CN105055348A - Medicinal erdosteine composition tablet for treating respiratory tract inflammation and preparation method of tablet - Google Patents

Medicinal erdosteine composition tablet for treating respiratory tract inflammation and preparation method of tablet Download PDF

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Publication number
CN105055348A
CN105055348A CN201510456524.6A CN201510456524A CN105055348A CN 105055348 A CN105055348 A CN 105055348A CN 201510456524 A CN201510456524 A CN 201510456524A CN 105055348 A CN105055348 A CN 105055348A
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Prior art keywords
erdosteine
weight portion
tablet
composition tablet
hpc21
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刘学键
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Qingdao Lanshengyang Medical Biological Technology Co Ltd
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Qingdao Lanshengyang Medical Biological Technology Co Ltd
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Abstract

The invention relates to a medicinal erdosteine composition tablet for treating respiratory tract inflammation and a preparation method of the composition tablet, belonging to the technical field of medicine. The composition tablet is prepared from erdosteine, sodium carboxymethyl starch, lactose, L-HPC21, 95% of ethanol, magnesium stearate and peppermint essence. The erdosteine is a novel crystalline compound; as shown in X-ray powder diffraction pattern 1 obtained from Cu-K alpha-ray measurement, the erdosteine is different from that reported in the prior art; tests discover that the erdosteine novel crystalline compound is relatively good in dissolution and relatively high in stability; and the prepared tablet is high in dissolution degree, good in stability and quite suitable for clinical application.

Description

Medicine erdosteine composition tablet for the treatment of respiratory inflammation and preparation method thereof
Technical field
The invention belongs to medical art, relate to a kind of medicine erdosteine composition tablet for the treatment of respiratory inflammation.
Background technology
Expectorant is the product of respiratory inflammation, can stimulate respiratory mucosa, causes cough and asthma, and can increase the weight of to infect.When acute/chronic bronchitis or chronic lung diseases respiratory failure, spend height as patient's thick sputum or form expectorant bolt, can clogs airways and cause suffocating.Therefore, use sticky expectorant regulator, make patient's phlegm dissolving, thinning, viscosity reduces, and accelerate respiratory mucosa ciliary movement, improve transport function, tool is of great significance.
This is smooth etc. for the sticky expectorant regulator of current listing such as bromhexine, mesna, carboxylic first, all has sticky expectorant regulating action in various degree, but its pharmacology or there are some defects clinically.Sulfydryl free in molecular structure can adsorb gastrointestinal tract mucin, gastrointestinal tract local damage can be produced after oral, side effect is larger, the antibacterial activity of penicillin, cephalosporins, erythromycin, tetracycline etc. can be weakened, unsuitable drug combination, not high to the improvement effect of some respiration parameter as expectorant viscosity etc.
Erdosteine is a kind of prodrug, with the sulfydryl closed of non-free in its structure, to local mucin inactive, after oral through metabolism produce three containing free sulfhydryl groups metabolite and play pharmacological action, thus oral rear without obvious gastrointestinal side effect.Experiment proves; erdosteine cylinder metabolism-ure can make mucinous disulfide bonds in bronchial secretion; and change secretions composition and rheological property; reduce sputum viscosity; improve downtrod respiratory function; this product energy scavenging free radicals, the oxidation deactivation that available protecting a1-antitrypsin brings out from cigarette, dirt, prevents the damage to elastance of lung albumen and neutrophilic granulocyte.This product obviously can also increase IgA/ albumin, lactoferrin/albuminous ratio, weakens local inflammation, strengthens and improves the osmosis of antibiotic to bronchial mucosa, be conducive to the treatment of the various inflammation of respiratory tract.External clinical clinical studies show: with like product as acetylcysteine, this is smooth for carboxylic first, ambroxol etc. compares, this product has good curative effect to acute/chronic bronchitis, more effective to the improvement of some respiratory function parameter, there is not drug accumulation in heavy dose of administration, Liver and kidney function moderate obstacle to this product characteristics of pharmacokinetics without obvious change.
The water solublity of erdosteine is poor, effective bioavailability in human body is low, and medicine in vivo infiltration rate usually determined by the speed dissolved, medicine in solid preparation is before being absorbed, have to pass through disintegrate and dissolve the process then transferring solution to, if medicine not easily discharges from preparation or the dissolution velocity of medicine is very slow, then the infiltration rate of said preparation Chinese medicine or degree just likely have problems.
The approach of existing solution erdosteine poorly water-soluble mainly comprises change dosage form, as CN101606931B is made into dispersible tablet, although above-mentioned preparation improves the water solublity of medicine to a certain extent, also there is many defects.Therefore, the erdosteine compound that a kind of performance improvement is provided is necessary.
The present inventor starts with from the research of erdosteine solid chemical material existence, a kind of erdosteine compound crystal has been prepared through a large amount of tests, surprisingly find through overtesting, this erdosteine crystal compound has good dissolubility and higher stability, the Dissolution of Tablet made is high, good stability, is very applicable to clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine erdosteine composition tablet for the treatment of respiratory inflammation.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine erdosteine composition tablet for the treatment of respiratory inflammation, described composition tablet is made up of erdosteine, sodium starch glycolate, lactose, L-HPC21,95% ethanol, magnesium stearate, Mint Essence; Described erdosteine is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: with parts by weight, and described composition tablet is made up of the erdosteine of 0.10-0.20 weight portion, the sodium starch glycolate of 0.02-0.04 weight portion, the lactose of 0.06-0.10 weight portion, 95% ethanol of L-HPC21,0.08-0.12 weight portion of 0.03-0.07 weight portion, the magnesium stearate of 0.002-0.006 weight portion, the Mint Essence of 0.003-0.007 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described composition tablet is made up of the erdosteine of 0.15 weight portion, the sodium starch glycolate of 0.03 weight portion, the lactose of 0.08 weight portion, the L-HPC21 of 0.05 weight portion, 95% ethanol of 0.10 weight portion, the magnesium stearate of 0.004 weight portion, the Mint Essence of 0.005 weight portion.
3rd optimal technical scheme of the present invention is: the preparation method of described compositions comprises the following steps:
1) supplementary material process: by erdosteine, sodium starch glycolate, lactose, L-HPC21 whole mistake 80 mesh sieve;
2) weigh: weigh according to technology preparation;
3) mixing granulation: the erdosteine of recipe quantity, sodium starch glycolate, lactose, L-HPC21 are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add 95% alcoholic solution, wet mixing cutting 100-120 soft material second, selects 16 order nylon wires to be arranged in oscillating granulator and granulates;
4) dry: to regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture 1.5%-2.5%;
5) always mix: the Mint Essence of the dry granule after granulate and recipe quantity, magnesium stearate are joined in mixer, mixing velocity 12r/min, open mixer and mix 15 minutes;
6) select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-9kgf;
7) pack.
4th optimal technical scheme of the present invention is: the preparation method of described erdosteine crystal comprises the following steps: get erdosteine crude drug, the volume adding 30 DEG C is in the mixed solvent A of the acetone of erdosteine weight 8 times, cyclohexane extraction, N-methylacetamide, acetone, cyclohexane extraction, N-methylacetamide volume ratio are 3:2:2, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is erdosteine weight 10 times of methanol, isobutanol, water, the volume ratio of methanol, isobutanol, water is 2:3:4; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described erdosteine crystal.
The present invention is by the precise controlling to crystallization condition, prepare a kind of novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this erdosteine crystal unlike the prior art, simultaneously due to the ins and outs of this crystal formation, find through test, this erdosteine crystal compound has good dissolubility and higher stability, and the Dissolution of Tablet made is high, good stability, is very applicable to clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the erdosteine crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of erdosteine crystal
Get erdosteine crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the acetone of erdosteine weight 8 times, cyclohexane extraction, N-methylacetamide, acetone, cyclohexane extraction, N-methylacetamide volume ratio are 3:2:2, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is erdosteine weight 10 times of methanol, isobutanol, water, the volume ratio of methanol, isobutanol, water is 2:3:4; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described erdosteine crystal.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the erdosteine crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of erdosteine sheet, step is as follows:
Prescription: with parts by weight
Preparation method:
1) supplementary material process: by erdosteine, sodium starch glycolate, lactose, L-HPC21 whole mistake 80 mesh sieve;
2) weigh: weigh according to technology preparation;
3) mixing granulation: the erdosteine of recipe quantity, sodium starch glycolate, lactose, L-HPC21 are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add 95% alcoholic solution, wet mixing cutting 100-120 soft material second, selects 16 order nylon wires to be arranged in oscillating granulator and granulates;
4) dry: to regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture 1.5%-2.5%;
5) always mix: the Mint Essence of the dry granule after granulate and recipe quantity, magnesium stearate are joined in mixer, mixing velocity 12r/min, open mixer and mix 15 minutes;
6) select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-9kgf;
7) pack.
embodiment 3:the preparation of erdosteine sheet, step is as follows:
Prescription: with parts by weight
Preparation method:
1) supplementary material process: by erdosteine, sodium starch glycolate, lactose, L-HPC21 whole mistake 80 mesh sieve;
2) weigh: weigh according to technology preparation;
3) mixing granulation: the erdosteine of recipe quantity, sodium starch glycolate, lactose, L-HPC21 are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add 95% alcoholic solution, wet mixing cutting 100-120 soft material second, selects 16 order nylon wires to be arranged in oscillating granulator and granulates;
4) dry: to regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture 1.5%-2.5%;
5) always mix: the Mint Essence of the dry granule after granulate and recipe quantity, magnesium stearate are joined in mixer, mixing velocity 12r/min, open mixer and mix 15 minutes;
6) select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-9kgf;
7) pack.
embodiment 4:the preparation of erdosteine sheet, step is as follows:
Prescription: with parts by weight
Preparation method:
1) supplementary material process: by erdosteine, sodium starch glycolate, lactose, L-HPC21 whole mistake 80 mesh sieve;
2) weigh: weigh according to technology preparation;
3) mixing granulation: the erdosteine of recipe quantity, sodium starch glycolate, lactose, L-HPC21 are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add 95% alcoholic solution, wet mixing cutting 100-120 soft material second, selects 16 order nylon wires to be arranged in oscillating granulator and granulates;
4) dry: to regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture 1.5%-2.5%;
5) always mix: the Mint Essence of the dry granule after granulate and recipe quantity, magnesium stearate are joined in mixer, mixing velocity 12r/min, open mixer and mix 15 minutes;
6) select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-9kgf;
7) pack.
experimental example 1:
This experimental example is the stability test of product of the present invention
1, accelerated test
Three batches of products of Example 1, in temperature be 40 ± 2 DEG C, relative humidity be the condition of 75 ± 5% under place 6 months, respectively at 0,1,2,3,6 the end of month sampling once, measure, in table 1 by high spot reviews project.
Table 1, accelerated test result (temperature 40 ± 2 DEG C, relative humidity 75% ± 5%)
Result shows, this product temperature be 40 ± 2 DEG C, relative humidity be 75 ± 5% conditions under place 6 months, its related substances is low, and each index has no significant change, and this product quality stability is good.
2, long term test
Example 1 product, in temperature be 25 DEG C, relative humidity be 60% ± 10% place, respectively at 0,3,6,9,12,18,24 the end of month sampling and measuring.Measure character, content and related substance according to pertinent regulations under " quality standard " item, record result (the results are shown in following table 2), and compare with criticizing to record for 0 month.
Table 2, long-term test results (temperature 25 ± 2 DEG C, relative humidity 60% ± 5%)
Shown by long-term test results: erdosteine compound of the present invention is 25 ± 2 DEG C in temperature, relative humidity is place under the condition of 60% ± 5% to stablize for 24 months, and indices is without significant change.
experimental example 2:
The water solublity that this experimental example carries out the 3 batch sample erdosteine tablets testing the embodiment of the present invention 3 is tested, compared with commercially available erdosteine.Specific experiment method is: in the low capacity bottle of constant temperature jacket, add appropriate distilled water, experimental drug is added to no longer dissolving at 25 DEG C, start magnetic stirrer, Keep agitation under constant temperature, in experimentation, system is in the state of two-phase coexistent all the time, after 70 minutes system liquid phase in the concentration of erdosteine be dissolubility at this temperature.Carry out sample analysis after 2 hours, get the close meansigma methods of adjacent two times result as measured value of experiment, before sampling, in order to make solid-liquid fully be separated, after stopping stirring, not molten erdosteine is deposited to the bottom of low capacity bottle, extract a small amount of upper clear supernate with syringe, filter with the filter of 0.45 micron, sample thief from filtrate, the content of erdosteine is measured, specifically in table 3 by HPLC.
The water solublity of erdosteine compound of the present invention under table 3 room temperature
From upper table analysis, the relatively commercially available erdosteine of water solublity of erdosteine tablet provided by the invention is higher.

Claims (5)

1. treat a medicine erdosteine composition tablet for respiratory inflammation, it is characterized in that: described composition tablet is made up of erdosteine, sodium starch glycolate, lactose, L-HPC21,95% ethanol, magnesium stearate, Mint Essence; Described erdosteine is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine erdosteine composition tablet for the treatment of respiratory inflammation according to claim 1, it is characterized in that: with parts by weight, described composition tablet is made up of the erdosteine of 0.10-0.20 weight portion, the sodium starch glycolate of 0.02-0.04 weight portion, the lactose of 0.06-0.10 weight portion, 95% ethanol of L-HPC21,0.08-0.12 weight portion of 0.03-0.07 weight portion, the magnesium stearate of 0.002-0.006 weight portion, the Mint Essence of 0.003-0.007 weight portion.
3. the medicine erdosteine composition tablet for the treatment of respiratory inflammation according to claim 2, it is characterized in that, with parts by weight, described composition tablet is made up of the erdosteine of 0.15 weight portion, the sodium starch glycolate of 0.03 weight portion, the lactose of 0.08 weight portion, the L-HPC21 of 0.05 weight portion, 95% ethanol of 0.10 weight portion, the magnesium stearate of 0.004 weight portion, the Mint Essence of 0.005 weight portion.
4. prepare a method for the medicine erdosteine composition tablet according to the arbitrary described treatment respiratory inflammation of claim 1-3, it is characterized in that comprising the following steps:
1) supplementary material process: by erdosteine, sodium starch glycolate, lactose, L-HPC21 whole mistake 80 mesh sieve;
2) weigh: weigh according to technology preparation;
3) mixing granulation: the erdosteine of recipe quantity, sodium starch glycolate, lactose, L-HPC21 are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add 95% alcoholic solution, wet mixing cutting 100-120 soft material second, selects 16 order nylon wires to be arranged in oscillating granulator and granulates;
4) dry: to regulate boiling drier inlet temperature 55 ~ 65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture 1.5%-2.5%;
5) always mix: the Mint Essence of the dry granule after granulate and recipe quantity, magnesium stearate are joined in mixer, mixing velocity 12r/min, open mixer and mix 15 minutes;
6) select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-9kgf;
7) pack.
5. the medicine erdosteine composition tablet for the treatment of respiratory inflammation according to claim 1, is characterized in that: the preparation method of the crystal of described erdosteine comprises the following steps:
Get erdosteine crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the acetone of erdosteine weight 8 times, cyclohexane extraction, N-methylacetamide, acetone, cyclohexane extraction, N-methylacetamide volume ratio are 3:2:2, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is erdosteine weight 10 times of methanol, isobutanol, water, the volume ratio of methanol, isobutanol, water is 2:3:4; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described erdosteine crystal.
CN201510456524.6A 2015-07-30 2015-07-30 Medicinal erdosteine composition tablet for treating respiratory tract inflammation and preparation method of tablet Withdrawn CN105055348A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1720911A (en) * 2004-06-18 2006-01-18 江苏恒瑞医药股份有限公司 Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof
WO2009062659A2 (en) * 2007-11-16 2009-05-22 Edmond Pharma S.R.L. Polymorphs of enantiopure erdosteine
CN101606931A (en) * 2009-08-06 2009-12-23 山东罗欣药业股份有限公司 A kind of erdosteine composition and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1720911A (en) * 2004-06-18 2006-01-18 江苏恒瑞医药股份有限公司 Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof
WO2009062659A2 (en) * 2007-11-16 2009-05-22 Edmond Pharma S.R.L. Polymorphs of enantiopure erdosteine
CN101606931A (en) * 2009-08-06 2009-12-23 山东罗欣药业股份有限公司 A kind of erdosteine composition and preparation method thereof

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Inventor after: Fan Dongmei

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Application publication date: 20151118

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