CN102327277B - Fosinopril sodium and hydrochlorothiazide pharmaceutical composition and preparation method thereof - Google Patents
Fosinopril sodium and hydrochlorothiazide pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a fosinopril sodium and hydrochlorothiazide pharmaceutical composition and a preparation method thereof. The pharmaceutical composition is a tablet or capsule prepared from hydrochlorothiazide crystal, fosinopril sodium and pharmaceutically acceptable auxiliary materials. The composition comprises the following components in parts by weight: 5-45 parts of fosinopril sodium, 5-30 parts of hydrochlorothiazide crystal, 10-50 parts of pregelatinized starch, 20-25 parts of sodium carboxymethyl starch, 15-35 parts of microcrystalline cellulose PH102, 10-45 parts of hydroxypropyl cellulose and 0.5-1 part of magnesium stearate. The pharmaceutical composition has the advantages of reasonable prescription, stable and reliable quality, and better disintegration time limit and dissolution rate. In the invention, a powder direct tabletting process is adopted, thus the preparation method has the advantages of simple process, short production period and low production cost and can easily realize industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of fosinopril sodium hydrochlorothiazide tablet and preparation method thereof.
Background technology
Hypertension is one of healthy modal cardiovascular disease of harm humans, is the great public health problem in the global range.The hypertension control rate of major country is not high in the world at present, and ministry of Health of China is state-owned nearly 1.6 hundred million hyperpietics in the national nutrient health status investigation of announcement in 2002 then shows, and the control rate of blood pressure is merely 6.16%.Verified the rising of a large amount of Study of evidence based medicine along with blood pressure; The danger of cardiovascular event can obviously increase; Especially in the today that is tending towards aging; And the original new drug of researching and developing great, the multiple diseases prevention and treatment demand that satisfies China's cardiovascular and cerebrovascular disease spectrum is urgent especially, and the control rate that therefore improves blood pressure should receive special attention, especially more should pay attention to for developing country.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.
Fosinopril is that a kind of plain CEI of phosphorated novel hypertension (ACE inhibitor) suppresses Angiotensin-Converting, and ACE is the conversion of catalytic angiotensin one vaso-excitor material of peptide peptidase, Angiotensin II.Fosinopril is the precursor medicine, to the ACE direct repression a little less than, but oral back slowly and not exclusively absorbs, and changes active stronger diacid metabolite fosinoprilat (fosinoprilat) rapidly into.Fosinoprilat is through the combination of zinc ion in next phosphate group and the ACE active site, and it is active to suppress ACE.This medicine produces column effect down to the inhibitory action of ACE: 1. Angiotensin II content obviously reduces.The aldosterone secretion is reduced, and water-sodium retention is reduced.3. reduce Catecholamine matter and discharge, reduce sympathetic tone.In addition, fosinopril slows down the Kallidin I inactivation through the inhibitory action to kininase II, and the vasodilator effect of Kallidin I is strengthened.In all ACE inhibitor, the characteristics of fosinopril are: 1. the inhibitory action to ACE is strong.2. acting duration is long, can make behind the once oral fosinopril more than the ACE activity inhibited 24h.3. can drain from kidney and liver sausage simultaneously, be difficult for accumulating.After fosinopril was used, plasma renin and angiotensin I concentration increased, and Angiotensin II and aldosterone concentration descend.To hemodynamic effects, can produce favourable influence to systemic blood flow kinetics to hyperpietic's fosinopril.Once oral fosinopril 10～40mg can make patient's tranquillization mean arterial pressure descend 10%～14%, and systolic pressure descends 10%～14%, and diastolic pressure descends 6%～17%, and total peripheral vascular resistance descends 14%～27%.Fosinopril still can be kept hemodynamic effect after motion.It occurs in the back 5～7h that takes medicine to hemodynamic ceiling effect behind the oral fosinopril, and effect can be kept 24h.This medicine does not have obvious influence to heart rate, and whenever the amount of fighting slightly rises with cardiac output, is respectively 6%～10% and 6%～9%, and fosinopril only has slight negative inotropic action, but it is favourable to improving left chamber diastolic function.
Hydrochlorothiazide is a kind of 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 makes kidney increase and the generation diuresis the drainage of sodium chloride, is a kind of middle diuretic of imitating.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.
Bring high blood pressure down through fosinopril, be considered to main inhibition RAAS.The electrolyte that hydrochlorothiazide then influences kidney duct mechanism heavily absorbs, and the sodium and the chlorine that directly increase equivalent number are drained.Indirectly, the effect of hydrochlorothiazide diuretic has reduced increases plasma renin activity thus, and the aldosterone secretion increases plasma volume, increases the loss of urine potassium, and blood potassium is descended.The contact of aldosterone is by angiotensin mediation, so ACE inhibitor share row's potassium diuretic and can play complementary effect.
Hydrochlorothiazide, Chinese: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, English name: Hydrochlorothiazide, molecular formula: C
7H
8ClN
3O
4S
2, molecular weight: 297.73.Structural formula:
Character: white crystalline powder.Dissolve 273-275 ℃ of point, be dissolved in acetone, be slightly soluble in alcohol, water insoluble, chloroform, ether are dissolved in sodium hydroxide solution, but facile hydrolysis.Mildly bitter flavor.These article are typical case's representative of imitating diuretic in the thiazide, and sales amount of medicine in 1985 ranked first the position in the U.S..Because of taking convenience, act on mediumly, and be applicable to various edema, therefore be that clinically Chang Yin has the untoward reaction of row's potassium property, need replenish potassium salt during application.
Patent application 200810155780.1 discloses a kind of hypertensive compound preparation that is used to treat.Said preparation comprises that dosage is the fosinopril of 2-50mg and the hydrochlorothiazide of 5-30mg.It has overcome when using fosinopril and hydrochlorothiazide clinically now, for guaranteeing that curative effect increases drug dose, causes side effect obviously to increase when list uses a medicine.Above-mentioned application provides a kind of new compound preparation, and fosinopril and hydrochlorothiazide two medicines share, collaborative, complementary action that curative effect has; Increase patient's toleration, improve compliance, reduce consumption, alleviate untoward reaction, taking convenience, cheap.But the poor stability of hydrochlorothiazide in the above-mentioned preparation, thereby the curative effect of preparation exerted an influence.
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 Form II I (as shown in Figure 2), the result shows, the formulation products that the compositions of forming with hydrochlorothiazide Form II I 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, and special proposition the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of fosinopril sodium hydrochlorothiazide pharmaceutical composition; Described Pharmaceutical composition is that hydrochlorothiazide crystal and fosinopril sodium add the oral formulations that acceptable accessories is prepared into, and described oral formulations is tablet or capsule.
Described hydrochlorothiazide 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.
The crystalline fusing point of described hydrochlorothiazide is 269-271 ℃.
The following method of described hydrochlorothiazide crystal by adopting is prepared from:
(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.
The following method of preferred described hydrochlorothiazide crystal by adopting is prepared from:
(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.
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, the bioavailability of common fosinopril sodium hydrochlorothiazide tablet is generally on the low side.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.In view of this; The inventor is after having carried out secular big quantity research to commercially available ordinary hydrogen chlorothiazide; Obtained certain hydrochlorothiazide crystal unexpectedly, this crystal efficiently solves the variety of issue that existing fosinopril sodium Esidrix occurs, and 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 disclosed other hydrochlorothiazide crystal of prior art on stability and dissolution.
Second purpose of the present invention is to provide a kind of hydrochlorothiazide crystalline method for preparing: the crystalline method for preparing of described hydrochlorothiazide 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.
Compound preparation of the present invention is remembered by weight, comprises following raw material: fosinopril sodium 5-45 part, hydrochlorothiazide crystal 5-30 part, 10～50 parts of pregelatinized Starch, carboxymethyl starch sodium 20-25 part, microcrystalline Cellulose PH10215～35 part, 10～45 parts of hydroxypropyl celluloses, 0.5～1 part of magnesium stearate.
Preferably comprise: 10 parts in fosinopril sodium 10 or 20 parts or 40 parts, hydrochlorothiazide crystal or 25 parts, 25～35 parts of pregelatinized Starch, carboxymethyl starch sodium 22-24 part, microcrystalline Cellulose PH10220～28 part, 25～30 parts of hydroxypropyl celluloses, 0.6～0.8 part of magnesium stearate;
More preferably comprise: fosinopril sodium 10 or 20 parts, 12.5 parts in hydrochlorothiazide crystal, 28 parts of pregelatinized Starch, 23 parts of carboxymethyl starch sodium, microcrystalline Cellulose PH10225 part, 28 parts of hydroxypropyl celluloses, 0.7 part of magnesium stearate.
Second purpose of the present invention is to provide a kind of method for preparing of above-mentioned fosinopril sodium Aquazide H Pharmaceutical composition, and the present invention adopts direct powder compression to make, and simple and feasible, favorable reproducibility has stronger practicality.The fosinopril sodium hydrochlorothiazide tablet of gained has good stability, impurity content is few, purity is high, advantage such as disintegration and dissolution preferably.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose, magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, subsequent use;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose, magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the hydrochlorothiazide 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 gets described pharmaceutical composition.
Described coating is that the coating solution that adopts Opadry II and purified water to form carries out coating.
The present invention specifically studies from powder flowbility, compressibility, lubricity, mixing homogeneity, dissolution and six aspects of dispersing uniformity.
The prescription key for design of direct powder compression is to select proper supplementary material and confirms its consumption.The adjuvant of direct powder compression removes and meets flowability, compression forming property, also needs bigger medicine saturation (promptly adding more medicine and unlikely mobile and significant harmful effect of compression molding property generation to it) and lubricity.In technique of direct powder compression, in order to reduce the tablet weight variation of tablet, improve the mechanical strength and the uniform content degree of tablet, powder will have good flowability, compressibility and the compatibility etc.The present invention adopts is safe and reliable pharmaceutic adjuvant, and the inventor has done a large amount of screening property tests to the selection of each adjuvant, has confirmed that finally like prescription of the present invention, above-mentioned adjuvant plays extraordinary assosting effect for the fosinopril sodium hydrochlorothiazide tablet.Its consumption also is to grope final affirmation through a large amount of tests, and prepared fosinopril sodium hydrochlorothiazide tablet has good quality stability.
Another object of the present invention is to provide the method for preparing of a kind of fosinopril sodium hydrochlorothiazide capsule agent, it is following that described capsule prepares process:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) it is subsequent use microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose to be crossed the 60-80 mesh sieve respectively;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose 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, under 60～80 ℃ of conditions, dried by the fire 2～4 hours, obtain particulate powder;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide by recipe quantity, mix with the step 3) resulting granules sprills equivalent method of progressively increasing, 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 of the present invention 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.
In addition; Because the prescription of Pharmaceutical composition of the present invention is reasonable; Therefore the method for preparing of fosinopril sodium hydrochlorothiazide capsule according to the invention agent includes but are not limited to above-mentioned method for preparing; Those skilled in the art combine the professional general knowledge of self can select disclosed other method for preparinies of prior art to prepare the fosinopril sodium hydrochlorothiazide capsule, and those skilled in the art can predict and adopt the capsule of other rational method for preparing gained to have ideal stability and curative effect.
Description of drawings
Fig. 1 hydrochlorothiazide crystal powder of the present invention diffraction pattern
The disclosed hydrochlorothiazide Form II of Fig. 2 CN101659643A I 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 fosinopril sodiums-hydrochlorothiazide tablet
Prescription (1000):
Fosinopril sodium 10g, hydrochlorothiazide crystal 12.5g, pregelatinized Starch 28g, carboxymethyl starch sodium 23g, microcrystalline Cellulose PH10225g, hydroxypropyl cellulose 28g, magnesium stearate 0.7g.
Method for preparing:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose, magnesium stearate were dried by the fire 3 hours under 70 ℃ of conditions respectively, cross 70 mesh sieves, subsequent use;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose, magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the hydrochlorothiazide 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, the coating solution that adopts Opadry II and purified water to form carries out coating, promptly gets described pharmaceutical composition.
The preparation of embodiment 7 fosinopril sodiums-hydrochlorothiazide tablet
Prescription (1000):
Fosinopril sodium 10g, hydrochlorothiazide crystal 10g, pregelatinized Starch 25g, carboxymethyl starch sodium 22g, microcrystalline Cellulose PH10220g, hydroxypropyl cellulose 25g, magnesium stearate 0.6g;
Method for preparing:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose, 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 fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose, magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the hydrochlorothiazide 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, the coating solution that adopts Opadry II and purified water to form carries out coating, promptly gets described pharmaceutical composition.
The preparation of embodiment 8 fosinopril sodiums-hydrochlorothiazide tablet
Prescription (1000):
Fosinopril sodium 20g, hydrochlorothiazide crystal 2 5g, pregelatinized Starch 35g, carboxymethyl starch sodium 24g, microcrystalline Cellulose PH10228g, hydroxypropyl cellulose 30g, magnesium stearate 0.8g;
Method for preparing:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose, magnesium stearate were dried by the fire 4 hours under 60 ℃ of conditions respectively, cross 60 mesh sieves, subsequent use;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose, magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the hydrochlorothiazide 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, the coating solution that adopts Opadry II and purified water to form carries out coating, promptly gets described pharmaceutical composition.
The preparation of embodiment 9 fosinopril sodiums-hydrochlorothiazide tablet
Compare with embodiment 6, distinctive points only is: present embodiment prescription (1000):
Fosinopril sodium 5g, hydrochlorothiazide crystal 5 g, pregelatinized Starch 10g, carboxymethyl starch sodium 20g, microcrystalline Cellulose PH102 15g, hydroxypropyl cellulose 10g, magnesium stearate 0.5g.
The preparation of embodiment 10 fosinopril sodiums-hydrochlorothiazide tablet
Compare with embodiment 7, distinctive points only is: present embodiment prescription (1000):
Fosinopril sodium 45g, hydrochlorothiazide crystal 3 0g, pregelatinized Starch 50g, carboxymethyl starch sodium 25g, microcrystalline Cellulose PH102 35g, hydroxypropyl cellulose 45g, magnesium stearate 1g.
Embodiment 11-14
Compare with embodiment 6, the distinctive points of embodiment 11-14 only is to adopt following prescription to be prepared from (it is prepared that wherein, the hydrochlorothiazide crystal among the embodiment 11-14 is respectively embodiment 1-4):
| Name of material | Example 11 | Example 12 | Example 13 | Example 14 |
| Fosinopril sodium | 20g | 40g | 30g | 25g |
| The hydrochlorothiazide crystal | 12.5g | 25g | 12.5g | 12.5g |
| Pregelatinized Starch | 28g | 30g | 35g | 32g |
| Carboxymethyl starch sodium | 23g | 23g | 25g | 25g |
| Microcrystalline Cellulose | 25g | 26g | 28g | 35g |
| Hydroxypropyl cellulose | 28g | 28g | 30g | 35g |
| Magnesium stearate | 0.7g | 0.7g | 0.8g | 0.9g |
The preparation of embodiment 15 fosinopril sodium hydrochlorothiazide capsules
Prescription: with embodiment 9
Method for preparing:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) it is subsequent use microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose to be crossed 70 mesh sieves respectively;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose 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, baking is 3 hours under 70 ℃ of conditions, obtains particulate powder;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide by recipe quantity, mix with the step 3) resulting granules sprills equivalent method of progressively increasing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
The preparation of embodiment 16 fosinopril sodium hydrochlorothiazide capsules
Prescription: with embodiment 10
Method for preparing:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) it is subsequent use microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose to be crossed 60 mesh sieves respectively;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose 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, baking is 2 hours under 80 ℃ of conditions, obtains particulate powder;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide by recipe quantity, mix with the step 3) resulting granules sprills equivalent method of progressively increasing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
In order further to verify stability, safety and the curative effect thereof of the fosinopril sodium hydrochlorothiazide tablet 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
Experimental group 1: the embodiment of the invention 6, wherein the hydrochlorothiazide crystal is embodiment 1 a gained hydrochlorothiazide crystal;
Experimental group 2: the embodiment of the invention 7; Wherein the hydrochlorothiazide crystal is embodiment 1 a gained hydrochlorothiazide crystal;
Matched group 1: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts disclosed hydrochlorothiazide Form II I among the CN101659643A;
Matched group 2: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts commercially available ordinary hydrogen chlorothiazide in the prior art;
Matched group 3: commercially available fosinopril sodium sheet (10mg, the accurate word H20064148 of traditional Chinese medicines)+hydrochlorothiazide tablet (12.5mg, the accurate word H14020118 of traditional Chinese medicines).
Getting above-mentioned tablet respectively, is solvent with 0.5% lauryl sodium sulfate aqueous solution 900ml, and Revolution Per Minute 120 changes measures its dissolution, and the result sees table 1:
Table 1
The result shows: fosinopril sodium hydrochlorothiazide tablet of the present invention has good dissolution, basically can 100% stripping in 10 minutes, and experimental group 1 is compared with 2, there was no significant difference, but the dissolution of experimental group 1 is slightly excellent; Experimental group 1 is compared with matched group 1; Though adopt identical consumption and method for preparing; Because experimental group 1 adopts the hydrochlorothiazide crystal of the present invention's preparation, and matched group 1 adopts disclosed hydrochlorothiazide Form II I among the CN101659643A, dissolution also has significant difference; Experimental group 1 dissolution in 5min reaches 97.2, and matched group 1 is 89.1%; In addition, experimental group 1 and 2 and matched group 2,3, dissolution has had significant improvement, and its dissolution rate obviously is superior to matched group.
Because fosinopril sodium hydrochlorothiazide tablet of the present invention has adopted the hydrochlorothiazide crystal of the present invention's preparation, and method for preparing science, reasonable, so the present invention has significantly improved dissolution.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: the embodiment of the invention 7; Wherein the hydrochlorothiazide crystal is embodiment 1 a gained hydrochlorothiazide crystal;
Matched group 1: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts disclosed hydrochlorothiazide Form II I among the CN101659643A;
Matched group 2: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts commercially available ordinary hydrogen chlorothiazide in the prior art;
Matched group 3: commercially available fosinopril sodium sheet (10mg, the accurate word H20064148 of traditional Chinese medicines)+hydrochlorothiazide tablet (12.5mg, the accurate word H14020118 of traditional Chinese medicines).
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 dispersible tablet with HPLC; With result's contrast in 0 month, the result saw table 2.
The method of assay can be with reference to commonly used any of prior art, and concrete operations are grasped by those skilled in the art.
Table 2: fosinopril sodium Aquazide H composition stable property investigation
The result shows: after quickening 3 months study on the stability, the drug content of experimental group 1,2 is all significantly stable than matched group 1,2,3.Other embodiment is carried out same experiment, draw identical conclusion.
3, pharmacokinetic parameter research
1 data and method
1.1 the old essential hypertension people of diagnostic criteria that 160 of clinical data picked at random meet 2002 " Chinese hypertension prevention and control guide " studies.Inclusion criteria: among the adult of age＞60 year old; Do not take under the situation of antihypertensive drug; Systolic pressure >=140mmHg (1mmHg=0.133kPa) and/or diastolic pressure >=90mmHg, ISH is meant systolic pressure >=140mmHg, diastolic pressure＜90mmHg.Exclusion standard: secondary hypertension.Eligible person's 160 examples are divided into experimental group 1, matched group 1, matched group 2 and matched group 3 at random, every group 40 example.
Experimental group 1: male 22 examples, women 18 examples; 60 years old～79 years old age (66.0 years old ± 6.8 years old); The course of disease 2 years～39 years (19.8 ± 9.8 years); 1 grade of 14 example of hypertension, 2 grade of 10 example, 3 grade of 16 example.
Matched group 1, wherein male 20 examples, women 20 examples; 60 years old～77 years old age (65.0 years old ± 6.7 years old); The course of disease 2 years～38 years (19.6 ± 9.5 years); 1 grade of 13 example of hypertension, 2 grade of 12 example, 3 grade of 15 example.
Matched group 2, wherein male 21 examples, women 19 examples; 60 years old～75 years old age (65.0 years old ± 6.1 years old); The course of disease 2 years～37 years (19.6 ± 9.2 years); 1 grade of 12 example of hypertension, 2 grade of 12 example, 3 grade of 16 example.
Matched group 3, wherein male 19 examples, women 21 examples; 61 years old～75 years old age (65.0 years old ± 6.7 years old); The course of disease 2 years～36 years (19.6 ± 9.0 years); 1 grade of 13 example of hypertension, 2 grade of 11 example, 3 grade of 16 example.
The equal not statistically significant of blood pressure level (P＞0.05) before above-mentioned four groups of patient age, sex, the course of disease, the treatment has comparability.
Original antihypertensive drugs is treated preceding measuring blood pressure, heart rate, blood fat, blood glucose, blood electrolyte, hepatic and renal function, routine blood test more than 1 week 1.2 all stop using before two groups of patient of Therapeutic Method.Each group is taken following preparation (all containing hydrochlorothiazide 12.5mg, fosinopril sodium 10mg) once a day, is for 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;
Matched group 1: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts disclosed hydrochlorothiazide Form II I among the CN101659643A;
Matched group 2: compare with the embodiment of the invention 6, distinctive points only is: the principal agent in the prescription adopts commercially available ordinary hydrogen chlorothiazide in the prior art;
Matched group 3: commercially available fosinopril sodium sheet (10mg, the accurate word H20064148 of traditional Chinese medicines)+hydrochlorothiazide tablet (12.5mg, the accurate word H14020118 of traditional Chinese medicines).
2.1 experimental result is seen table 3,4.
Table 3:8 respectively organizes the hyperpietic after week therapeutic effect compares
Table 4:8 respectively organizes hyperpietic's adverse effect situation after week
The above results shows: after 8 weeks; The compound preparation of experimental group 1, matched group 1,2 significantly is superior to matched group 3 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 experimental group 1 all is lower than other groups at the systolic pressure and the diastolic pressure in each stage, the antihypertensive effect of visible experimental group 1 is the most desirable.In addition; From the untoward reaction incident in view of a situation arises; The untoward reaction of experimental group 1, matched group 1,2 significantly is less than matched group 3, and wherein experimental group 1 number that untoward reaction occurs only accounts for 7.5%, far below 40% of matched group 3; It is thus clear that the compound preparation that the present invention requires to protect is safe, suitablely apply 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 (11)
1. a fosinopril sodium hydrochlorothiazide pharmaceutical composition is characterized in that, described Pharmaceutical composition is that hydrochlorothiazide crystal and fosinopril sodium add the oral formulations that acceptable accessories is prepared into, and described oral formulations is tablet or capsule; 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; Wherein, by weight, fosinopril sodium 5-45 part, hydrochlorothiazide crystal 5-30 part.
2. Pharmaceutical composition according to claim 1 is characterized in that: the crystalline fusing point of described hydrochlorothiazide is 269-271 ℃.
3. Pharmaceutical composition according to claim 1 and 2 is characterized in that: the following method of described hydrochlorothiazide crystal by adopting is prepared from:
(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.
4. Pharmaceutical composition according to claim 3 is characterized in that: 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 2:3-7:6 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.
5. Pharmaceutical composition according to claim 3 is characterized in that: the following method of described hydrochlorothiazide crystal by adopting is prepared from:
(1) hydrochlorothiazide is dissolved in the acetone, obtains the acetone soln that concentration is the 0.1g/ml hydrochlorothiazide;
(2) under the stirring of 160r/min, in acetone soln, drip distilled water, occur muddy to solution;
(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.
6. Pharmaceutical composition according to claim 1; It is characterized in that: described compositions is remembered by weight, comprises following raw material: fosinopril sodium 5-45 part, hydrochlorothiazide crystal 5-30 part, 10～50 parts of pregelatinized Starch, carboxymethyl starch sodium 20-25 part, 15～35 parts of microcrystalline Cellulose PH102,10～45 parts of hydroxypropyl celluloses, 0.5～1 part of magnesium stearate.
7. Pharmaceutical composition according to claim 6; It is characterized in that: described compositions is remembered by weight, comprises following raw material: 10 parts in fosinopril sodium 10 or 20 parts or 40 parts, hydrochlorothiazide crystal or 25 parts, 25～35 parts of pregelatinized Starch, carboxymethyl starch sodium 22-24 part, 20～28 parts of microcrystalline Cellulose PH102,25～30 parts of hydroxypropyl celluloses, 0.6～0.8 part of magnesium stearate.
8. Pharmaceutical composition according to claim 7; It is characterized in that: described compositions is remembered by weight, comprises following raw material: fosinopril sodium 10 or 20 parts, 12.5 parts in hydrochlorothiazide crystal, 28 parts of pregelatinized Starch, 23 parts of carboxymethyl starch sodium, 25 parts of microcrystalline Cellulose PH102,28 parts of hydroxypropyl celluloses, 0.7 part of magnesium stearate.
9. the method for preparing of claim 7 or 8 said Pharmaceutical compositions, it is characterized in that: described compositions is a tablet, and its preparation method comprises the steps:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose, magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, subsequent use;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose, magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take by weighing the hydrochlorothiazide 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 gets described pharmaceutical composition.
10. the method for preparing of the said Pharmaceutical composition of claim 9 is characterized in that, described coating is that the coating solution that adopts Opadry II and purified water to form carries out coating.
11. the method for preparing of claim 7 or 8 said Pharmaceutical compositions is characterized in that, described compositions is a capsule, and its preparation method comprises the steps:
1) fosinopril sodium and hydrochlorothiazide are sieved respectively, subsequent use;
2) it is subsequent use microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose to be crossed the 60-80 mesh sieve respectively;
3) take by weighing above-mentioned subsequent use fosinopril sodium, microcrystalline Cellulose, hydroxypropyl cellulose 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, under 60～80 ℃ of conditions, dried by the fire 2～4 hours, obtain particulate powder;
4) take by weighing above-mentioned subsequent use hydrochlorothiazide by recipe quantity, mix with the step 3) resulting granules sprills equivalent method of progressively increasing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, promptly get described pharmaceutical composition.
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