CN104758269A - Acetylcysteine effervescent tablet - Google Patents
Acetylcysteine effervescent tablet Download PDFInfo
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- CN104758269A CN104758269A CN201510075413.0A CN201510075413A CN104758269A CN 104758269 A CN104758269 A CN 104758269A CN 201510075413 A CN201510075413 A CN 201510075413A CN 104758269 A CN104758269 A CN 104758269A
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- acetylcysteine
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Abstract
The invention discloses an acetylcysteine effervescent tablet and a preparation method thereof, and belongs to the technical field of medicines. The effervescent tablet comprises acetylcysteine, an alkali source, a sweetening agent, a filler and a lubricant. The effervescent tablet has the advantages of being less in excipient varieties, good in external properties, good in stability, simple in process, and easy in large-scale production, and the like.
Description
Technical field
The invention discloses a kind of acetylcysteine effervescent tablet, belong to medical art.
Background technology
Acetylcysteine is white or off-white color crystalline powder, has the foul smell of similar Bulbus Allii, sour in the mouth; Have draw moist; Easily molten in water or ethanol, almost insoluble in chloroform; Fusing point is 104-110 DEG C; Chemistry is by name: ACETYLCYSTEINE.
Chemical structural formula:
Molecular formula: C
5h
9nO
3s
Molecular weight: 163.20
Acetylcysteine (acetylcysteine) is an amino acid derivativges containing sulfydryl (SH), is the precursor substance that cell maintains the important compound reduced glutathion (GSH) of normal physiological function.From the sixties in 19th century, acetylcysteine is just widely used in the treatment of eliminating the phlegm of respiratory system disease as mucolytic agent, a large amount of domestic and international clinical researches proves that acetylcysteine effervescent tablet has remarkable clinical efficacy in treatment is eliminated the phlegm in acute and chronic respiratory tract infection, and toleration is good.At present both at home and abroad widely for the therapeutic alliance of the acute attack and idiopathic pulmonary fibrosis (IPF) that prevent respiratory system commonly encountered diseases chronic obstructive pulmonary disease (COPD).Domestic and international COPD and IPF practice guidelines unanimously recommends acetylcysteine effervescent tablet to be used for preventing the antioxidation of COPD acute attack and IPF treatment, and through a large amount of clinical research confirmation can effectively reduce COPD patient acute attack, delay or stop pulmonary fibrosis process, improve pulmonary function.
After 19 century 70 ends find that acetylcysteine has specially good effect Detoxication to the excessive induced Acute liver failure of acetaminophen, its powerful antioxidant activity and cytoprotection come into one's own.Along with deepening continuously of being familiar with this medicine, find that it all has obvious effect in treatment acquired immune deficiency syndrome (AIDS), cancer, medicine and heavy metal poisoning, heart disease, parkinson disease and smoking infringement etc.Because acetylcysteine has protective effect to liver cell; its vein and oral formulations are widely used in the poisoning caused hepatotoxicity damage for the treatment of acetaminophen (acetaminophen); recent domestic clinical research proves that application acetylcysteine not only can treat the excessive liver failure caused of acetaminophen, also shows good efficacy to the liver failure that other causes of disease cause.
COPD, IPF patient needs for a long time, large dose oral administration acetylcysteine is treated, and therefore, requires that curative effect of medication is definite, untoward reaction is low, patient can well tolerate.In the peroral dosage form that acetylcysteine is all, have effervescent tablet only and be well positioned to meet this kind of special population Treatment need, reason is as follows: because acetylcysteine is in acid (pH value about about 2), main at harmonization of the stomach intestinal absorption, have obvious stimulation to gastric mucosa, again because of in molecular structure with sulfydryl, there is off-odor, therefore be not suitable for making oral normal release dosage form, have effervescent tablet only and can overcome above shortcoming completely.
Effervescent tablet is a kind of tablet containing gas-producing disintegrant.The mixture of so-called gas-producing disintegrant normally organic acid and sodium carbonate, sodium bicarbonate; The dry moisture-free of effervescent tablet itself, two kinds of materials in gas-producing disintegrant are unionized can not react; After water put into by effervescent tablet, two kinds of material generation acid-base reactions, produce a large amount of bubble (carbon dioxide), make the rapid disintegrate of tablet and thawing, and the bubble produced during disintegrate also can make tablet roll up and down in water, accelerates its disintegrate and thawing.The carbon dioxide produced during disintegration of tablet is partially dissolved in drinking-water, has the aesthetic feeling as soda pop when drinking-water is drunk in entrance.Effervescent tablet has following advantage: effervescent tablet disintegrate fast, taking convenience, onset be rapid.Bioavailability is high, can improve clinical efficacy.Be specially adapted to child, old people and the patient of pill difficulty of swallowing.But the adjuvant used by effervescent tablet has stronger hygroscopicity, medicine is mainly granulated by the preparation method of some effervescent tablets of current bibliographical information together with acid source or carbon dioxide source, then with remaining mixing of materials, and tabletting.Therefore its tableting processes be always easy to generation hang fill, sticking phenomenon, how to solve the sticking problem in effervescent tablet production process, be one of insoluble problem of pharmaceutical production one line technology personnel always.
US Patent No. 6066335 discloses a kind of acetylcysteine effervescent tablet, and this effervescent tablet prescription consists of: acetylcysteine, aspartame, cherry essence, propylene glycol, citric acid, sodium bicarbonate, magnesium stearate; Technique is: acetylcysteine mixes 3 minutes with aspartame, cherry essence, granulate as binding agent with propylene glycol, after drying under the humidity environment being less than 25% again with citric acid, sodium bicarbonate mixing 10-15 minute, finally add hard magnesium mix homogeneously, tabletting.This process conditions humidity environment is less than 25%, higher to the requirement of workshop, and GMP workshop is temperature 18-26 DEG C, humidity 45%-65% to temperature, humidity requirement.Humidity is made to be down to less than 25%, to transform on a large scale existing workshop, this will inevitably increase production cost, make troubles to production operation, and the effervescent blade prepared according to the method for this patent is when being dissolved in water, can be floated some materials, to the sensation of a kind of discomfort of people on surface.
US Patent No. 5762951 discloses another acetylcysteine effervescent tablet; the prescription of this effervescent tablet consists of: acetylcysteine, through spray-dired sodium dihydrogen citrate, sodium bicarbonate, micronized fatty acid, polyethylene glycol 6000, stearic acid acyl alcohol fumaric acid sodium, appropriate flavoring agent; wherein alkali and organic acid control particle diameter; and organic acid have passed through process, spraying dry or micronization.Technique is: direct compression.In this prescription, adjuvant will through pre-treatment.Spraying dry or micronization all will increase new equipment and operation sequence, add the difficulty of production.
Chinese patent CN102233139B discloses a kind of acetylcysteine effervescent tablet, the prescription of this effervescent tablet consists of: acetylcysteine 2-6 part, organic acid 3.2-13 part, sodium bicarbonate 3-9.5 part, filler 1.5-13.5 part, dehydrated alcohol 3-4 part, pvpk300.2-0.6 part, glycerol 0.05-0.25 part, sodium chloride 0.05-0.35 part, essence 0.1-0.75 part, sweeting agent 0.1-0.4 part, lubricant 0.15-1.55 part.In this prescription, supplementary material needs complicated pretreatment.50 DEG C of drying under reduced pressure are needed to be less than 1% to moisture.Particle drying part needs first predrying 5 minutes, continues drying again after pre-granulate.Add complex process degree.
Chinese patent CN101947211A discloses a kind of acetylcysteine effervescent tablet, the formula of this effervescent tablet is: a kind of acetylcysteine effervescent tablet, it is characterized in that by the lubricant of the binding agent of the filler of the effervescent of the acetylcysteine of 5-35% weight, 30-70% weight, 0-25% weight, 0-3% weight, 0-5% weight, 0.5-2% weight sweeting agent, the aromatic of 0-10% weight, the interleaving agent of 0.3-2% weight form.The method that this technical scheme adopts interleaving agent dimethicone to carry out wrapping up acid source in effervescent prepares acetylcysteine effervescent tablet.The acid source now adopted and principal agent acetylcysteine granularity are necessary for 0.1-1 millimeter, add technology difficulty.
Italy praises acetylcysteine effervescent tablet that nation (Zambon S.P.A) produces in China's import, trade name " Fluimucil " consists of every sheet containing active component N-acetylcystein 600mg, adjuvant is sodium bicarbonate, anhydrous citric acid, aspartame.Extensively sell in China market, this sheet edge is slightly crude.
Therefore, prior art still need a kind of preparation technology simple, to prepare environment without particular/special requirement, appearance looks elegant, be applicable to the acetylcysteine effervescent tablet of suitability for industrialized production.
Summary of the invention
The invention provides a kind of acetylcysteine effervescent tablet, comprise acetylcysteine, alkali source, filler, lubricant.Wherein, described alkali source is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, one or more in potassium bicarbonate, preferred sodium bicarbonate; Described filler is selected from lactose, compound lactose, mannitol, sorbitol, one or more in soluble starch, preferred lactose; Described lubricant is selected from: polyethylene glycol 6000, Macrogol 4000, sodium chloride, leucine, magnesium stearate, micropowder silica gel, one or more in Pulvis Talci, preferred polyethylene glycol 6000, Macrogol 4000, sodium chloride, leucine, further preferred leucine.
Not containing acid source in the adjuvant of acetylcysteine effervescent tablet of the present invention.Described acid source can be organic acid, includes but not limited to citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, maleic acid, acetone acid, gluconic acid etc.
Optionally, acetylcysteine effervescent tablet of the present invention can also contain sweeting agent, coloring agent, aromatic etc. further.Described sweeting agent includes but not limited to aspartame, stevioside, one or more in sucrose, preferred aspartame; Described coloring agent includes but not limited to sunset yellow, chlorophyll, monascorubin, safflower red pigment, Carthamus yellow, methylene blue, Lac is red, erythrosine, erythrosine aluminum lake, Gardenia Yellow, citron is yellow, tartrazine aluminum lake, medicinal iron oxide red, medicinal iron oxide yellow, medicinal iron oxide violet, medicinal iron oxide palm fibre, carmine, beet red, curcumin, Rhizoma Curcumae Longae aluminum color lake, beet red, grape skin color, newly red, indigo, indigo aluminum color lake; Described aromatic includes but not limited to Fructus Citri Limoniae essence, orange flavor, cherry essence.
Technical scheme of the present invention is adopted to prepare acetylcysteine effervescent tablet, preparation technology is simple, does not need the pretreatment of raw material drying process to less than 1% and not needing to carry out to isolate, the technique such as parcel before tabletting, during tabletting to ambient humidity without particular/special requirement, simultaneously, be applicable to industrialized great production, can not produce the phenomenons such as stagnant punching, sticking, the tablet surface of making is smooth, sheet edge is neat, disintegrate is rapid, stable in properties, overcomes the shortcoming of prior art, achieves excellent effect.
Acetylcysteine effervescent tablet of the present invention, containing (by weight percentage):
Acetylcysteine 8-45%
Alkali source 3-20%
Filler 30-85%
Lubricant 0.5-10%.
Preferably, effervescent tablet of the present invention contains (by weight percentage):
Acetylcysteine 15-35%
Alkali source 5-15%
Filler 35-60%
Lubricant 1-8%.
Wherein, not containing acid source in described acetylcysteine effervescent tablet adjuvant, lubricant is leucine.Described alkali source is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, one or more in potassium bicarbonate, preferred sodium bicarbonate; Described filler is selected from lactose, compound lactose, mannitol, sorbitol, one or more in soluble starch, preferred lactose.
Optionally, sweeting agent, coloring agent, aromatic and/or disintegrating agent etc. can also be contained further in adjuvant.Described sweeting agent includes but not limited to aspartame, stevioside, one or more in sucrose, preferred aspartame; Described coloring agent includes but not limited to sunset yellow, chlorophyll, monascorubin, safflower red pigment, Carthamus yellow, methylene blue, Lac is red, erythrosine, erythrosine aluminum lake, Gardenia Yellow, citron is yellow, tartrazine aluminum lake, medicinal iron oxide red, medicinal iron oxide yellow, medicinal iron oxide violet, medicinal iron oxide palm fibre, carmine, beet red, curcumin, Rhizoma Curcumae Longae aluminum color lake, beet red, grape skin color, newly red, indigo, indigo aluminum color lake; Described aromatic includes but not limited to Fructus Citri Limoniae essence, orange flavor, cherry essence; Described disintegrating agent includes but not limited to sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, starch, microcrystalline Cellulose.
The every sheet of acetylcysteine effervescent tablet of the present invention is 100-1200mg containing the amount of acetylcysteine, preferred 300-900mg, more preferably 400-800mg, most preferably 600mg.Containing alkali source 40-460mg, preferred 100-400mg, more preferably 200-300mg, most preferably 230mg.
On the other hand, the invention provides a kind of method preparing acetylcysteine effervescent tablet, comprise following preparation process: the preparation method of the acetylcysteine effervescent tablet described in above arbitrary claim, comprises following preparation process:
(1) to cross 30 mesh sieves for subsequent use for acetylcysteine;
(2) take acetylcysteine and other adjuvants except lubricant by recipe quantity, mix homogeneously, adds the lubricant of recipe quantity, mix homogeneously, puts into tabletting machine.Control hardness and be greater than 8kg.
Wherein, described accessory package is containing alkali source, filler, lubricant etc.Wherein, described alkali source is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, one or more in potassium bicarbonate, preferred sodium bicarbonate; Described filler is selected from lactose, compound lactose, mannitol, sorbitol, one or more in soluble starch, preferred lactose; Described lubricant is leucine.
Detailed description of the invention
To be illustrated by embodiment below and realize technical scheme of the present invention, these embodiments are not used for limiting the present invention.Those skilled in the art carry out equivalent replacement or corresponding logic improvement according to existing knowledge to the present invention, belong to scope of the present invention.
Following examples are all suppressed in the tabletting workshop meeting GMP standard, adopt the rotary tablet machine of suitability for industrialized production.
Embodiment 1
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 4.6 |
| Aspartame | 0.4 |
| Lactose flowlac100 | 19.6 |
| Leucine | 2.4 |
Technical process:
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine, carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 20 DEG C, humidity 50%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 2
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 6 |
| Sodium bicarbonate | 2.5 |
| Aspartame | 0.4 |
| Lactose flowlac100 | 27.7 |
| Leucine | 2.4 |
Technical process:
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine, carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 22 DEG C, humidity 45%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 3
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 2 |
| Sodium bicarbonate | 0.8 |
| Aspartame | 0.4 |
| Lactose flowlac100 | 19.6 |
| Leucine | 1.44 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine, carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 22 DEG C, humidity 55%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 4
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 24 |
| Sodium bicarbonate | 9.2 |
| Aspartame | 0.4 |
| Lactose flowlac100 | 19.6 |
| Leucine | 3 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine, carry out tabletting, control hardness and be greater than 8kg.
Tabletting ambient temperature 24 DEG C, humidity 60%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 5
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 4.6 |
| Aspartame | 0.4 |
| Mannitol | 19.6 |
| Leucine | 2.4 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, mannitol by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 26 DEG C, humidity 65%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 6
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium carbonate | 4.6 |
| Aspartame | 0.4 |
| Lactose flowlac100 | 19.6 |
| Leucine | 2.4 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium carbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 25 DEG C, humidity 64%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 7
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 4.6 |
| Aspartame | 0.4 |
| Mannitol | 9.8 |
| Lactose flowlac100 | 9.8 |
| Leucine | 2.4 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, mannitol, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 20 DEG C, humidity 60%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 8
Prescription 20,000 unit g
| Composition | Consumption (g) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 4.6 |
| Aspartame | 0.4 |
| Lactose flowlac100 | 19.6 |
| Polyethylene glycol 6000 | 2.4 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
Polyethylene glycol 6000 crosses 100 mesh sieves, for subsequent use.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the polyethylene glycol 6000 mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 45%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 9
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 4.6 |
| Stevioside | 0.4 |
| Lactose flowlac100 | 19.6 |
| Leucine | 2.4 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, stevioside, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 50%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 10
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 4 |
| Aspartame | 0.2 |
| Lactose flowlac100 | 23.4 |
| Leucine | 0.4 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 50%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 11
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12 |
| Sodium bicarbonate | 5.25 |
| Aspartame | 0.75 |
| Lactose flowlac100 | 16.5 |
| Leucine | 3 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 50%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Embodiment 12
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12.00 |
| Sodium bicarbonate | 4.60 |
| Aspartame | 0.40 |
| Lactose flowlac100 | 17.65 |
| Polyvinylpolypyrrolidone | 1.95 |
| Leucine | 2.40 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, sodium bicarbonate, aspartame, lactose by recipe quantity, mix homogeneously, add polyvinylpolypyrrolidone and the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 50%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
Comparative example 1
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12.00 |
| Anhydrous citric acid | 6.00 |
| Sodium bicarbonate | 6.60 |
| Aspartame | 0.40 |
| Lactose flowlac100 | 11.60 |
| Leucine | 2.40 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, anhydrous citric acid, sodium bicarbonate, aspartame, lactose flowlac100 by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 50%, finds obvious stagnant punching and sticking phenomenon during result tabletting 100, cannot continue smooth tabletting.
Comparative example 2
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12.00 |
| Tartaric acid | 6.00 |
| Sodium bicarbonate | 6.60 |
| Aspartame | 0.40 |
| Lactose flowlac100 | 11.60 |
| Leucine | 2.40 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that 100 mesh sieves crossed by leucine.
Take acetylcysteine, tartaric acid, sodium bicarbonate, aspartame, lactose flowlac100 by recipe quantity, mix homogeneously, add the leucine mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 20 DEG C, humidity 48%, finds obvious stagnant punching and sticking phenomenon during result tabletting 100, cannot continue smooth tabletting.
Comparative example 3
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12.00 |
| Anhydrous citric acid | 6.00 |
| Sodium bicarbonate | 6.60 |
| Aspartame | 0.40 |
| Lactose flowlac100 | 11.60 |
| Polyethylene glycol 6000 | 2.40 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
It is for subsequent use that polyethylene glycol 6000 crosses 100 mesh sieves.
By recipe quantity take acetylcysteine, anhydrous citric acid, aspartame, lactose flowlac100, mix homogeneously, adds the polyethylene glycol 6000 mix homogeneously of recipe quantity, puts into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 22 DEG C, humidity 48%, finds obvious stagnant punching and sticking phenomenon during result tabletting 100, cannot continue smooth tabletting.
Comparative example 4
Prescription 20,000
| Composition | Consumption (kg) |
| Acetylcysteine | 12.00 |
| Anhydrous citric acid | 6.00 |
| Sodium bicarbonate | 6.60 |
| Aspartame | 0.40 |
| Lactose flowlac100 | 13.20 |
| Magnesium stearate | 0.80 |
It is for subsequent use that acetylcysteine crosses 30 mesh sieves.
Magnesium stearate 100 mesh sieve is for subsequent use.
Take acetylcysteine by recipe quantity, anhydrous citric acid, sodium bicarbonate, aspartame, lactose flowlac100, mannitol, mix homogeneously, add the magnesium stearate mix homogeneously of recipe quantity, put into tablet machine and carry out tabletting.Control hardness and be greater than 8kg.
Tabletting ambient temperature 18 DEG C, humidity 50%, continuously compacting 20,000, without stagnant punching, sticking phenomenon.
The each embodiment product of experimental example 1 and commercially available product " Fluimucil " and comparative example's product appearance COMPARISON OF CHARACTERS the results are shown in following table.
Epidemic situation comparison after each embodiment product and commercially available product Fluimucil and comparative example's product appearance character and disintegrate
| Appearance character | State after disintegrate | |
| Embodiment 1 product | White tablets, smooth surface | Clear liquid |
| Embodiment 2 product | White tablets, smooth surface | Clear liquid |
| Embodiment 3 product | White tablets, smooth surface | Clear liquid |
| Embodiment 4 product | White tablets, smooth surface | Clear liquid |
| Embodiment 5 product | White tablets, smooth surface | Clear liquid |
| Embodiment 6 product | White tablets, smooth surface | Clear liquid |
| Embodiment 7 product | White tablets, smooth surface | Clear liquid |
| Embodiment 8 product | White tablets, smooth surface | Clear liquid |
| Embodiment 9 product | White tablets, smooth surface | Clear liquid |
| Embodiment 10 product | White tablets, smooth surface | Clear liquid |
| Embodiment 11 product | White tablets, smooth surface | Clear liquid |
| Fluimucil | White tablets, slice, thin piece edge is slightly crude | Clear liquid |
| Comparative example 1 product | White tablets, rough | Clear liquid |
| Comparative example 2 product | White tablets, rough | Clear liquid |
| Comparative example 3 product | White tablets, rough | Clear liquid |
| Comparative example 4 product | White tablets, smooth surface | There is one deck float on surface |
Conclusion: each embodiment institute tablet agent outward appearance is white tablets, smooth in appearance, and be clear liquid after disintegrate, each embodiment outward appearance is all better than commercially available second cysteine tablet.Each embodiment outward appearance is all better than comparative example 1 to comparative example 3, although comparative example 4 outward appearance is suitable with embodiment product, comparative example 4 dissolves rear surface has one deck float to the sensation of a kind of discomfort of people.
Experimental example 2 disintegration time measures
Get the made tablet of each embodiment and check that the disintegration of each embodiment product sees the following form according to Chinese Pharmacopoeia version in 2010 two annex XA according to inspection technique disintegration.
Each embodiment product and commercially available product Fluimucil and comparative example's product compare disintegration
| 1 | 2 | 3 | 4 | 5 | 6 | Disintegration | |
| Embodiment 1 product | 85 | 88 | 90 | 95 | 110 | 127 | 127 |
| Embodiment 2 product | 113 | 124 | 136 | 144 | 152 | 153 | 153 |
| Embodiment 3 product | 125 | 126 | 130 | 151 | 170 | 178 | 178 |
| Embodiment 4 product | 111 | 112 | 128 | 138 | 149 | 153 | 153 |
| Embodiment 5 product | 95 | 105 | 116 | 120 | 128 | 129 | 129 |
| Embodiment 6 product | 112 | 138 | 146 | 150 | 156 | 156 | 136 |
| Embodiment 7 product | 105 | 116 | 137 | 146 | 150 | 155 | 155 |
| Embodiment 8 product | 99 | 119 | 135 | 147 | 148 | 150 | 150 |
| Embodiment 9 product | 111 | 113 | 127 | 145 | 149 | 152 | 152 |
| Embodiment 10 product | 97 | 110 | 139 | 144 | 146 | 156 | 156 |
| Embodiment 11 product | 80 | 85 | 90 | 110 | 112 | 115 | 126 |
| Fluimucil | 100 | 105 | 110 | 115 | 123 | 130 | 130 |
| Comparative example 1 product | 88 | 111 | 128 | 136 | 142 | 142 | 192 |
| Comparative example 2 product | 95 | 105 | 112 | 116 | 128 | 137 | 177 |
| Comparative example 3 product | 110 | 115 | 147 | 156 | 168 | 172 | 172 |
| Comparative example 4 product | 130 | 133 | 136 | 156 | 180 | 185 | 185 |
Conclusion: each embodiment, comparative example, commercially available acetylcysteine effervescent tablet Fluimucil, disintegration time is all between 80-190 second, and be all less than 5 minutes (300 seconds) of Chinese Pharmacopoeia 2010 editions regulation disintegration, disintegration all conforms with the regulations.
Experimental example 3 mouthfeel is tested
Get the present embodiment 1 product and Fluimucil puts into the disintegrate of 200ml water respectively, after disintegrate is complete, point do not invite 20 people to taste, according to mouthfeel administration scoring (0-5 divides) respectively, the PTS of result this product 81 points, Fluimucil PTS 79 points, this product is suitable with Fluimucil mouthfeel.
Experimental example 4 uses forward stability
" Fluimucil " is put in 200ml water and is dissolved, respectively at 0.5 hour, 2 hours, measure related substance in accordance with the following methods to get the present embodiment 1 product (hereinafter referred to as own product) and commercially available acetylcysteine effervescent tablet.
Precision takes CYSTINE 20mg, puts in the measuring bottle of 50ml, and the hydrochloric acid 10ml jolting adding 1mol/L makes dissolving, adds 0.025mol/L pH2.0 phosphate buffer-methanol (95: 5) and is diluted to scale, shake up, as CYSTINE reference substance storing solution.Another precision takes N, N ' diacetyl-CYSTINE, Cys, N, S ' diacetyl-each 20mg of Cys reference substance, puts in the measuring bottle of 50ml, add 0.025mol/L pH2.0 phosphate buffer-methanol (95: 5) dissolved dilution, to scale, to shake up.Essence gets above-mentioned solution and each 5ml of CYSTINE reference substance storing solution, puts in the measuring bottle of 50ml, with 0.025mol/L pH2.0 phosphate buffer-methanol (95: 5) dilution standardize solution, as impurity reference substance solution.Get this product 13, put in beaker, add 0.025mol/L pH2.0 phosphate buffer-methanol (95: 5) and make dissolving in right amount, and be transferred in 1000ml measuring bottle completely, with 0.025mol/L pH2.0 phosphate buffer-methanol (95: 5) dilution standardize solution, shake up, filter, get subsequent filtrate as test liquid.Essence gets 1ml test liquid, puts in the volumetric flask of 100ml, with 0.025mol/L pH2.0 phosphate buffer-methanol (95: 5) dilution standardize solution, shakes up, in contrast solution.According to the chromatographic condition under assay item, essence gets each 20ul of impurity contrast solution, contrast solution and need testing solution respectively, injection liquid chromatography, and record chromatogram is to 5 times of main constituent peak retention time.If any impurity peaks in need testing solution chromatogram, impurity A, B, C, D, by external standard method with calculated by peak area, each known impurity level must not cross 0.5%, and known impurities total amount must not cross 1.0%.Single unknown impuritie must not cross 0.1% of contrast solution peak area, and the summation of unknown impuritie must not cross 1.0% of contrast solution peak area.
The present embodiment 1 product and commercially available product use forward stability to compare
Seen by upper table, place after the present embodiment product and the disintegrate of commercially available product Fluimucil and stablize for 2 hours, impurity A, B, C, D, maximum contaminant and other total impuritieses have no significant change.
Experimental example 5 influence factor tests
The present embodiment 1 product (hereinafter referred to as own product) and commercially available acetylcysteine effervescent tablet " Fluimucil " are placed influence factor's test according to the condition of influence factor's test respectively, respectively at sampling in 5 days 10 days, carry out appearance character, content, disintegration, pH value checks, and carries out Related substances separation according to the inspection method of related substance, the results are shown in following table.
Acetylcysteine effervescent tablet high temperature (40 DEG C) test-related substance result
High temperature (40 DEG C) result of the test of acetylcysteine effervescent tablet
| Appearance character | Content (%) | Disintegration (second) | PH value | |
| Fluimucil 0 day | White tablets, edge is slightly crude | 99.9 | 130 | 3.9 |
| Fluimucil 5 days | White tablets, edge is slightly crude | 100.2 | 135 | 3.9 |
| Fluimucil 10 days | White tablets, edge is slightly crude | 99.8 | 132 | 3.9 |
| Own product 0 day | White tablets | 99.5 | 157 | 3.8 |
| Own product 5 days | White tablets | 99.6 | 152 | 3.7 |
| Own product 10 days | White tablets | 99.4 | 151 | 3.8 |
Acetylcysteine effervescent tablet illumination (45001x) test-related substance
Acetylcysteine effervescent tablet illumination (45001x) is tested
| Appearance character | Content (%) | Disintegration (second) | PH value | |
| Fluimucil 0 day | White tablets, edge is slightly crude | 99.9 | 130 | 3.9 |
| Fluimucil 5 days | White tablets, edge is slightly crude | 100.2 | 135 | 3.9 |
| Fluimucil 10 days | White tablets, edge is slightly crude | 99.8 | 132 | 3.9 |
| Own product 0 day | White tablets | 99.5 | 127 | 3.8 |
| Own product 5 days | White tablets | 99.6 | 130 | 3.7 |
| Own product 10 days | White tablets | 99.4 | 125 | 3.8 |
Acetylcysteine effervescent tablet high humidity (75%) test-related substance
Acetylcysteine effervescent tablet high humidity (75%) is tested
| Appearance character | Content (%) | Disintegration (second) | PH value | |
| Fluimucil 0 day | White tablets, edge is slightly crude | 99.9 | 130 | 3.9 |
| Fluimucil 5 days | White tablets, edge is slightly crude | 99.8 | 135 | 3.9 |
| Fluimucil 10 days | White tablets, edge is slightly crude | 99.5 | 132 | 3.9 |
| Own product 0 day | White tablets | 99.5 | 157 | 3.8 |
| Own product 5 days | White tablets | 100.0 | 162 | 3.7 |
| Own product 10 days | White tablets | 99.2 | 183 | 3.8 |
Experimental example 6 accelerated test
Get the present embodiment 1 product (hereinafter referred to as own product) and place accelerated test sample according to the method in Chinese Pharmacopoeia 2010 version annex XIXC " crude drug and pharmaceutical preparation stability test guideline ", and respectively at 0,1,2,3, sampling in 6 months, carries out appearance character, content, disintegration, pH value checks, and carries out Related substances separation according to the inspection method of related substance, the results are shown in following table.
Own product product accelerated test stability
| Appearance character | Content (%) | Disintegration (second) | PH value | |
| 0 month | White tablets | 99.7 | 127 | 3.8 |
| Accelerate 1 month | White tablets | 99.6 | 125 | 3.8 |
| Accelerate 2 months | White tablets | 99.7 | 120 | 3.7 |
| Accelerate 3 months | White tablets | 99.5 | 121 | 3.8 |
| Accelerate 6 months | White tablets | 100.0 | 122 | 3.7 |
Own product accelerated test stability-related substance
Experimental example 7 long term test
Get the present embodiment 1 product (hereinafter referred to as own product) and place long term test sample according to the method in Chinese Pharmacopoeia 2010 version annex XIXC " crude drug and pharmaceutical preparation stability test guideline ", and respectively at 0,3,6,9,12,18, sampling in 24 months, carries out appearance character, content, disintegration, pH value checks, and carries out Related substances separation according to the inspection method of related substance, the results are shown in following table.
Own product long term test stability
| Appearance character | Content (%) | Disintegration (second) | PH value | |
| 0 month | White tablets | 99.7 | 127 | 3.8 |
| Long-term 3 months | White tablets | 100.1 | 125 | 3.7 |
| Long-term 6 months | White tablets | 99.7 | 124 | 3.8 |
| Long-term 9 months | White tablets | 100.4 | 128 | 3.7 |
| Long-term 12 months | White tablets | 99.6 | 123 | 3.8 |
| Long-term 18 months | White tablets | 100.3 | 125 | 3.7 |
| Long-term 24 months | White tablets | 100.3 | 123 | 3.7 |
Own product long term test stability-related substance
Claims (10)
1. an acetylcysteine effervescent tablet, comprises acetylcysteine, alkali source, sweeting agent, filler and lubricant.
2. acetylcysteine effervescent tablet according to claim 1, is characterized by described alkali source and comprises sodium carbonate, potassium carbonate, sodium bicarbonate, one or more the mixture in potassium bicarbonate.
3. acetylcysteine effervescent tablet according to claim 1, is characterized by described alkali source and is selected from sodium bicarbonate and/or sodium bicarbonate.
4. acetylcysteine effervescent tablet according to claim 1, is characterized by described filler and comprises lactose, compound lactose, mannitol, sorbitol, one or more the mixture in soluble starch.
5. acetylcysteine effervescent tablet according to claim 1, is characterized by described filler and contains lactose and/or mannitol.
6. acetylcysteine effervescent tablet according to claim 1, is characterized by described lubricant and is selected from polyethylene glycol 6000, Macrogol 4000, sodium chloride, leucine, magnesium stearate, micropowder silica gel, one or more the mixture in Pulvis Talci.
7. acetylcysteine effervescent tablet according to claim 1, is characterized by described lubricant and is selected from leucine.
8. the acetylcysteine effervescent tablet according to claim arbitrary in claim 1-7, contains by weight percentage:
Acetylcysteine 8-45%
Alkali source 3-20%
Filler 30-85%
Lubricant 0.5-10%.
9. the acetylcysteine effervescent tablet more than described in arbitrary claim, it is characterized by described alkali source and be selected from sodium bicarbonate, described sweeting agent is selected from aspartame, and described filler is selected from lactose, and described lubricant is selected from leucine.
10. the preparation method of the acetylcysteine effervescent tablet more than described in arbitrary claim, comprises following preparation process:
(1) to cross 30 mesh sieves for subsequent use for acetylcysteine;
(2) take acetylcysteine and other adjuvants except lubricant by recipe quantity, mix homogeneously, adds the lubricant of recipe quantity, mix homogeneously, puts into tabletting machine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108078948A (en) * | 2018-01-05 | 2018-05-29 | 扬州奥锐特药业有限公司 | A kind of acetylcysteine effervescent tablet and preparation method thereof |
| CN113559078A (en) * | 2021-07-02 | 2021-10-29 | 安徽省先锋制药有限公司 | Preparation method of acetylcysteine effervescent tablets |
| CN114886860A (en) * | 2022-06-28 | 2022-08-12 | 山东达因海洋生物制药股份有限公司 | Acetylcysteine pharmaceutical composition, preparation and preparation process thereof |
| WO2022262388A1 (en) * | 2021-06-15 | 2022-12-22 | 广州市妇女儿童医疗中心 | Application of n-acetylcysteine in preparation of product for treating biliary atresia, and drug for treating biliary atresia |
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| CN101947211A (en) * | 2010-08-28 | 2011-01-19 | 浙江金华康恩贝生物制药有限公司 | Method for preparing acetylcysteine effervescent tablet |
| CN102233139A (en) * | 2010-04-21 | 2011-11-09 | 重庆健能医药开发有限公司 | Acetylcysteine effervescent tablet and preparation method and application thereof |
| EP2662077A1 (en) * | 2012-05-08 | 2013-11-13 | Alpex Pharma SA | Effervescent compositions containing N-acetylcysteine |
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| CN102233139A (en) * | 2010-04-21 | 2011-11-09 | 重庆健能医药开发有限公司 | Acetylcysteine effervescent tablet and preparation method and application thereof |
| CN101947211A (en) * | 2010-08-28 | 2011-01-19 | 浙江金华康恩贝生物制药有限公司 | Method for preparing acetylcysteine effervescent tablet |
| EP2662077A1 (en) * | 2012-05-08 | 2013-11-13 | Alpex Pharma SA | Effervescent compositions containing N-acetylcysteine |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108078948A (en) * | 2018-01-05 | 2018-05-29 | 扬州奥锐特药业有限公司 | A kind of acetylcysteine effervescent tablet and preparation method thereof |
| CN108078948B (en) * | 2018-01-05 | 2020-01-07 | 扬州奥锐特药业有限公司 | Preparation method of acetylcysteine effervescent tablets |
| WO2022262388A1 (en) * | 2021-06-15 | 2022-12-22 | 广州市妇女儿童医疗中心 | Application of n-acetylcysteine in preparation of product for treating biliary atresia, and drug for treating biliary atresia |
| CN113559078A (en) * | 2021-07-02 | 2021-10-29 | 安徽省先锋制药有限公司 | Preparation method of acetylcysteine effervescent tablets |
| CN114886860A (en) * | 2022-06-28 | 2022-08-12 | 山东达因海洋生物制药股份有限公司 | Acetylcysteine pharmaceutical composition, preparation and preparation process thereof |
| CN114886860B (en) * | 2022-06-28 | 2023-04-25 | 山东达因海洋生物制药股份有限公司 | Acetylcysteine pharmaceutical composition, preparation and preparation process thereof |
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