CN101780089B - Irbesartan hydrochlorothiazide capsule and preparation method thereof - Google Patents
Irbesartan hydrochlorothiazide capsule and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an irbesartan hydrochlorothiazide capsule and a preparation method thereof, belonging to the technical field of medicines. In the preparation method, the kinds and the dosages of a bulking agent, a disintegrating agent, an adhesion agent and a glidant are screened, and process conditions that raw auxiliary materials are screened by a specific sieving mesh number, hydrochlorothiazide is uniformly mixed by using an equivalent gradual increase method, grains are fluidized and dried, and the like are adopted in the preparation process, thus the prepared capsule has good dissolution, small loading quantity difference, high stability and bioavailability, good curative effect and good patient compliance because the capsule can conceal the bitter taste of the medicines; and besides, the invention has few auxiliary material kinds in a prescription, simple production process and low cost.
Description
Technical field
The present invention relates to hypertensive compound medicine capsule of a kind of treatment and preparation method thereof, particularly a kind of irbesartan hydrochlorothiazide capsule and preparation method thereof belongs to medical technical field.
Background technology
In recent years, hypertension has become the main killer of harm humans health.According to statistics, the U.S. has 4,300 ten thousand people to suffer from hypertension, and China has 1.2 hundred million people to suffer from hypertension approximately, and in the speed increment with annual 3000000 people.
Irbesartan is the sartans that latest developments are got up, and clinical practice shows, this product oral to light, moderate hypertension patient efficacy of antihypertensive treatment is definite, long-term oral untoward reaction is few, better tolerance.Hydrochlorothiazide is a kind of thiazide diuretic, reduces blood volume by natriuretic diuretic, reaches the blood pressure lowering purpose.
Irbesartan and hydrochlorthiazide is united use can have following pharmacological action: bring high blood pressure down; Improve heart failure; Prevent vessel wall thickening and myocardial hypertrophy that hypertension is concurrent; Have the kidney protective effect, renal blood flow increasing, glomerular filtration rate increases the discharge of urine and urine sodium, uric acid, can reduce adrenal gland's aldosterone and adrenergic secretion, but causes that also plasma renin activity increases.
Irbesartan and hydrochlorthiazide not only can be brought into play collaborative hypotensive effect after uniting use, and more any single medicine antihypertensive effect is stronger, and onset is faster, and serum potassium ion concentration was maintained in normal range, thereby improves antihypertensive effect, alleviates side effect.Have following clinical characters: oral effective, high-affinity, high selectivity, high specificity, no agonist activity, irbesartan and hydrochlorthiazide are united use and are suitable for single with the invalid essential hypertension of Angiotensin II antagonist for treating.Through clinical research confirmation, irbesartan and hydrochlorthiazide is united use treatment hypertension, and 90% patient treatment is effective, and the blood pressure compliance rate reaches 83%.
The capsule dissolution is low, mobility of particle is poor, content uniformity is big, uniformity of dosage units is defective because two kinds of its consumptions of principal agent, the different capsules that prepare of physicochemical property exist, listing at present dispersible tablet arranged, but because of its supplementary product kind many, complicated process of preparation, technology has specific (special) requirements to equipment, there is the cost height, length consuming time, shortcomings such as the easy moisture absorption.
The inventor is by systematically test, filter out the kind and the consumption of filler, disintegrating agent, binding agent, fluidizer, suitable process conditions, solved irbesartan hydrochlorothiazide capsule well and caused difficulties such as the content uniformity that dissolution is low, the mobility of particle difference causes is big, uniformity of dosage units is defective as granule is really up to the mark, and avoided the degradation problem of irbesartan hydrochlorothiazide capsule because of what two kinds of principal agent consumptions, physicochemical property difference existed.Medicine of the present invention is compared with tablet and is disperseed soon, good absorbing, and the bioavailability height, supplementary product kind is few, does not need the tabletting of tablet, and production process is simple, and cost is low.In addition, capsule is good to patient compliance, can cover bitter taste of drug, and the opaque capsule shells of packing into has improved stability of drug.Therefore, the invention irbesartan hydrochlorothiazide capsule is very necessary.
Summary of the invention
The invention provides a kind of irbesartan hydrochlorothiazide capsule;
The invention provides a kind of preparation method of irbesartan hydrochlorothiazide capsule;
The present invention mainly is achieved by the following technical solution:
Irbesartan hydrochlorothiazide capsule prescription of the present invention is composed as follows:
Irbesartan 120-170 weight portion
Hydrochlorothiazide 10-15 weight portion
Microcrystalline Cellulose 40-50 weight portion
Cross-linking sodium carboxymethyl cellulose 18-23 weight portion
Silicon dioxide 0.3-0.8%
Magnesium stearate 0.3-0.8%
Polyvidone is an amount of.
Irbesartan hydrochlorothiazide capsule prescription composition of the present invention is preferably as follows:
Irbesartan 122 weight portions
Hydrochlorothiazide 14.8 weight portions
Microcrystalline Cellulose 40 weight portions
Cross-linking sodium carboxymethyl cellulose 19.5 weight portions
Silicon dioxide 0.68%
Magnesium stearate 0.36%
Polyvidone is an amount of.
Irbesartan hydrochlorothiazide capsule composition of the present invention is preferably as follows:
Irbesartan 163 weight portions
Hydrochlorothiazide 11.2 weight portions
Microcrystalline Cellulose 47.9 weight portions
Cross-linking sodium carboxymethyl cellulose 22.1 weight portions
Silicon dioxide 0.30%
Magnesium stearate 0.68%
Polyvidone is an amount of.
Irbesartan hydrochlorothiazide capsule prescription composition of the present invention is preferably as follows:
Irbesartan 150 weight portions
Hydrochlorothiazide 12.5 weight portions
Microcrystalline Cellulose 45 weight portions
Cross-linking sodium carboxymethyl cellulose 20 weight portions
Silicon dioxide 0.5%
Magnesium stearate 0.5%
Polyvidone is an amount of.
" % " of the present invention is " percentage by weight ".
The preparation method of its irbesartan hydrochlorothiazide capsule is:
A, to take by weighing polyvidone an amount of, with dissolve with ethanol solution and make povidone solution, as binding agent, standby;
B, irbesartan, hydrochlorothiazide, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are sieved respectively, standby;
C, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mixing, mixture I;
D, with the irbesartan mix homogeneously of said mixture I and recipe quantity, be binding agent system soft material with the povidone solution, the system wet granular; Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate; Add magnesium stearate and silicon dioxide, mix homogeneously;
E, mensuration intermediate content calculate loading amount, and is encapsulated.
Wherein irbesartan is crossed 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves; Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively.Be to carry out mixing among the above-mentioned step c according to the equivalent method of progressively increasing.Step a povidone solution is 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30.
The inventor is by systematically test, filter out the kind and the consumption of filler, disintegrating agent, binding agent, fluidizer, suitable process conditions, solved irbesartan hydrochlorothiazide capsule well and caused difficulties such as the content uniformity that dissolution is low, the mobility of particle difference causes is big, uniformity of dosage units is defective as granule is really up to the mark, and avoided the degradation problem of irbesartan hydrochlorothiazide capsule because of what two kinds of principal agent consumptions, physicochemical property difference existed.Medicine of the present invention is compared with tablet and is disperseed soon, good absorbing, and the bioavailability height, supplementary product kind is few, does not need the tabletting of tablet, and production process is simple, and cost is low.In addition, capsule is good to patient compliance, can cover bitter taste of drug, and the opaque capsule shells of packing into has improved stability of drug.
Beneficial technical effects
By following test example and embodiment technical method of the present invention is further described, but not as limitation of the present invention.
The screening of test example 1 filler kind
The mobile investigation with α＜35 ° angle of repose, flowability is " good "; α＞35 °, flowability is " generally "; Mobilely carry out for the standard of " poor " α 〉=45 °.
Taking by weighing the method mixing that recipe quantity filler shown in hydrochlorothiazide 12.5g, the following table adopts equivalent to progressively increase, mixes with irbesartan 150g, is binding agent system soft material with 50% alcoholic solution of an amount of 4% 30 POVIDONE K 30 BP/USP 30, granulation.Wet granular is dry below 60 ℃, and pellet moisture is controlled at below 2～3%, and 20 mesh sieve granulate add magnesium stearate and silicon dioxide respectively 0.5%, and mix homogeneously is encapsulated.Dissolution with particulate flowability and principal agent is an evaluation index, and The selection result sees Table.
Screening (the unit: g) of filler
As seen from the above table, prescription 1,3,5 particulate flowabilities are bad, and it is defective content uniformity to occur in the fill capsule process; Prescription 2, prescription 4, prescription 6 are better with prescription 7 mobility of particle, but that 4,6,7 the dissolution of writing out a prescription is all write out a prescription is 2 low.Therefore, filler preferably contains the prescription 2 of microcrystalline Cellulose.
The screening of test example 2 disintegrating agent kinds
Taking by weighing the method mixing that following table recipe quantity hydrochlorothiazide 12.5g, microcrystalline Cellulose 45g and disintegrating agent adopt equivalent to progressively increase, mixes with the irbesartan 150g of recipe quantity, is binding agent system soft material with 50% alcoholic solution of an amount of 4% 30 POVIDONE K 30 BP/USP 30, granulation.Wet granular is dry below 60 ℃, and pellet moisture is controlled at below 2～3%, and 20 mesh sieve granulate add magnesium stearate and silicon dioxide respectively 0.5%, and mix homogeneously is encapsulated.Dissolution with disintegration time and principal agent is an evaluation index, and The selection result sees the following form.
Screening (the unit: g) of disintegrating agent kind
As seen from the above table, the prescription 8-11 obviously shortening of 12 disintegration times (above 10 minutes) of writing out a prescription, 11 the disintegration time dissolution the shortest, principal agent of wherein writing out a prescription is the highest.Therefore preferred cross-linking sodium carboxymethyl cellulose is as the disintegrating agent of irbesartan hydrochlorothiazide capsule.
The screening of experimental example 3 disintegrating agent consumptions
Below further investigate the disintegrating agent consumption, dissolution is further improved.
Take by weighing the method mixing that hydrochlorothiazide 12.5g, microcrystalline Cellulose 45g and cross-linking sodium carboxymethyl cellulose according to the form below recipe quantity adopt equivalent to progressively increase, mix with irbesartan 150g again, 50% alcoholic solution with an amount of 4% 30 POVIDONE K 30 BP/USP 30 is a binding agent system soft material, granulates.Wet granular is dry below 60 ℃, and pellet moisture is controlled at below 2～3%, and 20 mesh sieve granulate add magnesium stearate and silicon dioxide respectively 0.5%, and mix homogeneously is encapsulated.The selection result sees the following form.
Screening (the unit: g) of disintegrating agent consumption
As seen from the above table, prescription 13, prescription 14 disintegrating agent consumptions are respectively 4.5%, 6.5%, and its dissolution is on the low side; Prescription 15,16,17 disintegrating agent consumptions difference 7.5%, 8.5%, 10%, its result of extraction is all fine, the 16 disintegrating agent consumptions of wherein writing out a prescription are that the dissolution of 8.5% o'clock hydrochlorothiazide is the highest, determine that therefore the addition of disintegrating agent is 7.5%-10%, and optimum is 8.5%.
The selection of test example 4 binding agent kinds
In the prescription screening process, the amount of irbesartan is big and hydrophobicity is stronger, and the inventor screens binding agent emphatically, and the selection suitable bonding is all very important for the loading amount of capsule, stripping etc.; The binding agent of selecting has water, ethanol, hypromellose solution, polyvidone aqueous solution, polyvidone alcoholic solution, and estimates with indexs such as particle appearance, flowability, moisture and dissolutions.
Take by weighing the method mixing that hydrochlorothiazide 12.5g, microcrystalline Cellulose 45g and cross-linking sodium carboxymethyl cellulose 20g adopt equivalent to progressively increase, mix with irbesartan 150g, the soft material of binding agent system shown in the following table is granulated; Wet granular is dry below 60 ℃, and pellet moisture is controlled at below 2～3%, and 20 mesh sieve granulate add magnesium stearate and silicon dioxide respectively 0.5%, and mix homogeneously is encapsulated.The selection result sees the following form.
Screening (the unit: g) of binding agent kind
As seen from the above table, prescription 18, prescription 20, prescription 21, prescription 23 material viscosity are big, are difficult for moistening, the difficulty of granulating; It is many that prescription 19 usefulness ethanol are made the binding agent fine powder, and mobile poor, content uniformity is big, and its grain graininess is poor, because mechanical shock easily produces lamination, makes flowability poorer in the production process, and industrialization is difficulty; Prescription 22 usefulness 4% 30 POVIDONE K 30 BP/USP 3050% alcoholic solution is during as binding agent, and granule is mixing easily, and material viscosity is moderate, easily granulates, and mobile better behind the particle drying, the dissolution of principal agent composition is also better; It is sticking slightly that prescription 24 usefulness 10% 30 POVIDONE K 30 BP/USP 3050% alcoholic solution is made the binding agent material, more easily granulates, poorer slightly than the effect that prescription 22 usefulness 4% 30 POVIDONE K 30 BP/USP 3050% alcoholic solution reaches.Therefore binding agent is defined as 4% 30 POVIDONE K 30 BP/USP, 3050% alcoholic solution.
The screening of test example 5 fluidizer consumptions
Take by weighing hydrochlorothiazide 12.5g, microcrystalline Cellulose 45g and cross-linking sodium carboxymethyl cellulose 20g, the method mixing that adopts equivalent to progressively increase mixes with irbesartan 150g again, and 50% alcoholic solution system soft material of 4% 30 POVIDONE K 30 BP/USP 30 is granulated.Wet granular is dry below 60 ℃, and pellet moisture is controlled at below 2～3%, and 20 mesh sieve granulate add magnesium stearate and silicon dioxide according to recipe quantity shown in the following table, and mix homogeneously is encapsulated.The selection result sees the following form.
Screening (the unit: g) of fluidizer
As seen from the above table, its content uniformity did not obtain the essence improvement when prescription 25,26 used silicon dioxide or magnesium stearate separately, prescription 27,28,29 content uniformity that contain silicon dioxide and magnesium stearate simultaneously all have more obviously to be improved, but it is 28,29 better to write out a prescription, the two does not have significant difference, and 28 supplementary product consumptions of writing out a prescription are less, are 0.5% so determine the consumption of magnesium stearate and silicon dioxide.
The screening of test example 6 optimum preparation conditions
1, Shai Fen purpose is in order to obtain the material of uniform particle size, and this all has an important meaning smoothly to drug quality and preparation production.In unit operationss such as mixing, granulation, tabletting, sieve degree of mixing, filling, content uniformity etc. are all had a significant effect.
Take by weighing the method mixing that hydrochlorothiazide 12.5g, microcrystalline Cellulose 45g and cross-linking sodium carboxymethyl cellulose 20g adopt equivalent to progressively increase, mix with irbesartan 150g, 50% alcoholic solution system soft material of 4% 30 POVIDONE K 30 BP/USP 30 is granulated.Wet granular is dry below 60 ℃, and pellet moisture is controlled at below 2～3%, and 20 mesh sieve granulate add magnesium stearate and silicon dioxide respectively 0.5%, and mix homogeneously is encapsulated.The selection result sees the following form.
Craft screening
As seen from the above table, supplementary material is all crossed 80 mesh sieves in the prescription 30, and content uniformity is defective, and the hydrochlorothiazide dissolution is on the low side.31 supplementary materials of writing out a prescription are all crossed 100 mesh sieves, and the hydrochlorothiazide dissolution is on the low side, and irbesartan is difficult for sieving.So pulverize 120 orders when hydrochlorothiazide, then its dissolution can't reach 90%.32 supplementary materials of writing out a prescription are all crossed 120 mesh sieves, and irbesartan and other adjuvant are difficult for sieving, and stick with paste sieve easily, make material response rate in preparation process on the low side.Irbesartan is crossed 80 mesh sieves in the prescription 33, hydrochlorothiazide is crossed 120 mesh sieves, other adjuvants are crossed 100 mesh sieves, reduced drug particle size, increase specific surface area, flowability, filling and the content uniformity of degree of mixing, particle all are significantly improved, and improved the dissolubility and the dissolution velocity of irbesartan and hydrochlorothiazide, reached and improved the purpose of dissolution, thereby made medicine bring into play drug effect better.Therefore, determine that irbesartan and hydrochlorothiazide should sieve before adding, irbesartan is crossed 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves; Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively.
2, in the product of the present invention, the content uniformity is a key issue, and the inventor at first adopts the powder fill, since mobile poor, cause a method of double differences different big, and because mechanical vibration cause the material layering phenomenon, the medicament contg uniformity is defective as a result in the pouring process.The inventor adopts the wet granulation fill afterwards, because irbesartan and hydrochlorothiazide consumption differ greatly, wherein irbesartan is 12 times of hydrochlorothiazide weight, so, the inventor is irbesartan and other adjuvant equivalent method mixing that progressively increases the most at last, carry out fill after adopting wet granulation, the medicament contg uniformity is good as a result.Therefore, the inventive method adopts the equivalent method of progressively increasing to carry out mixing.
3, the present invention adopts fluid-bed drying, and wet granular to be dried seethes up and down under the blowing of heat-flash air, is in the fluid boiling state, and realizes contacting of fullest with thermal current, thereby obtains dry rapidly.Fluid-bed drying and conventional drying method are relatively, and be simple in structure, easy to operate; Relative motion fierceness during operation between granule and air-flow, contact area is big, has strengthened heat transfer, mass transfer, shortens drying time, has improved dry rate.Among the present invention with wet granular airpillow-dry below 60 ℃ to moisture less than 3.0%, used temperature is relatively low just can to reach same effect, effectively guaranteed irbesartan and hydrochlorthiazide stability, and drying effect is good, the granule that is dried is dynamic, do not have in the dry run that uneven drying is even to make phenomenons such as the principal agent composition departs from, the dried amount is big, can realize industrialization production.
4, the irbesartan hydrochlorothiazide capsule made of the present invention has the following advantages:
(1) can cover the abnormal smells from the patient of irbesartan and hydrochlorthiazide crude drug: because of medicine is wrapped in the capsule, so can cover the bitterness and the bad smell of medicine;
(2) can improve the stability of irbesartan and hydrochlorthiazide:,, improve medicine stability so can completely cut off contacting of medicine and light, air and dampness because of medicine is wrapped in the capsule;
(3) bioavailability height: because of the preparation of capsule plus-pressure not, do not need disintegrate and molten loosing, so in gastrointestinal, disperse soon, good absorbing, bioavailability height;
(4) preparation method of irbesartan hydrochlorothiazide capsule provided by the present invention, not only overcome the degradation problem of irbesartan and hydrochlorthiazide well, and the irbesartan and hydrochlorthiazide mobility of particle that adopts this method to obtain is good, drug dissolution is good, the capsule content uniformity is little.
Test example 7 stability tests
Test sample: according to three batches of embodiment 1 prescription and prepared irbesartan hydrochlorothiazide capsules.
(1) accelerated test
Three batch sample commercially available backs place under 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition and placed 6 months, and gainer is checked in sampling during respectively at 1,2,3,6 month, and result of the test sees the following form.
Accelerated test result
Conclusion: as seen from the experiment, this product is placed after 6 months under acceleration environment, and every index does not all have obvious variation, and having good stability of this product is described.
(2) long term test
Declare the production sample commercially available back, place under room temperature (25 ℃ ± 2 ℃, relative humidity 60% ± 10%) condition, in the stipulated time sampling, check gainer, result of the test sees the following form.
Long-term test results
Conclusion: as seen from the experiment, after this product was placed 36 months at ambient temperature, every index did not all have significant change.
8 clinical trials of test example
22 health volunteers single oral is developed by Beijing Sihuankebao Pharmaceutical Co., Ltd. under the empty stomach condition irbesartan hydrochlorothiazide capsules of the present invention (being subjected to test preparation) and commercially available irbesartan and hydrochlorthiazide sheet (An Bonuo, reference preparation) compares, Bioavailability of Human Body is: irbesartan: 100.7% ± 19.4%, hydrochlorothiazide: 98.5% ± 13.3%, stipulate in the equivalence margin, through to the AUC that is subjected to test preparation after the number conversion
0-tThen judge two medicine bioequivalences in the 80%-125% of reference preparation scope, therefore, its bioavailability meets the requirements; Statistical results show, two preparations have bioequivalence.
22 health volunteers single oral irbesartan and hydrochlorthiazide of the present invention under the empty stomach condition is subjected to test preparation and reference preparation, and researcher carries out close clinical observation to all experimenters in the process of the test.The result shows, in this research process adverse events does not take place.Its vital sign and physical examination are all no abnormal after 22 healthy volunteer's administrations.Studies show that health volunteer's single oral has good safety by the irbesartan hydrochlorothiazide capsule of the present invention of Beijing Sihuankebao Pharmaceutical Co., Ltd.'s development.
In sum, irbesartan hydrochlorothiazide capsule of the present invention is quality controllable, safety, effectively.
Test example 9 contrast experiments
The present invention compares its dissolution and content uniformity, related substance, content according to product irbesartan hydrochlorothiazide capsule and the patent 02146334 disclosed irbesartan hydrochlorothiazide capsule that embodiment 1 obtains.The results are shown in following table.
Publication product: respectively adjuvant is crossed 100 mesh sieves, stronger principal agent irbesartan 150g and hydrochlorothiazide 12.5g owing to viscosity, granule is very little, with its oven dry, claim adjuvant by formula ratio, pregelatinized corn starch 25g (diluent), lactose 120g (diluent, correctives), microcrystalline Cellulose 30g (diluent, disintegrating agent), cross-linking sodium carboxymethyl cellulose 10g (disintegrating agent), silicon dioxide 3g (fluidizer), with the principal agent mix homogeneously, add 15g binding agent 10% polyvinylpyrrolidone-K30, wet method system soft material, cross 20 mesh sieves, in 50 ℃ of baking ovens after the aeration-drying, add magnesium stearate 1.5g (lubricant), cross 20 mesh sieve granulate, pack into No. 1 or No. 0 capsule in.
Comparative test result
The inventor experimentizes according to patent 02146334 disclosed scheme, finds that the capsule dissolution of preparing is low, and content uniformity is big, and prescription of the present invention and technology are much better than patent 02146334 disclosed scheme.
Adopt pregelatinized corn starch, microcrystalline Cellulose, lactose to do filler in the 02146334 disclosed irbesartan hydrochlorothiazide capsule prescription, cross-linking sodium carboxymethyl cellulose is made disintegrating agent, and 10% 30 POVIDONE K 30 BP/USP 30 is as binding agent.When the inventor finds to adopt microcrystalline Cellulose and pregelatinized corn starch, lactose use in conjunction, dissolution is bad, by analysis main cause have following some: microcrystalline Cellulose has the dual function of filler and disintegrating agent, it has spongiform porous tubular structured, after making it meet water, impel the capsule disintegrate.But experimental results show that this kind has particularity, may weaken the short disintegration of microcrystalline Cellulose when microcrystalline Cellulose and lactose, pregelatinized corn starch use in conjunction; In addition, this patent is big as its actual pelletization material viscosity of binding agent with 10% 30 POVIDONE K 30 BP/USP 30, is difficult for moistening, the difficulty of granulating, and the high concentration povidone solution also can influence its capsule disintegrate and stripping as binding agent, is not ideal capsules preparation technique.
Following embodiment all can realize the described effect of above-mentioned experimental example
Following specific embodiment further describes the present invention, but described embodiment only is used to illustrate the present invention rather than restriction the present invention.
Embodiment 1
Irbesartan 150g
Hydrochlorothiazide 12.5g
Microcrystalline Cellulose 45g
Cross-linking sodium carboxymethyl cellulose 20g
Silicon dioxide 0.5%
Magnesium stearate 0.5%
30 POVIDONE K 30 BP/USP 30 is an amount of.
Make 1000 altogether
A, to take by weighing 30 POVIDONE K 30 BP/USP 30 an amount of, with 50% dissolve with ethanol solution and make 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, as binding agent, standby;
B, with irbesartan cross 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves, and is standby;
C, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively, standby;
D, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, the method mixing that cross-linking sodium carboxymethyl cellulose adopts equivalent to progressively increase, mixture I;
E, with the irbesartan mix homogeneously of said mixture I and recipe quantity, be binding agent system soft material with 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, high speed shear system wet granular.Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate.Add magnesium stearate and silicon dioxide, mix homogeneously;
F, mensuration intermediate content calculate loading amount, and is encapsulated;
G, product inspection, the packing warehouse-in.
Embodiment 2
Irbesartan 122g
Hydrochlorothiazide 14.8g
Microcrystalline Cellulose 40g
Cross-linking sodium carboxymethyl cellulose 19.5g
Silicon dioxide 0.68%
Magnesium stearate 0.36%
30 POVIDONE K 30 BP/USP 30 is an amount of.
Make 1000 altogether
A, to take by weighing 30 POVIDONE K 30 BP/USP 30 an amount of, with 50% dissolve with ethanol solution and make 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, as binding agent, standby;
B, with irbesartan cross 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves, and is standby;
C, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively, standby;
D, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, the method mixing that cross-linking sodium carboxymethyl cellulose adopts equivalent to progressively increase, mixture I;
E, with the irbesartan mix homogeneously of said mixture I and recipe quantity, be binding agent system soft material with 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, high speed shear system wet granular.Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate.Add magnesium stearate and silicon dioxide, mix homogeneously;
F, mensuration intermediate content calculate loading amount, and is encapsulated;
G, product inspection, the packing warehouse-in.
Embodiment 3
Irbesartan 163g
Hydrochlorothiazide 11.2g
Microcrystalline Cellulose 47.9g
Cross-linking sodium carboxymethyl cellulose 22.1g
Silicon dioxide 0.30%
Magnesium stearate 0.68%
30 POVIDONE K 30 BP/USP 30 is an amount of.
Make 1000 altogether
A, to take by weighing 30 POVIDONE K 30 BP/USP 30 an amount of, with 50% dissolve with ethanol solution and make 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, as binding agent, standby;
B, with irbesartan cross 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves, and is standby;
C, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively, standby;
D, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, the method mixing that cross-linking sodium carboxymethyl cellulose adopts equivalent to progressively increase, mixture I;
E, with the irbesartan of said mixture I and recipe quantity with putting in the mixer-granulator, mix, be binding agent system soft material with 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, high speed shear system wet granular.Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate.Add magnesium stearate and silicon dioxide, mix homogeneously;
F, mensuration intermediate content calculate loading amount, and is encapsulated;
G, product inspection, the packing warehouse-in.
Embodiment 4
Irbesartan 122g
Hydrochlorothiazide 14.8g
Microcrystalline Cellulose 40g
Cross-linking sodium carboxymethyl cellulose 19.5g
Silicon dioxide 0.68%
Magnesium stearate 0.36%
30 POVIDONE K 30 BP/USP 30 is an amount of.
Make 1000 altogether
A, to take by weighing 30 POVIDONE K 30 BP/USP 30 an amount of, with 50% dissolve with ethanol solution and make 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, as binding agent, standby;
B, with irbesartan cross 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves, and is standby;
C, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively, standby;
D, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, the method mixing that cross-linking sodium carboxymethyl cellulose adopts equivalent to progressively increase, mixture I;
E, with the irbesartan of said mixture I and recipe quantity with putting in the mixer-granulator, mix, be binding agent system soft material with 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, high speed shear system wet granular.Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate.Add magnesium stearate and silicon dioxide, mix homogeneously;
F, mensuration intermediate content calculate loading amount, and is encapsulated;
G, product inspection, the packing warehouse-in.
Embodiment 5
Irbesartan 163g
Hydrochlorothiazide 11.2g
Microcrystalline Cellulose 47.9g
Cross-linking sodium carboxymethyl cellulose 22.1g
Silicon dioxide 0.30%
Magnesium stearate 0.68%
30 POVIDONE K 30 BP/USP 30 is an amount of.
Make 1000 altogether
A, to take by weighing 30 POVIDONE K 30 BP/USP 30 an amount of, with 50% dissolve with ethanol solution and make 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, as binding agent, standby;
B, with irbesartan cross 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves, and is standby;
C, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively, standby;
D, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, the method mixing that cross-linking sodium carboxymethyl cellulose adopts equivalent to progressively increase, mixture I;
E, with the irbesartan of said mixture I and recipe quantity with putting in the mixer-granulator, mix, be binding agent system soft material with 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, high speed shear system wet granular.Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate.Add magnesium stearate and silicon dioxide, mix homogeneously;
F, mensuration intermediate content calculate loading amount, and is encapsulated;
G, product inspection, the packing warehouse-in.
Embodiment 6
Irbesartan 150g
Hydrochlorothiazide 12.5g
Microcrystalline Cellulose 45g
Cross-linking sodium carboxymethyl cellulose 20g
Silicon dioxide 0.5%
Magnesium stearate 0.5%
30 POVIDONE K 30 BP/USP 30 is an amount of.
Make 1000 altogether
A, to take by weighing 30 POVIDONE K 30 BP/USP 30 an amount of, with 50% dissolve with ethanol solution and make 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, as binding agent, standby;
B, with irbesartan cross 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves, and is standby;
C, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively, standby;
D, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, the method mixing that cross-linking sodium carboxymethyl cellulose adopts equivalent to progressively increase, mixture I;
E, with the irbesartan of said mixture I and recipe quantity with putting in the mixer-granulator, mix, be binding agent system soft material with 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30, high speed shear system wet granular.Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate.Add magnesium stearate and silicon dioxide, mix homogeneously;
F, mensuration intermediate content calculate loading amount, and is encapsulated;
G, product inspection, the packing warehouse-in.
Claims (8)
1. irbesartan hydrochlorothiazide capsule is characterized in that this capsule prescription is composed as follows:
Irbesartan 120-170 weight portion
Hydrochlorothiazide 10-15 weight portion
Microcrystalline Cellulose 40-50 weight portion
Cross-linking sodium carboxymethyl cellulose 18-23 weight portion
Silicon dioxide 0.3-0.8%
Magnesium stearate 0.3-0.8%
Polyvidone is an amount of.
2. irbesartan hydrochlorothiazide capsule as claimed in claim 1 is characterized in that this capsule prescription composition is preferably as follows:
Irbesartan 122 weight portions
Hydrochlorothiazide 14.8 weight portions
Microcrystalline Cellulose 40 weight portions
Cross-linking sodium carboxymethyl cellulose 19.5 weight portions
Silicon dioxide 0.68%
Magnesium stearate 0.36%
Polyvidone is an amount of.
3. irbesartan hydrochlorothiazide capsule as claimed in claim 1 is characterized in that this capsule prescription composition is preferably as follows:
Irbesartan 163 weight portions
Hydrochlorothiazide 11.2 weight portions
Microcrystalline Cellulose 47.9 weight portions
Cross-linking sodium carboxymethyl cellulose 22.1 weight portions
Silicon dioxide 0.30%
Magnesium stearate 0.68%
Polyvidone is an amount of.
4. irbesartan hydrochlorothiazide capsule as claimed in claim 1 is characterized in that this capsule prescription composition is preferably as follows:
Irbesartan 150 weight portions
Hydrochlorothiazide 12.5 weight portions
Microcrystalline Cellulose 45 weight portions
Cross-linking sodium carboxymethyl cellulose 20 weight portions
Silicon dioxide 0.5%
Magnesium stearate 0.5%
Polyvidone is an amount of.
5. as the arbitrary described irbesartan hydrochlorothiazide capsule of claim 2-4, it is characterized in that the preparation method of described irbesartan hydrochlorothiazide capsule is:
A, to take by weighing polyvidone an amount of, with dissolve with ethanol solution and make povidone solution, as binding agent, standby;
B, irbesartan, hydrochlorothiazide, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are sieved respectively, standby;
C, take by weighing recipe quantity hydrochlorothiazide, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mixing, mixture I;
D, with the irbesartan mix homogeneously of said mixture I and recipe quantity, be binding agent system soft material with the povidone solution, the system wet granular; Wet granular is at airpillow-dry below 60 ℃, and pellet moisture is controlled at below 2～3%, 20 mesh sieve granulate; Add magnesium stearate and silicon dioxide, mix homogeneously;
E, mensuration intermediate content calculate loading amount, and is encapsulated.
6. capsule according to claim 5 is characterized in that among the described preparation method step c be to carry out mixing according to the equivalent method of progressively increasing.
7. capsule according to claim 5 is characterized in that described preparation method step b irbesartan is crossed 80 mesh sieves, hydrochlorothiazide is crossed 120 mesh sieves; Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are crossed 100 mesh sieves respectively.
8. capsule according to claim 5 is characterized in that described preparation method step a povidone solution is 50% alcoholic solution of 4% 30 POVIDONE K 30 BP/USP 30.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010112077XA CN101780089B (en) | 2010-02-23 | 2010-02-23 | Irbesartan hydrochlorothiazide capsule and preparation method thereof |
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| CN101780089B true CN101780089B (en) | 2011-08-17 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1199641C (en) * | 2002-10-24 | 2005-05-04 | 王登之 | Compound irbesartan capsule for curing high blood pressure |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1199641C (en) * | 2002-10-24 | 2005-05-04 | 王登之 | Compound irbesartan capsule for curing high blood pressure |
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