CN102119930B - Olmesartan medoxomil tablets and preparation method thereof - Google Patents
Olmesartan medoxomil tablets and preparation method thereof Download PDFInfo
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- CN102119930B CN102119930B CN 201010224565 CN201010224565A CN102119930B CN 102119930 B CN102119930 B CN 102119930B CN 201010224565 CN201010224565 CN 201010224565 CN 201010224565 A CN201010224565 A CN 201010224565A CN 102119930 B CN102119930 B CN 102119930B
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- lactose
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Abstract
The invention discloses olmesartan medoxomil tablets and a preparation method thereof. The cores of 1000 olmesartan medoxomil tablets comprise 20g of olmesartan medoxomil, 60-95g of lactose (1), 30g of lactose (2), 45-50g of microcrystalline cellulose, 5g of polyvinylpyrrolidone K30 (PVPK30), 8g of low-substituted hydroxypropyl cellulose (L-HPC), 1g of magnesium stearate and an ethanol water solution for preparing a soft material. The invention solves the problem that no olmesartan medoxomil tablets can be used clinically at present.
Description
Technical field
The present invention relates to medicine field, in particular to a kind of olmesartan medoxomil tablet and preparation method.
Background technology
Death toll it is said also higher than the summation of other 7 kinds of underlying cause of death diseases (comprising that cancer and AIDS/HIV infect) due to the cardiovascular diseases.Hypertension is the most popular among the cardiovascular diseases and becomes a problem of new drug development merchant emphasis.F﹠amp; The estimation of S market research agency, the growth of hypertension therapeutic will stimulate the expansion in cardiovascular drug market, the world, will contribute approximately 10 percentage points for the year overall growth rate of cardiovascular drug by 2002.Add that pharmacy industry faces huge chance to demand effective, the medicine that has no side effect.
Antihypertensive claims again depressor, means effectively to reduce blood pressure the medicine for the treatment of vascular hypertension.Position according to Main Function can be divided into multiclass, and wherein the focus of research is (1) calcium antagonist: nifedipine, nimodipine, nitrendipine, non-promise Horizon, bepridil.(2) angiotensin converting enzyme inhibitor; (3) Angiotensin Ⅱ receptor antagonist.Olmesartan medoxomil is one of state-of-the art Angiotensin Ⅱ receptor antagonist.The effect of the Olmesartan pair AT2 receptor not too relevant with cardiovascular system than AT1 receptor a little less than 12500 times.Therefore because Olmesartan does not suppress ACE, it does not affect the degraded of Kallidin I, on the not impact of effect of Kallidin I, on the serum potassium level without impact.
Olmesartan medoxomil tablet can be used for each phase hypertension.But also there is not at present clinically spendable olmesartan medoxomil tablet.The preparation method of any olmesartan medoxomil tablet is not disclosed in the prior art in addition, yet.
Summary of the invention
For the problem that does not have spendable olmesartan medoxomil tablet clinically in the prior art and propose the present invention, for this reason, main purpose of the present invention is to provide a kind of olmesartan medoxomil tablet and preparation method, to address the above problem.
To achieve these goals, according to an aspect of the present invention, a kind of olmesartan medoxomil tablet is provided, and the label of 1000 olmesartan medoxomil tablets comprises: olmesartan medoxomil 20g, lactose 1. 60g to 95g, lactose 2. 30g, microcrystalline Cellulose 45g to 50g, 5g PVPK30, low-substituted hydroxypropyl cellulose L-HPC 8g, magnesium stearate 1g and be used for the ethanol water of soft material processed.
Preferably, the coating solution of described 1000 olmesartan medoxomil tablets comprises: coating powder 5.1g and 64ml ethanol water.
Preferably, described ethanol water is 50% ethanol water.
Preferably, 1. described lactose is 60g.
Preferably, described microcrystalline Cellulose is 45g.
To achieve these goals, according to another fermentation of the present invention, a kind of preparation method of above-mentioned olmesartan medoxomil tablet also is provided, comprise: lactose 2., microcrystalline Cellulose, PVPK30 and L-HPC all cross 80 mesh sieves, with olmesartan medoxomil and lactose 1. mixed grinding cross 100 after 2 hours, 120 or 160 mesh sieves, to contain olmesartan medoxomil powder and lactose 2. by recipe quantity, microcrystalline Cellulose, PVPK30, behind the L-HPC mix homogeneously, with ethanol water soft material processed, granulate with 24 mesh sieves, the oven dry, behind the 22 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity after, stamping is put into the coating pan coating with the gained sheet.
Preferably, olmesartan medoxomil and lactose 1. mixed grinding cross 120 mesh sieves after 2 hours.
Preferably, use 50 ℃ of oven dry.
Preferably, with φ 8mm stamping.
Preferably, the gained sheet is put into coating pan coating weightening finish 2-3%.
By the present invention, having solved does not have the clinically problem of spendable olmesartan medoxomil tablet at present.
Description of drawings
Accompanying drawing described herein is used to provide a further understanding of the present invention, consists of the application's a part, and illustrative examples of the present invention and explanation thereof are used for explaining the present invention, do not consist of improper restriction of the present invention.In the accompanying drawings:
Fig. 1 is the preparation technology's flow chart according to the olmesartan medoxomil tablet of the embodiment of the invention.
The specific embodiment
Need to prove, in the situation that do not conflict, embodiment and the feature among the embodiment among the application can make up mutually.Describe below with reference to the accompanying drawings and in conjunction with the embodiments the present invention in detail.
The tablet of olmesartan medoxomil tablet can have 5 milligrams, 20 milligrams, 40 milligrams three kinds of specifications, carries out the administration individuation to make things convenient for patient according to the state of an illness.In following enforcement with
One, prescription
20mg is that specification is studied in selection.By research, determine that this product prescription is:
1, Core formulation:
Olmesartan medoxomil 20g
Lactose is 60g 1.
Lactose is 30g 2.
Microcrystalline Cellulose 45g
PVPK30 5g
Low-substituted hydroxypropyl cellulose (L-HPC) 8g
50% ethanol water is an amount of
Magnesium stearate 1g
Make 1000
2, coating fluid prescription (1000):
Coating powder 5.1g
50% ethanol 64ml
Two, technique
Fig. 1 is the preparation technology's flow chart according to the olmesartan medoxomil tablet of the embodiment of the invention, as shown in Figure 1, lactose 2., microcrystalline Cellulose, PVPK30, L-HPC all crosses 80 mesh sieves, with principal agent and lactose 1. mixed grinding cross 120 mesh sieves after 2 hours, to contain principal agent powder and lactose 2. by recipe quantity, microcrystalline Cellulose, PVPK30, behind the L-HPC mix homogeneously, with 50% ethanol water soft material processed, granulate with 24 mesh sieves, 50 ℃ of oven dry, behind the 22 mesh sieve granulate, after adding the magnesium stearate mixing of recipe quantity, with φ 8mm stamping, the gained sheet is put into the coating pan coating increase weight to 2-3% and get final product.
Three, prescription screening
The result shows: prescription I dissolution very low (on average being about 13%); Prescription II principal agent dissolution after 160 orders sieve increases (being about 40%), but still lower; In prescription III and the IV principal agent and part lactose through mixed grinding after 2 hours dissolution reach more than 80%, and prescription and prescription III are relatively, it is smooth that prescription IV gained sheet shows, mobility of particle is good, hardness is suitable, so select the prescription IV finally to write out a prescription as this product.
Five, the influence factor of pilot sample test
Get this product pilot sample (lot number: 030819), remove outer package, 30 every part, place respectively the glass dish of having weighed.Place respectively 40 ℃ of baking ovens, 60 ℃ of baking ovens, fill saturated nacl aqueous solution exsiccator, fill the exsiccator of saturated potassium nitrate solution and the lighting box of 4500Lx, placed 10 days, weigh in sampling in the 5th and 10 day, and inspection appearance character, related substance, dissolution and content, the results are shown in Table 1, relevant collection of illustrative plates is seen accompanying drawing.
Table 1 olmesartan medoxomil tablet influence factor result of the test
The result shows, olmesartan medoxomil tablet is under influence factor's experimental condition, and except high temperature was slightly weightless, high humility slightly increases weight, other indices had no significant change.As seen this product is stable under influence factor's experimental condition, writes out a prescription feasible.
The Olmesartan pharmacokinetics
Ordinary circumstance
Olmesartan medoxomil is through possessing biological activity rapidly and behind the fully steatolysis generation Olmesartan after the gastrointestinal absorption.Olmesartan is eliminated with Double-phase, and approximately 13 hours half-life is eliminated at the end mutually.With 320 milligrams single oral dose administrations or high to 80 milligrams dosage repeatedly during oral administration pharmacokinetics present linear feature.
The plasma concentration of Olmesartan reached stable state after the administration in 3～5 days once a day, did not produce and accumulated.The absolute bioavailability of Olmesartan approximately is 26%.In the time of 1～3 hour, reach peak serum concentration (Cmax) after taking medicine.Food does not affect the bioavailability of Olmesartan.
Metabolism and drainage
After olmesartan medoxomil was rapidly absorbed and changes into Olmesartan fully, Olmesartan was not in fact by further metabolism.The blood plasma total body clearance of Olmesartan is 1.3L/h, and the kidney clearance rate is 0.6L/h.Approximately 35%～50% the amount of being absorbed is detected in urine, and remainder is by feces or bile excretion.
Distribute
The distribution volume of Olmesartan approximately is 17 liters.The combination rate of Olmesartan and plasma protein high (99%) impermeablely enters erythrocyte.When giving the medicine of recommended amounts, Olmesartan and plasma protein secure bond.Olmesartan is difficult to the blood brain barrier by rat, even can not pass through blood brain barrier.Olmesartan can enter tire by the Rat Placenta barrier.The Olmesartan of small part can be distributed into the milk of rat.
Special population
The child: patient's the pharmacokinetic data available that is lower than 18 years old is not bright.
The old people: in the pharmacokinetic studies of the old people above 65 years old, the maximum plasma concentration of Olmesartan is similar to the adolescent.Observe the phenomenon of accumulating of moderate behind the multiple dosing.CLR 30%, the AUCss that approximately descends approximately rises 33%.
Sex: only have small difference.Women's AUC and Cmax are all approximately high by 10～15%.
The renal insufficiency patient: renal insufficiency patient's serum Olmesartan concentration is high than the intact person of renal function.AUC approximately rises to 3 multiples behind the severe renal function sufferer multiple dosing.The patient who need is carried out Kidney Dialysis does not carry out Medication study.
Hepatic insufficiency patient: moderate hepatic insufficiency patient's AUC0-∞ and Cmax approximately exceed 60% than the coupling matched group.
Clinical experiment
7 take placebo as the contrast antihypertensive clinical experiment in, the dosage of olmesartan medoxomil is 2.5～80mg, 6～12 weeks of administration cycle; The effect of peak value and valley all occurs significantly reducing blood pressure.Among the typical hypertensive patient of 2693 examples (administration group 2145 examples, placebo group 548 examples), once a day administration of olmesartan medoxomil can reduce systolic pressure and diastolic pressure, effect and dosage positive correlation (as shown in the figure) altogether.
Every day, 20 milligrams olmesartan medoxomil caused blood pressure valley decline 10/6mmHg.Every day, 40 milligrams olmesartan medoxomil caused blood pressure valley decline 12/7mmHg.The medicine that is higher than 40 milligrams there is no stronger effect.Antihypertensive function occurred within one week of administration, and is obvious after 2 weeks.
The effect that reduces blood pressure was all arranged in 24 hours after the once a day administration of olmesartan medoxomil, the valley of contraction, diastole effect/peak value ratio is between 60～80%.No matter with the hydrochlorothiazide coupling, the effect that reduces blood pressure of olmesartan medoxomil can be maintained until 1 year.Long-term prescription occurs without drug resistance, and withdrawal is without bounce-back after the term medication.
It is similar that age is lower than the pressure reduction effect that 65 years old male female patients uses behind the olmesartan medoxomil.The group difference response class that occurs with ACE inhibitor, angiotensin receptor blocker and beta-blockers seemingly, olmesartan medoxomil is on the weak side to Black people's effect.When being additional to hydrochlorothiazide, olmesartan medoxomil has extra antihypertensive effect.
Untoward reaction
In the 3825 routine hypertensive patients that are evaluated (3275 examples are patients that experiment was selected in of tool matched group), the olmesartan medoxomil medication surpasses 900 examples that have in June, and medication surpasses 525 examples in 1 year.Olmesartan medoxomil is by well tolerable, and the incidence rate of untoward reaction is similar to placebo.
Untoward reaction is gentle, and is of short duration, uncorrelated with the olmesartan medoxomil administration, and total incidence rate is uncorrelated with dosage.
The ratio that withdraws from test because of adverse events is 2.4%, 2.7% (Olmesartan group vs. matched group); In the test of placebo, the ratio that withdraws from test because of adverse events is 3%, 1% (Olmesartan group vs. matched group);
Above-mentioned digital proof, the olmesartan medoxomil tablet of the present embodiment is safely and effectively.
The above is the preferred embodiments of the present invention only, is not limited to the present invention, and for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (4)
1. olmesartan medoxomil tablet, it is characterized in that: the label of 1000 olmesartan medoxomil tablets comprises: olmesartan medoxomil 20g, lactose 1. 60g, lactose 2. 30g, microcrystalline Cellulose 45g to 50g, 5g PVPK30, low-substituted hydroxypropyl cellulose L-HPC8g, magnesium stearate 1g and be used for the ethanol water of soft material processed; Its preparation method is as follows: lactose 2., microcrystalline Cellulose, PVPK30 and L-HPC all cross 80 mesh sieves, with olmesartan medoxomil and lactose 1. mixed grinding cross 100,120 or 160 mesh sieves after 2 hours, by recipe quantity will contain olmesartan medoxomil powder and lactose 2., behind the microcrystalline Cellulose, PVPK30, L-HPC mix homogeneously, with ethanol water soft material processed, granulate oven dry with 24 mesh sieves, behind the 22 mesh sieve granulate, after adding the magnesium stearate mixing of recipe quantity, stamping is put into the coating pan coating with the gained sheet.
2. olmesartan medoxomil tablet according to claim 1, it is characterized in that: the coating solution of described 1000 olmesartan medoxomil tablets comprises: coating powder 5.1g and 64ml ethanol water.
3. olmesartan medoxomil tablet according to claim 1 and 2, it is characterized in that: described ethanol water is 50% ethanol water.
4. olmesartan medoxomil tablet according to claim 1, it is characterized in that: described microcrystalline Cellulose is 45g.
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| CN104398485B (en) * | 2014-12-10 | 2017-05-10 | 哈药集团技术中心 | Olmesartan medoxomil tablet and preparation method thereof |
| CN105640913B (en) * | 2016-01-22 | 2018-11-02 | 山东省医学科学院药物研究所 | A kind of olmesartan medoxomil tablet and preparation method thereof |
| CN110638772A (en) * | 2019-10-29 | 2020-01-03 | 白喜平 | Olmesartan medoxomil tablet and preparation method thereof |
| CN111557924B (en) * | 2020-05-13 | 2022-05-10 | 重庆赛凌医药有限公司 | Preparation method of olmesartan medoxomil hydrochlorothiazide tablet and olmesartan medoxomil hydrochlorothiazide tablet |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066264A (en) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | Solid olmesartan medoxmil dispersion and its prepn and medicinal application |
| CN101478966A (en) * | 2006-06-27 | 2009-07-08 | 第一三共株式会社 | Compressed preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101478966A (en) * | 2006-06-27 | 2009-07-08 | 第一三共株式会社 | Compressed preparation |
| CN101066264A (en) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | Solid olmesartan medoxmil dispersion and its prepn and medicinal application |
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