, and this method for preparing comprises the steps:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate are crossed the 60-80 mesh sieve respectively, subsequent use;
3) take by weighing above-mentioned subsequent use olmesartan medoxomil, Levamlodipine, microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity; Adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get an amount of purified water adding and carry out wet method cutting granulation, in fluidized bed granulation coating machine, obtain particulate powder after dry 1 hour under 60～80 ℃ of conditions;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide and step 3) resulting granules sprills by recipe quantity, adopt the equivalent method of progressively increasing to mix, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
Below the present invention is done further in detail to introduce:
Most of hyperpietics need more than one antihypertensive to come controlling blood pressure, and the serious hyperpietic of minority needs 3 kinds or the next strict controlling blood pressure of more medicine.Prior art discloses hydrochlorothiazide, amlodipine and olmesartan medoxomil three coupling and has treated hypertensive technical scheme; Normally adopt the tablet take two or three; Like hydrochlorothiazide olmesartan medoxomil compound recipe sheet+amlodipine sheet or hydrochlorothiazide tablet+amlodipine sheet+olmesartan medoxomil sheet; And in the actual clinical test, find; The above-mentioned mode one of taking is that dosage is big, and especially the hyperpietic is generally the old people, takes medicine all must take at least two or three and bring inconvenience to the old people at every turn; The 2nd, because every kind of tablet all contains a large amount of adjuvants, different auxiliary materials produces Different Effects to the release of active constituents of medicine, therefore, is difficult to control three kinds of active component after taking and discharges with ideal speed, influences therapeutic effect.Therefore, a kind of compound medicinal formulation that contains three components of exploitation is significant.
The present invention puts forth effort on the compound preparation that contains hydrochlorothiazide, Levamlodipine and olmesartan medoxomil of a kind of brand-new prescription of exploitation, selects more activated Levamlodipine can obtain better therapeutic.This is the undocumented technical scheme of prior art.Core more, the inventor is devoted to study selection and the consumption of this compound preparation adjuvant curative effect with further improvement above-mentioned compound preparation.
Nearest 20 years, many medicine-adjuvant Study of Interaction papers that relate to have been delivered.These researchs are intended to optimize writes out a prescription, and comprises the aspects such as dissolubility, increase dissolution, increase drug release rate, raising stability, change therapeutic activity and raising bioavailability that improve insoluble medicine.
Those skilled in the art will know that; To the body drug administration; Which kind of approaches and methods all need adopt the pharmaceutical dosage form that adapts with it, and adjuvant can be given the necessary physics of pharmaceutical dosage form or physical chemistry, biological property to adapt to medical use and to guarantee therapeutic effect.Active medicine is substantive theme part in the dosage form, is determining the whole direction of effect.Adjuvant guarantees that then medicine optionally is transported to tissue site with certain procedure, prevents that medicine from disengaging preceding inactivation from main body, and makes medicine in vivo by certain speed and time, discharge at certain position.Therefore, the dosage form of being made up of suitable adjuvant has positive pivotal role to the practical application of medicine and the performance of curative effect.Therefore the inventor is to the physicochemical property of hydrochlorothiazide, Levamlodipine and olmesartan medoxomil; On the basis of big quantity research and screening test, a kind of brand-new prescription has been proposed; Selected to have the adjuvant of synergy with the three and confirmed the best weight proportion of each component, to reach the purpose of final raising compound preparation curative effect.
Though what adopt in the present composition is prior art adjuvant commonly used; But those skilled in the art will know that; Contain the compound preparation of three kinds of medicinal active ingredients because the usage variance of principal agent is bigger, contain 12.5mg hydrochlorothiazide/2.5mg Levamlodipine/20mg olmesartan medoxomil like common every of compound preparation of the present invention.For three kinds of effective ingredient can be discharged synchronously; And can reasonably discharge with rational speed in the time; Usually need to use a large amount of disintegrating agent and lubricant, it is heavy so just to have increased sheet, causes patient's difficulty of swallowing; Therefore, be the key problem that the present invention need solve how at the consumption that guarantees to reduce under the desirable prerequisite that discharges of medicine adjuvant as far as possible.The inventor has finally confirmed the best of breed of microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide, magnesium stearate, and has confirmed following weight proportion on the bases of a large amount of experiments:
Hydrochlorothiazide 5-25 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 20-40 weight portion, microcrystalline Cellulose 40～120 weight portions, amylum pregelatinisatum 30～90 weight portions, low-substituted hydroxypropyl cellulose 15～40 weight portions, crospolyvinylpyrrolidone 10～45 weight portions, silicon dioxide 3-8 weight portion and magnesium stearate 1-2 weight portion.
Preferably: hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 20 weight portions, microcrystalline Cellulose 40～60 weight portions, amylum pregelatinisatum 40～60 weight portions, low-substituted hydroxypropyl cellulose 25～40 weight portions, crospolyvinylpyrrolidone 30～45 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 40 weight portions, microcrystalline Cellulose 70～120 weight portions, amylum pregelatinisatum 50～90 weight portions, low-substituted hydroxypropyl cellulose 25～40 weight portions, crospolyvinylpyrrolidone 30～45 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
More preferably: hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, olmesartan medoxomil 20 weight portions, microcrystalline Cellulose 50 weight portions, amylum pregelatinisatum 50 weight portions, low-substituted hydroxypropyl cellulose 32 weight portions, crospolyvinylpyrrolidone 38 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, olmesartan medoxomil 40 weight portions, microcrystalline Cellulose 80 weight portions, amylum pregelatinisatum 50 weight portions, low-substituted hydroxypropyl cellulose 32 weight portions, crospolyvinylpyrrolidone 38 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
Because the present invention greatly reduces the consumption of adjuvant under the prerequisite that guarantees curative effect, therefore, it is heavy both to have reduced sheet, makes things convenient for the patient to take, the quality Control of also having avoided supplementary product consumption to bring greatly simultaneously.
It is crude drug that pharmaceutical composition of the present invention can adopt commercially available hydrochlorothiazide, but as a kind of preferred version of the present invention, the present invention preferably adopts a kind of stability and the good hydrochlorothiazide crystal of dissolution.
One skilled in the art will appreciate that stripping is slow because hydrochlorothiazide is slightly soluble in water; Had a strong impact on bioavailability of medicament, in addition, hydrochlorothiazide is owing to contain sulfonamide structure in the molecule; Less stable is easy to hydrolysis, is prone to produce the quality wild effect; Therefore, it is generally on the low side to contain the pharmaceutical preparation bioavailability of hydrochlorothiazide.Prior art mainly solves the problems referred to above through dosage form or the method for preparing that changes its pharmaceutical preparation.As preparation being made fast dissolving dosage forms such as dispersible tablet, effervescent tablet, promote its disintegrate through using a large amount of adjuvant (disintegrating agent), reach qualified dissolution.
Though adopt technique scheme can play improvement effect to a certain degree, DeGrain.Patent application CN101659643A discloses crystal form of a kind of hydrochlorothiazide and uses thereof; To the ubiquitous hydrochlorothiazide stripping of prior art slowly, the problem of bioavailability difference; Through hydrochlorothiazide is handled; Obtain a kind of new hydrochlorothiazide crystalline form iii (as shown in Figure 2), the result shows, the formulation products that the compositions of forming with hydrochlorothiazide crystalline form iii or hydrochlorothiazide III and other types depressor is processed; Its dissolution rate can reach and the external similar level of like product, has solved the slow problem of hydrochlorothiazide dissolution rate to a certain extent.But stability of formulation does not significantly improve yet, and the curative effect of pharmaceutical preparation is also undesirable.
In view of this, the inventor has obtained certain hydrochlorothiazide crystal unexpectedly after hydrochlorothiazide has carried out secular big quantity research, and this crystal efficiently solves the variety of issue of the compound preparation appearance that contains hydrochlorothiazide, has obtained beyond thought technique effect.
As shown in Figure 1, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that hydrochlorothiazide crystal use Cu-K alpha ray of the present invention measures.
Fig. 2 discloses the crystalline powder X-ray diffraction pattern of hydrochlorothiazide among the CN101659643A; Can know from accompanying drawing; Above-mentioned crystal is different from hydrochlorothiazide crystal of the present invention; In addition, through a large amount of control experiments of inventor, crystal of the present invention significantly is superior to the disclosed hydrochlorothiazide crystal of prior art on stability and dissolution.
The crystalline method for preparing of hydrochlorothiazide of the present invention comprises the steps:
(1) hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln of hydrochlorothiazide;
(2) under agitation in acetone soln, drip distilled water, occur muddy to solution;
(3) under ultrasonic field, in step 2 gained solution, flow the organic mixed solution that adds ethanol and ether, continue to stir;
(4) continued ultrasonic 1-3 minute, leave standstill, growing the grain filters, and filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
The acetone soln concentration of hydrochlorothiazide is 0.05-0.2g/ml in the said step 1; The mixing speed of the preferred said step 2 of 0.08-0.15g/ml is 80-180r/min, preferred 120-180r/min, and the mixing speed in the said step 3 is 20-30r/min; Flow acceleration is 10-15ml/min, and the power of said ultrasonic field is 0.4～0.6KW, and the volume ratio of ethanol and ether is 2 in said organic mixed solution: 3-7: 6, and the volume ratio of said mixed liquor and acetone is 4: 5-8: 5; The growing the grain that leaves standstill of said step 4 is at 12-18 ℃ of following growing the grain 1.5-2.5 hour.
Described method for preparing comprises the steps:
(1) hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.1g/ml hydrochlorothiazide;
(2), occur muddy to solution at the following distilled water that in acetone soln, drips of the stirring of 160r/min;
(3) power be under the ultrasonic field of 0.5KW in step 2 gained solution stream add organic mixed solution of ethanol and ether, the stirring of lasting 25r/min; The volume ratio of ethanol and ether is 5: 6 in wherein organic mixed solution, and the volume ratio of said mixed liquor and acetone is 1: 1;
(4) continue ultrasonic 2 minutes, leave standstill, 16 ℃ of following growing the grains 2 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
The present invention introduces ultrasound wave control in crystalline process.Those skilled in the art will know that; Crystallization is the process of a complicacy, and each factor of crystallization process all can influence crystalline formation and control thereof like time-temperature of choice of Solvent and consumption thereof, mixing speed, growing the grain etc.; After the present invention introduces ultrasonic field and is used for crystallization; Ultransonic power and time are the crystal formation key of influence equally, and the present invention utilizes ultrasound wave to control nucleation and growth course, thereby crystallization process is optimized more.Above-mentioned method for preparing is the best method for preparing that the inventor finally confirms through a large amount of experiments back, and the hydrochlorothiazide crystal of gained possesses the remarkable result that prior art can't obtain.
Hydrochlorothiazide of the present invention is a hydrochlorothiazide powder commercially available in the prior art, the hydrochlorothiazide crystal of described hydrochlorothiazide crystal for adopting commercially available hydrochlorothiazide powder to be prepared from by method of the present invention.
In addition; The present invention also provides a kind of method for preparing of above-mentioned solid pharmaceutical composition tablet; One skilled in the art will appreciate that compound tablet compositions of the present invention is scientific and reasonable owing to what write out a prescription, therefore can predict and adopt disclosed other method for preparing tablet thereof of prior art also can obtain eutherapeutic tablet composition; Preferred but the method for preparing that is not limited only to be described below of the present invention, this method for preparing comprises the steps:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, subsequent use;
3) take by weighing above-mentioned subsequent use hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the olmesartan medoxomil of recipe quantity, with the resulting mixed powder mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, promptly get described pharmaceutical composition.
Wherein, described coating solution adopts commonly used the getting final product of prior art, specifically is chosen as those skilled in the art and grasps.
The inventor has confirmed the method for preparing of above-mentioned tablet composition to the characteristic of main ingredient, is to simplify production process, keeps the activity of ingredient as far as possible, and the present invention adopts direct pressure closing to prepare compound tablet.The reasonable release that to control hydrochlorothiazide, olmesartan medoxomil and Levamlodipine that is used in combination owing to microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate; Therefore, Pharmaceutical composition of the present invention can obtain better therapeutic effect than prior art formulations.
The 3rd purpose of the present invention is to provide a kind of method for preparing of above-mentioned composition capsule; Those skilled in the art will know that; Compound preparation of the present invention is owing to prescription is scientific and reasonable; Therefore can predict and adopt disclosed other capsule preparation method thereofs of prior art also can obtain eutherapeutic tablet composition, the preferred but method for preparing that is not limited only to be described below of the present invention, this method for preparing comprises the steps:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate are crossed the 60-80 mesh sieve respectively, subsequent use;
3) but take by weighing above-mentioned subsequent use olmesartan medoxomil, Levamlodipine, microcrystalline Cellulose die mould starch, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity; Adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get an amount of purified water adding and carry out wet method cutting granulation, in fluidized bed granulation coating machine, obtain particulate powder after dry 1 hour under 60～80 ℃ of conditions;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide and step 3) resulting granules sprills by recipe quantity, adopt the equivalent method of progressively increasing to mix, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
Wherein, the method for a kind of mixed material medicine that the equivalent method of progressively increasing is used always for those skilled in the art, concrete operations are familiar with by those skilled in the art and are grasped.The consumption of purified water is as the criterion can mixed powder being carried out wet method cutting granulation in the step 3, and concrete consumption is to be determined on a case-by-case basis in the practical operation, and this selection and judgement are also grasped by those skilled in the art.
Adopt technique scheme: the present invention has following beneficial effect:
1, the medicinal compositions drug content of oral administration solid of the present invention is high, and supplementary product consumption is merely the 1/5-1/3 of prior art.
2, the present invention adopt with 3 kinds of medicines be combined in 11 time on the one, this compound tablet is taken more convenient, helps to control better patient's blood pressure.
3, the present invention writes out a prescription rationally, and bioavailability significantly improves, and shows than all 2 above same dose medication combined use reduction systolic pressures 16%～48% and diastolic pressure 18%～52% more.
Description of drawings
Fig. 1 hydrochlorothiazide crystal powder of the present invention diffraction pattern
The disclosed hydrochlorothiazide crystalline form iii of Fig. 2 CN101659643A powder diagram
The specific embodiment
Following embodiment will do to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
The crystalline preparation of embodiment 1 hydrochlorothiazide
(1) the 1kg hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.1g/ml hydrochlorothiazide;
(2), occur muddy to solution at the following distilled water that in acetone soln, drips of the stirring of 160r/min;
(3) power be under the ultrasonic field of 0.5KW in step 2 gained solution stream add organic mixed solution of ethanol and ether, the stirring of lasting 25r/min; The volume ratio of ethanol and ether is 5: 6 in wherein organic mixed solution, and the volume ratio of said mixed liquor and acetone is 1: 1;
(4) continue ultrasonic 2 minutes, leave standstill, 16 ℃ of following growing the grains 2 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that present embodiment gained hydrochlorothiazide crystal use Cu-K alpha ray measures.
The crystalline preparation of embodiment 2 hydrochlorothiazide
(1) the 1kg hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.2g/ml hydrochlorothiazide;
(2), occur muddy to solution at the following distilled water that in acetone soln, drips of the stirring of 120r/min;
(3) power be under the ultrasonic field of 0.4KW in step 2 gained solution stream add organic mixed solution of ethanol and ether, the stirring of lasting 20r/min; The volume ratio of ethanol and ether is 2: 3 in wherein organic mixed solution, and the volume ratio of said mixed liquor and acetone is 4: 5;
(4) continue ultrasonic 2 minutes, leave standstill, 12 ℃ of following growing the grains 1.5 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that present embodiment gained hydrochlorothiazide crystal use Cu-K alpha ray measures.
The crystalline preparation of embodiment 3 hydrochlorothiazide
(1) the 1kg hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.08g/ml hydrochlorothiazide;
(2), occur muddy to solution at the following distilled water that in acetone soln, drips of the stirring of 180r/min;
(3) power be under the ultrasonic field of 0.6KW in step 2 gained solution stream add organic mixed solution of ethanol and ether, the stirring of lasting 30r/min; The volume ratio of ethanol and ether is 7: 6 in wherein organic mixed solution, and the volume ratio of said mixed liquor and acetone is 8: 5;
(4) continue ultrasonic 3 minutes, leave standstill, 18 ℃ of following growing the grains 2.5 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that present embodiment gained hydrochlorothiazide crystal use Cu-K alpha ray measures.
The crystalline preparation of embodiment 4 hydrochlorothiazide
(1) the 1kg hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.05g/ml hydrochlorothiazide;
(2), occur muddy to solution at the following distilled water that in acetone soln, drips of the stirring of 130r/min;
(3) power be under the ultrasonic field of 0.55KW in step 2 gained solution stream add organic mixed solution of ethanol and ether, the stirring of lasting 20r/min; The volume ratio of ethanol and ether is 1: 1 in wherein organic mixed solution, and the volume ratio of said mixed liquor and acetone is 6: 5;
(4) continue ultrasonic 1.5 minutes, leave standstill, 12 ℃ of following growing the grains 1.5 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that present embodiment gained hydrochlorothiazide crystal use Cu-K alpha ray measures.
The crystalline preparation of embodiment 5 hydrochlorothiazide
(1) hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.15g/ml hydrochlorothiazide;
(2), occur muddy to solution at the following distilled water that in acetone soln, drips of the stirring of 80r/min;
(3) power be under the ultrasonic field of 0.45KW in step 2 gained solution stream add organic mixed solution of ethanol and ether, the stirring of lasting 20r/min; The volume ratio of ethanol and ether is 5: 6 in wherein organic mixed solution, and the volume ratio of said mixed liquor and acetone is 5: 4;
(4) continue ultrasonic 3 minutes, leave standstill, 18 ℃ of following growing the grains 2 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ in the X-ray powder diffraction pattern that present embodiment gained hydrochlorothiazide crystal use Cu-K alpha ray measures.
The preparation of embodiment 6 tablets
Prescription: (processing 1000)
Hydrochlorothiazide 12.5g, Levamlodipine 2.5g, olmesartan medoxomil 20g, microcrystalline Cellulose 50g, amylum pregelatinisatum 50g, low-substituted hydroxypropyl cellulose 32g, crospolyvinylpyrrolidone 38g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of present embodiment is the prepared hydrochlorothiazide crystal of embodiment 1.
Method for preparing:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 70 ℃ of conditions respectively, cross 70 mesh sieves, subsequent use;
3) take by weighing above-mentioned subsequent use hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the olmesartan medoxomil of recipe quantity, with the resulting mixed powder mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, promptly get described pharmaceutical composition.
The preparation of embodiment 7 tablets
Prescription: (processing 1000)
Hydrochlorothiazide 12.5g, Levamlodipine 2.5g, olmesartan medoxomil 40g, microcrystalline Cellulose 80g, amylum pregelatinisatum 50g, low-substituted hydroxypropyl cellulose 32g, crospolyvinylpyrrolidone 38g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of present embodiment is the prepared hydrochlorothiazide crystal of embodiment 1.
Method for preparing:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 60 ℃ of conditions respectively, cross 60 mesh sieves, subsequent use;
3) take by weighing above-mentioned subsequent use hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the olmesartan medoxomil of recipe quantity, with the resulting mixed powder mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, promptly get described pharmaceutical composition.
The preparation of embodiment 8 tablets
Prescription: (processing 1000)
Hydrochlorothiazide 6.25g, Levamlodipine 2.5g, olmesartan medoxomil 40g, microcrystalline Cellulose 70g, amylum pregelatinisatum 50g, low-substituted hydroxypropyl cellulose 25g, crospolyvinylpyrrolidone 30g, silicon dioxide 5g and magnesium stearate 1.5g.
Method for preparing
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 80 ℃ of conditions respectively, cross 80 mesh sieves, subsequent use;
3) take by weighing above-mentioned subsequent use hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the olmesartan medoxomil of recipe quantity, with the resulting mixed powder mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, promptly get described pharmaceutical composition.
The preparation of embodiment 9 tablets
Compare with embodiment 6, distinctive points only is that the present embodiment prescription is:
Hydrochlorothiazide 12.5g, Levamlodipine 5g, olmesartan medoxomil 40g, microcrystalline Cellulose 120g, amylum pregelatinisatum 90g, low-substituted hydroxypropyl cellulose 40g, crospolyvinylpyrrolidone 45g, silicon dioxide 5g and magnesium stearate 1.5g.
Wherein, the described hydrochlorothiazide of present embodiment is the prepared hydrochlorothiazide crystal of embodiment 4.
The preparation of embodiment 10 tablets
Compare with embodiment 6, distinctive points only is that the present embodiment prescription is:
Hydrochlorothiazide 6.25g, Levamlodipine 2.5g, olmesartan medoxomil 20g, microcrystalline Cellulose 40g, amylum pregelatinisatum 40g, low-substituted hydroxypropyl cellulose 25g, crospolyvinylpyrrolidone 30g, silicon dioxide 5g and magnesium stearate 1.5g
Embodiment 11 capsular preparations
Hydrochlorothiazide 12.5g, Levamlodipine 5g, olmesartan medoxomil 20g, microcrystalline Cellulose 60g, amylum pregelatinisatum 60g, low-substituted hydroxypropyl cellulose 40g, crospolyvinylpyrrolidone 45g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of present embodiment is the prepared hydrochlorothiazide crystal of embodiment 3.
Method for preparing:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate are crossed 70 mesh sieves respectively, subsequent use;
3) but take by weighing above-mentioned subsequent use olmesartan medoxomil, Levamlodipine, microcrystalline Cellulose die mould starch, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity; Adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get an amount of purified water adding and carry out wet method cutting granulation, in fluidized bed granulation coating machine, obtain particulate powder after dry 1 hour under 70 ℃ of conditions;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide and step 3) resulting granules sprills by recipe quantity, adopt the equivalent method of progressively increasing to mix, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
Embodiment 12 capsular preparations
Compare with embodiment 11, distinctive points only is that prescription is in the present embodiment:
Hydrochlorothiazide 5g, Levamlodipine 2.5g, olmesartan medoxomil 20g, microcrystalline Cellulose 40g, amylum pregelatinisatum 30g, low-substituted hydroxypropyl cellulose 15g, crospolyvinylpyrrolidone 10g, silicon dioxide 3g and magnesium stearate 1g.
Embodiment 13 capsular preparations
Compare with embodiment 11, distinctive points only is that prescription is in the present embodiment:
Hydrochlorothiazide 25g, Levamlodipine 5g, olmesartan medoxomil 40g, microcrystalline Cellulose 120g, amylum pregelatinisatum 90g, low-substituted hydroxypropyl cellulose 40g, crospolyvinylpyrrolidone 45g, silicon dioxide 8g and magnesium stearate 2g.Wherein, the described hydrochlorothiazide of present embodiment is the prepared hydrochlorothiazide crystal of embodiment 4.
In order further to verify stability, safety and the curative effect thereof of the medicinal composite preparation of oral administration solid that the present invention protected, the inventor has done a series of development test to the present invention, and is specific as follows:
Test Example 1 dissolution is investigated
The dissolution with the different tablets of dosage has been investigated in this test.
Experimental group 1: the embodiment of the invention 6, wherein the hydrochlorothiazide crystal is embodiment 1 a gained hydrochlorothiazide crystal;
Experimental group 2: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts disclosed hydrochlorothiazide crystalline form iii among the CN101659643A;
Experimental group 3: the embodiment of the invention 6; Wherein the hydrochlorothiazide crystal is the commercially available hydrochlorothiazide of prior art;
Experimental group 4: hydrochlorothiazide/olmesartan medoxomil sheet+Levamlodipine beaylate tablets;
Experimental group 5: hydrochlorothiazide tablet+Levamlodipine beaylate tablets+olmesartan medoxomil sheet.
Wherein, Hydrochlorothiazide tablet in the experimental group 4,5 is selected from Shanxi Heng Ruida pharmaceutical Co. Ltd (containing hydrochlorothiazide 12.5mg); Levamlodipine beaylate tablets is selected from Jiangxi SM Pharm. Co., Ltd.'s (containing Levamlodipine 2.5mg); The olmesartan medoxomil sheet is selected from Shanghai three pharmaceutical Co. Ltd's (containing olmesartan medoxomil 20mg) altogether, and hydrochlorothiazide/olmesartan medoxomil sheet is selected from Shanghai three pharmaceutical Co. Ltd altogether, (containing olmesartan medoxomil 20mg and hydrochlorothiazide 12.5mg).A, B, C represent hydrochlorothiazide, Levamlodipine besylate and olmesartan medoxomil respectively.
Test method:
According to 2005 editions two appendix dissolution determination first methods of Chinese Pharmacopoeia; With 0.05M; The PBS 1000ml of pH6.8 is as dissolution medium; Rotating speed is 50rmp, measures the dissolution of respectively organizing tablet at 0.5min, 0.8min, 1min, 2min, 5min, 8min, 10min, 15min, 20min respectively, and concrete experimental implementation is grasped by those skilled in the art.
The result sees table 1:
The result shows: the compound preparation that the present invention requires to protect has good dissolution; In entire test, can continue to realize discharging synchronously; Experimental group 1 is compared with experimental group 2,3, adopts identical consumption and method for preparing, and distinctive points only is that experimental group 1 adopts the hydrochlorothiazide crystal of the present invention's preparation; And experimental group 2 adopts disclosed hydrochlorothiazide crystalline form iii among the CN101659643A; Experimental group 3 adopts commercially available hydrochlorothiazide, and experimental group 2,3 also all can be realized synchronous release preferably, but the dissolution of hydrochlorothiazide is on the low side; In addition, experimental group 1-3 compares with experimental group 4-5, has not only realized synchronous release, and has significantly improved dissolution, therefore more can improve medicine in the intravital absorption of people, helps three's synergism to improve the preparation curative effect jointly.This is the beneficial effect that prior art can't obtain.
Other embodiment is carried out same experiment, draw identical conclusion.
Test Example 2 study on the stability
Experimental group 1: the embodiment of the invention 6, wherein the hydrochlorothiazide crystal is embodiment 1 a gained hydrochlorothiazide crystal;
Experimental group 2: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts disclosed hydrochlorothiazide crystalline form iii among the CN101659643A;
Experimental group 3: the embodiment of the invention 6; Wherein the hydrochlorothiazide crystal is the commercially available hydrochlorothiazide of prior art;
Experimental group 4: hydrochlorothiazide/olmesartan medoxomil sheet+Levamlodipine beaylate tablets;
Experimental group 5: hydrochlorothiazide tablet+Levamlodipine beaylate tablets+olmesartan medoxomil sheet.
Wherein, Hydrochlorothiazide tablet in the experimental group 4,5 is selected from Shanxi Heng Ruida pharmaceutical Co. Ltd (containing hydrochlorothiazide 12.5mg); Levamlodipine beaylate tablets is selected from Jiangxi SM Pharm. Co., Ltd.'s (containing Levamlodipine 2.5mg); The olmesartan medoxomil sheet is selected from Shanghai three pharmaceutical Co. Ltd's (containing olmesartan medoxomil 20mg) altogether, and hydrochlorothiazide/olmesartan medoxomil sheet is selected from Shanghai three pharmaceutical Co. Ltd altogether, (containing olmesartan medoxomil 20mg and hydrochlorothiazide 12.5mg).
Test method:
Method: 30 ± 2 ℃ of temperature, the condition held of relative humidity 60 ± 5% 3 months, each sampling in the 1st, 2,3 month that tests once; Measure drug content respectively, check catabolite, and observe the appearance character of tablet with HPLC; With result's contrast in 0 month, the result saw table 2.
Table 2: hydrochlorothiazide/Levamlodipine/telmisartan tablet composition study on the stability
The result shows: after quickening 3 months study on the stability, the drug content of experimental group 1-3 is all significantly stable than experimental group 4-5.Explanation has ideal stability according to the compound preparation of prescription of the present invention and method for preparing gained; Wherein, The stability of hydrochlorothiazide component is best with experimental group 1, explains and adopts hydrochlorothiazide crystal of the present invention more to help the stability that provides compound preparation whole.Other embodiment is carried out same experiment, all draw identical conclusion.
Test Example 3 pharmacodynamic experiments
One, data and method
1, case is selected " internal medicine " 2006 editions diagnostic criterias about " essential hypertension " with reference to the Wang Jiyao chief editor; Do not take under the antihypertensive drug situation systolic pressure >=140mgHg with (or) diastolic pressure >=90mgHg; Picked at random hyperpietic's 200 examples; The patient is divided into experimental group 1-5 at random, every group 40 example, each is organized those selected general clinical setting and sees table 3:
Table 3: each organizes hyperpietic's general clinical setting
2, research method
All patients inactive blood pressure lowering and other vasoactive agents in 2 weeks before test.According to different groups, the patient takes different antihypertensive drugs, and each organizes all in the morning 6 to 8 o'clock patient medicine time, and be 8 weeks the course of treatment.
Experimental group 1: the embodiment of the invention 6, wherein the hydrochlorothiazide crystal is embodiment 1 a gained hydrochlorothiazide crystal;
Experimental group 2: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts disclosed hydrochlorothiazide crystalline form iii among the CN101659643A;
Experimental group 3: the embodiment of the invention 6; Wherein the hydrochlorothiazide crystal is the commercially available hydrochlorothiazide of prior art;
Experimental group 4: hydrochlorothiazide/olmesartan medoxomil sheet+Levamlodipine beaylate tablets;
Experimental group 5: hydrochlorothiazide tablet+Levamlodipine beaylate tablets+olmesartan medoxomil sheet.
Wherein, Hydrochlorothiazide tablet in the experimental group 4,5 is selected from Shanxi Heng Ruida pharmaceutical Co. Ltd (containing hydrochlorothiazide 12.5mg); Levamlodipine beaylate tablets is selected from Jiangxi SM Pharm. Co., Ltd.'s (containing Levamlodipine 2.5mg); The olmesartan medoxomil sheet is selected from Shanghai three pharmaceutical Co. Ltd's (containing olmesartan medoxomil 20mg) altogether, and hydrochlorothiazide/olmesartan medoxomil sheet is selected from Shanghai three pharmaceutical Co. Ltd altogether, (containing olmesartan medoxomil 20mg and hydrochlorothiazide 12.5mg).
3, follow-up method 1 week before treatment, 2 weeks of taking medicine, 4 weeks, 6 weeks, 8 weeks are the blood pressure situation of measuring patient respectively, adds up to and follows up a case by regular visits to 5 times, and the instrument of blood pressure measurement and method all adopt prior art to use always, and this those skilled in the art of being measured as grasp.
4, drug safety evaluation
The patient all need carry out the drug safety evaluation, comprising the generation and the lab index (routine blood test and biochemical analysis) of untoward reaction incident in acceptance is followed up a case by regular visits at every turn.
5, experimental result: see table 4, table 5.
Table 4:8 respectively organizes the hyperpietic after week therapeutic effect compares
Table 5:8 respectively organizes hyperpietic's adverse effect situation after week
The above results shows: after 8 weeks; The compound preparation of experimental group 1-3 significantly is superior to experimental group 4-5 in the reduction effect to systolic pressure and diastolic pressure; In addition, in 1 week before treatment, 2 weeks of back of taking medicine, 4 weeks, 6 weeks, 8 weeks are the blood pressure situation of measuring patient respectively; Find that systolic pressure and the diastolic pressure of experimental group 1 in each stage all is lower than experimental group 2-5, the antihypertensive effect of visible experimental group 1 is the most desirable.In addition; In view of a situation arises, the untoward reaction of experimental group 1-3 significantly was less than experimental group 4-5 from the untoward reaction incident, and wherein experimental group 1 number that untoward reaction occurs only accounts for 10%; Far below 37.5% of experimental group 4; 42.5% of experimental group 5, the compound preparation that visible the present invention requires to protect is safe, suitablely applies clinically.
In addition, other embodiment of the present invention are done above-mentioned test, all can draw same conclusions, because length is limit, give an example no longer one by one here.
Claims (7)
1. medicinal compositions of oral administration solid; It is characterized in that; The oral formulations of described Pharmaceutical composition for being prepared from acceptable auxiliary on hydrochlorothiazide, Levamlodipine, olmesartan medoxomil and the pharmaceutics; Described oral formulations includes, but are not limited to be tablet or capsule; Described hydrochlorothiazide is the hydrochlorothiazide crystal, and it is that 4.1o, 8.2o, 9.8o, 12.1o, 15.1o, 16.7o, 19.3o, 20.0o, 22.1o, 23.3o, 26.8o show at 2 θ that described hydrochlorothiazide crystal uses in the X-ray powder diffraction pattern that the Cu-K alpha ray measures characteristic peak;
Described compositions contains following raw material by weight: hydrochlorothiazide 5-25 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 20-40 weight portion, microcrystalline Cellulose 40～120 weight portions, amylum pregelatinisatum 30～90 weight portions, low-substituted hydroxypropyl cellulose 15～40 weight portions, crospolyvinylpyrrolidone 10～45 weight portions, silicon dioxide 3-8 weight portion and magnesium stearate 1-2 weight portion;
Described compositions is a tablet, and its preparation method comprises the steps:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, subsequent use;
3) take by weighing above-mentioned subsequent use hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the olmesartan medoxomil of recipe quantity, with the resulting mixed powder mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, promptly get described pharmaceutical composition;
Described compositions is a capsule, and its preparation method comprises the steps:
1) hydrochlorothiazide, olmesartan medoxomil and Levamlodipine are sieved respectively, subsequent use;
2) microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate are crossed the 60-80 mesh sieve respectively, subsequent use;
3) take by weighing above-mentioned subsequent use olmesartan medoxomil, Levamlodipine, microcrystalline Cellulose, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, silicon dioxide and magnesium stearate by recipe quantity; Adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get an amount of purified water adding and carry out wet method cutting granulation, in fluidized bed granulation coating machine, obtain particulate powder after dry 1 hour under 60～80 ℃ of conditions;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide and step 3) resulting granules sprills by recipe quantity, adopt the equivalent method of progressively increasing to mix, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
2. Pharmaceutical composition according to claim 1 is characterized in that: described Levamlodipine includes but not limited to acid group such as benzenesulfonic acid, maleic acid, L-Aspartic Acid and the crystal that forms with Levamlodipine thereof.
3. Pharmaceutical composition according to claim 2 is characterized in that: described Levamlodipine is selected from Levamlodipine besylate.
4. Pharmaceutical composition according to claim 1 is characterized in that: described compositions contains following raw material by weight:
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 20 weight portions, microcrystalline Cellulose 40～60 weight portions, amylum pregelatinisatum 40～60 weight portions, low-substituted hydroxypropyl cellulose 25～40 weight portions, crospolyvinylpyrrolidone 30～45 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, olmesartan medoxomil 40 weight portions, microcrystalline Cellulose 70～120 weight portions, amylum pregelatinisatum 50～90 weight portions, low-substituted hydroxypropyl cellulose 25～40 weight portions, crospolyvinylpyrrolidone 30～45 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
5. Pharmaceutical composition according to claim 4 is characterized in that: described compositions contains following raw material by weight:
Hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, olmesartan medoxomil 20 weight portions, microcrystalline Cellulose 50 weight portions, amylum pregelatinisatum 50 weight portions, low-substituted hydroxypropyl cellulose 32 weight portions, crospolyvinylpyrrolidone 38 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, olmesartan medoxomil 40 weight portions, microcrystalline Cellulose 80 weight portions, amylum pregelatinisatum 50 weight portions, low-substituted hydroxypropyl cellulose 32 weight portions, crospolyvinylpyrrolidone 38 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
6. Pharmaceutical composition according to claim 1 is characterized in that: described hydrochlorothiazide crystal is prepared from through following steps:
(1) hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln of hydrochlorothiazide;
(2) under agitation in acetone soln, drip distilled water, occur muddy to solution;
(3) under ultrasonic field, in step 2 gained solution, flow the organic mixed solution that adds ethanol and ether, continue to stir;
(4) continued ultrasonic 1-3 minute, leave standstill, growing the grain filters, and filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
7. Pharmaceutical composition according to claim 6 is characterized in that: the acetone soln concentration of hydrochlorothiazide is 1.2-2.4g/ml in the said step 1; The mixing speed of said step 2 is 120-180r/min, and the mixing speed in the said step 3 is 20-30r/min; Flow acceleration is 10-15ml/min, and the power of said ultrasonic field is 0.4～0.6KW, and the volume ratio of ethanol and ether is 2:3-7:6 in said organic mixed solution, and the volume ratio of said mixed liquor and acetone is 4:5-8:5; The growing the grain that leaves standstill of said step 4 is at 12-18 ℃ of following growing the grain 1.5-2.5 hour.
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| CN102670534B (en) * | 2012-05-23 | 2013-07-31 | 石家庄开发区博欣医药科技开发有限公司 | Levamlodipine besylate tablets |
| CN113171352A (en) * | 2021-04-15 | 2021-07-27 | 海南锦瑞制药有限公司 | Preparation method of sartan antihypertensive compound preparation |
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| CN1415298A (en) * | 2002-10-24 | 2003-05-07 | 王登之 | Compound Irbesartan capsule for curing high blood pressure |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1415298A (en) * | 2002-10-24 | 2003-05-07 | 王登之 | Compound Irbesartan capsule for curing high blood pressure |
| CN101327213A (en) * | 2008-06-20 | 2008-12-24 | 海南锦瑞制药有限公司 | Irbesartan and hydrochlorothiazide pharmaceutical composition and preparation method thereof |
| CN102008484A (en) * | 2009-07-11 | 2011-04-13 | 邬林祥 | Olmesartan-containing compound preparation for treating hypertension |
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| CN102335178A (en) | 2012-02-01 |
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Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. |
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