CN100496459C - Compound licorice root medicinal preparation and preparing method thereof - Google Patents
Compound licorice root medicinal preparation and preparing method thereof Download PDFInfo
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- CN100496459C CN100496459C CNB2005101197535A CN200510119753A CN100496459C CN 100496459 C CN100496459 C CN 100496459C CN B2005101197535 A CNB2005101197535 A CN B2005101197535A CN 200510119753 A CN200510119753 A CN 200510119753A CN 100496459 C CN100496459 C CN 100496459C
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Abstract
The present invention is one kind of compound licorice preparation and its preparation process. The compound licorice preparation is orally taken gel, coated tablet, capsule or dripping pill prepared with licorice extractum, compounding camphor tincture, guaiacol, glycerin ether and supplementary material. Compared with available technology, the present invention has the advantages of high curative effect, easy taking and high bioavailability. It is used in trachitis, pharyngolaryngitis, etc. The present invention also provides the preparation process.
Description
Technical field
The present invention relates to a kind of compound licorice medicine preparation and preparation method thereof, belong to the technical field of medicine.
Technical background
Compound Radix Glycyrrhizae mixture; also claim Brown's mixture (Brownmixtrure); mainly form by Radix Glycyrrhizae fluidextract, Camphora, tinctura opii, benzoic acid, Oleum Anisi Stellati, antimony potassium tartrate etc.; be the mucous membrane protection cough medicine, can alleviate the stimulation of pharyngeal mucosa, and the slow gastrointestinal smooth muscular spasm effect of closing is arranged; be mainly used in tracheitis, pharyngolaryngitis and bronchial asthma etc.; said preparation is a suspension type, belongs to heterogeneous dispersion, so common glycerol adding is made suspending agent.Many pharmacy workers have done a large amount of research to it, and still in view of the toxicity problem of antimony potassium tartrate, the beginning of the nineties in last century, antimony potassium tartrate was cancelled medicinal specification, and Chinese Pharmacopoeia (nineteen ninety-five version) has been deleted this kind simultaneously.For this reason, national drug security control department in 1999 has organized the work that revalues to compound Radix Glycyrrhizae mixture.According to revaluing the result, compound Radix Glycyrrhizae mixture is renamed as " glycyrrhiza compound oral administration solution " from July 1st, 2004, change of prescription is Radix Glycyrrhizae fluidextract, paregoric, guaifenesin, wherein Radix Glycyrrhizae fluidextract is the protectiveness expectorant; Paregoric is a cough medicine; Guaifenesin is the expelling phlegm for arresting cough agent, and certain antisepsis is arranged; Studies show that adjusted prescription as paregoric, has increased its consumption with Camphora, tinctura opii, benzoic acid, Oleum Anisi Stellati combination system simultaneously, and has increased guaifenesin newly, antitussive is better than former prescription really with phlegm-dispelling functions; Though prescription increases the content that causes the dependency material, the potentiality that produce physical dependence are very little, and clinical practice is safe; Guaifenesin does not influence the safety of compound Radix Glycyrrhizae mixture medication, has both kept effectively eliminating the phlegm usefulness, has reduced the probability that toxic and side effects occurs again.But under sour environment, separate out the glycyrrhizic acid precipitation for preventing the effective ingredient glycyrrhizin in the Radix Glycyrrhizae fluidextract, the glycyrrhiza compound oral administration solution adds strong aqua ammonia and regulates pH value, strong aqua ammonia has stronger stink, the bottleneck throat mucosa also there is stimulation, untoward reaction and easily precipitation, moldy metamorphism, use inconvenience of oral liquid such as easily cause vomiting, feel sick; And disclosed number of patent application is " 96100065 " in the Chinese patent communique, name is called the application of " infantile inflammation diminishing antasthmatic and reparation technology ", used sulfadiazine, side effect is bigger, can cause in urinary system infringement, anaphylaxis, the hemopoietic system reaction in accidental leukopenia, agranulocytosis etc., liver function impairment, the gastrointestinal reaction as feel sick, vomiting etc.; Existing these kinds, dosage form are not the dosage form kinds that is fit to the bad patient's medication characteristics of function of deglutition such as child, old people, and the patient uses existing product that certain difficulty, displeased acceptance are arranged.In view of tracheitis, pharyngolaryngitis and bronchial asthma in the real life are old man child's commonly encountered diseases, frequently-occurring disease, they are poor to the ability to accept of general formulation, the outward appearance of medicine, mouthfeel directly influence the application and the curative effect of medicine, selecting suitable prescription control disease and suitable dosage form of taking is setting about a little of research and development, and it is very necessary developing bioavailability height, strong drug action, the divided dose desirable novel form accurate, that be convenient to take that a kind of market prospect is wide, the old man child takes like a shot.
Summary of the invention
The objective of the invention is to: a kind of compound licorice medicine preparation and preparation method thereof is provided; The present invention is directed to prior art, we are made the fluid that suited the taste of both old and young deeply or semi-fluid build or fruit jelly type oral gel, drop pill, capsule, tablet, dispersible tablet, oral cavity disintegration tablet, soft religion wafer, pellet, children's old man extremely is ready to take, reduced the trouble of taking, not only tasty, and therapeutical effect is good, has enriched the dosage form kind, and market prospect is very wide; We are made coated tablet, drop pill, capsule, can cover bad smell, the volatile ingredient paregoric is stable, good mouthfeel; We are made dispersible tablet, oral cavity disintegration tablet, soft capsule, pellet, have taking convenience, release is stable, the bioavailability height, and local irritation is little, and the disintegrate dissolution is excellent, and curative effect is brought into play advantages such as fast, carries convenient transportation simultaneously; Outward appearance U.S., mouthfeel is good, and the patient is easy to accept.The applicant has selected reasonable feasible substrate and technology, and quality controllable, curative effect is sure.
The present invention constitutes like this: it is by Radix Glycyrrhizae fluidextract 100～150ml, paregoric 150～200ml, guaifenesin 3～8g, adds appropriate amount of auxiliary materials and makes oral gel, dispersible tablet, soft capsule, oral cavity disintegration tablet, pellet, drop pill, capsule or tablet.Say accurately: it is mainly to use Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g, adds appropriate amount of auxiliary materials and makes oral gel, drop pill, capsule, tablet, dispersible tablet, soft capsule, oral cavity disintegration tablet, pellet.
Gel is such preparation: by mass percentage, with 0.6% card handkerchief type carrageenan, 0.2% amidatioon low methoxyl pectin, 8% sucrose, put into cold water, stir, make it to disperse, soak 20～30min, make the abundant water absorption and swelling of substrate, stir then, heat, filter; Extracting liquorice fluid extract, paregoric, guaifenesin add matrix solution, and mix homogeneously adds liquor ammoniae fortis and sodium bicarbonate, transfers pH8.0～9.0, join rapidly in the disinfecting container, seal, be cooled to rapidly about 30 ℃, condensation, drying promptly gets gel.
Gel is preparation like this: by mass percentage, with 0.3～0.5% agar as thickening agent and stabilizing agent, add appropriate amount of fluid glucose and distilled water, stir evenly, add Radix Glycyrrhizae fluidextract, paregoric, guaifenesin and an amount of stevioside, mix homogeneously joins in the disinfecting container, seal, promptly.
Drop pill prepares like this: get above-mentioned recipe quantity Radix Glycyrrhizae fluidextract, paregoric, guaifenesin, mixing, add sodium bicarbonate adjust pH 8.0～9.0, with the Macrogol 4000 is substrate, part by weight according to medicine: substrate=1:2 adds Macrogol 4000, mixing, the employing internal diameter is that 4.0mm, external diameter are the dropper of 6.0mm, dripping system temperature 70 ℃, droplet speed is that 25～35d/min, a distance are 4cm, splashing in the long cooling column of 120cm, is liquid coolant again with the methyl-silicone oil, cooling, pill promptly gets dropping pill formulation.
Tablet prepares like this: get above-mentioned recipe quantity Radix Glycyrrhizae fluidextract, guaifenesin, adding is the amylum pregelatinisatum of 1:3 with drug ratios, with drug ratios be the crospolyvinylpyrrolidone mix homogeneously of 1:3, make soft material with 3% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, adding is the carboxymethyl starch sodium of 1:1.5 with drug ratios, mix, spray into paregoric, tabletting, coating then, Opadry 2 is a coating material, and coating adopts top spray method: nozzle diameter 1mm, fluidisation air quantity 100m
3/ h, 50 ℃ of inlet temperature, 30 ℃ of bed body temperature degree, atomizing pressure 0.15MPa, hydrojet speed 8mL/min promptly gets tablet.
Capsule prepares like this: get above-mentioned recipe quantity Radix Glycyrrhizae fluidextract, paregoric, guaifenesin, add with drug ratios be 1: 3 amylum pregelatinisatum, with drug ratios be the microcrystalline Cellulose of 1:3, mix homogeneously, make soft material with 3% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, encapsulated, promptly get capsule preparations.
Soft capsule prepares like this: extracting liquorice fluid extract, paregoric, guaifenesin, press medicine: and substrate=1:1.2, the mixed-matrix of adding soybean oil, soybean lecithin, heating and melting, mixing gets soft capsule content; The preparation of glue: with gelatin: glycerol: water=1:0.5:0.7, get gelatin and add an amount of distilled water and make its imbibition, glycerol and remaining water are put be heated to 70～80 ℃ in the glue pot in addition, mix homogeneously adds expansible gelatin and stirs, and makes it to dissolve into uniform glue, in 70 ℃ of insulations 1～2 hour, leave standstill, remove the come-up foam, filter with cloth bag, in encapsulating machine, be pressed into soft capsule, put in the drum drying machine and finalize the design, whole ball, drying promptly gets soft capsule.
Pellet prepares like this: extracting liquorice fluid extract, guaifenesin; adding is the citric acid of 3:2 with drug ratios, and mix homogeneously adds dehydrated alcohol and makes wetting agent system soft material; cross 24 mesh sieves and make wet granular; dropping into rotating speed immediately is in the semi-automatic coating granulator of 80～100r/min, prepared 10～12 hours, and after placing 40 ℃ of baking oven dryings; spray into paregoric; take out, coating is in the coating process: fluidisation air quantity: 125～135m
3H
-1, inlet temperature: 55 ℃, temperature of charge: 45 ℃, atomizing pressure: 0.2Mpa, nozzle diameter: 1.4mm, hydrojet speed: 10mLmin-1, leaving air temp: 35 ℃; Coating, drying promptly gets pellet.
Dispersible tablet prepares like this: the extracting liquorice fluid extract, be dried and crushed into fine powder, with guaifenesin, calcium hydrogen phosphate, crospolyvinylpyrrolidone ratio mixing in 1:1.5:1.2, again by said medicine: adjuvant added low-substituted hydroxypropyl cellulose by 2: 1 and mixes evenly, cross sieve No. 5, make wetting agent system soft material with the 5%PVP alcoholic solution, cross the sieve series grain No. 2,60 ℃ of oven dry, No. 2 sieve granulate, simultaneously in medicine: the adjuvant ratio is that 1:1 adds steviosin, sprays into paregoric, compacting promptly gets dispersible tablet in flakes.
Like this preparation of oral cavity disintegration tablet: the extracting liquorice fluid extract, be dried and crushed into fine powder, with guaifenesin, 8% polyvinylpolypyrrolidone, 4.5% microcrystalline Cellulose, 4% citric acid, 3% sodium bicarbonate, an amount of mannitol mixing, spray into paregoric, compacting promptly gets oral cavity disintegration tablet in flakes.
Paregoric is preparation like this: get benzoic acid 5g, Camphora 3g, Oleum Anisi Stellati 3ml, adding concentration is after 56% ethanol 900ml dissolves, slowly to add tinctura opii 50ml and 56% ethanol 3ml, makes full dose become 1000ml, stirs evenly, and filters, promptly.
Compared with prior art, product formulation provided by the invention can alleviate the stimulation of pharyngeal mucosa, and the slow gastrointestinal smooth muscular spasm effect of closing arranged, be mainly used in tracheitis, treatment of diseases such as pharyngolaryngitis and bronchial asthma, the applicant makes we fluid type or the fruit jelly type oral gel that is suited the taste of both old and young deeply, coated tablet, capsule, drop pill, micropill, soft capsule, dispersible tablet, oral cavity disintegration tablet, children's old man extremely is ready to take, reduced the trouble of taking, not only tasty, and bioavailability height, be used for tracheitis, treatment of diseases such as pharyngolaryngitis and bronchial asthma, function well, enriched the dosage form kind, market prospect is very wide.
The applicant finds in the process of development fruit jelly type gel, effective ingredient glycyrrhizin in the Radix Glycyrrhizae fluidextract is separated out the glycyrrhizic acid precipitation under sour environment, pH value need be 8～9, regulate pH value if add strong aqua ammonia, strong aqua ammonia has stronger stink, the bottleneck throat mucosa is also had stimulation, and untoward reaction such as easily cause vomiting, feel sick is so use no bad abnormal smells from the patient instead, do not stimulate the sodium bicarbonate of throat to regulate pH value; But the poor stability of a large amount of gel-type vehicle alkali conditions, the applicant adopts alkali proof card handkerchief type carrageenan, and its retentiveness is poor, and easily syneresis has been improved retentiveness though add the amidatioon low methoxyl pectin, but makes gel become muddy; Add the A Outa carrageenan, though fragility is moderate, poor transparency; Add sucrose and improve transparency, but the sucrose amount is big, mouthfeel is sweet greasy, and the sucrose amount is few, acts on not obvious; For this reason, we have carried out a series of experiments, and the product mouthfeel, gel strength, the transparency that finally adopt 0.6% card handkerchief type carrageenan, 0.2% amidatioon low methoxyl pectin, the composite substrate of 8% sucrose to make are good;
In development fluid or semi-fluid build gel process, we have attempted multiple function glue, when finding with 0.3-0.5% agar at last as thickening agent and stabilizing agent, the modest viscosity of gel, have good stability, therefore, select thickening agent and the stabilizing agent of 0.3-0.5% agar as fluid or semi-fluid build gel;
The applicant finds in the process of development drop pill, this product is difficult to molding, the final medicine that adopts: the part by weight of substrate=1: 3 adds Macrogol 4000, mixing, the employing internal diameter is that 4.0mm, external diameter are the dropper of 6.0mm, dripping system temperature 70 ℃, droplet speed is that 25～35d/min, a distance are 4cm, splashes into the long cooling column of 120cm and just makes ideal drop pill;
The applicant finds in development tablet process, because paregoric is volatile, must carries out coating and could keep the stable of composition;
The applicant finds when the development soft capsule, find preparation and the kind of adjuvant and the quality that consumption all can have influence on soft capsule preparation of soft capsule content choice of base, glue, for this reason, the applicant through a large amount of experiment exams the substrate of soft capsule content and the selection of glue adjuvant and consumption; Find that through examination medicine: substrate=1:1.2 adds the mixed-matrix of soybean oil, soybean lecithin, can make material and substrate mix homogeneously, and is not stratified, while viscosity, flowability are all better; In capsule shells prescription screening, find to adopt gelatin: glycerol: water=1:0.5:0.7 flexibility, elasticity, toughness, film property are all better;
In development dispersible tablet process, find that the kind of disintegrating agent and consumption to the quality influence maximum of preparation,, find through a large amount of experiments for this reason, adopt the hardness of disintegration time, tablet of crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose preferable;
Be the science that guarantees its technology, reasonable, feasible, the preparation that obtains has effective therapeutic effect, and the applicant has carried out following a series of experiment.
Experimental example 1: Study on Forming
1.1 gel (fruit jelly type gel)
Effective ingredient glycyrrhizin in the Radix Glycyrrhizae fluidextract is separated out the glycyrrhizic acid precipitation under sour environment, pH value need be 8～9.Under the condition of this pH value, adopt different types of substrate to prepare gel, observe gel effect and mouthfeel, in the glue fruit jelly of the falling people cup for preparing, sealing sterilizes (85 ℃, 30m:n), room temperature, cryopreservation are carried out in cooling respectively, the liquid of separating out is poured out, the weight that the weighing gel alleviates, every 5d is once, measure one month, average, calculate and take off the liquid shrinkage factor, take off amount of liquid/gel gross mass * 100% that liquid shrinkage factor %=separates out.
1.1.1 gel effect
The gel effect table
Kind consumption % pH8.0 pH8.5 pH9.0
Gelatin 0.6 poor toughness poor toughness poor toughness
Card handkerchief type carrageenan 0.6 fragility is big, and it is big easily to shrink fragility, and it is big easily to shrink fragility, easily shrinks
Konjac glucomannan 0.6 not gel or not mouthfeel is not puckery
Locust bean gum 0.6 is gel gel not or not
The result shows: pH is salty and bitter greater than 9.0 gel mouthfeel; Gelatin easily will be separated in alkaline environment, and gel strength sharply descends; Card handkerchief type carrageenan is alkaline-resisting, but fragility is very big, easily takes off liquid and shrinks; Konjac glucomannan need pH greater than 9.0 condition under hydrolysis fall acetyl group, could form gel, mouthfeel is salty and bitter; Locust bean gum can't form gel separately; Be to strengthen the retentiveness of card handkerchief type carrageenan, and for reaching collaborative interaction, it is composite to carry out substrate.
1.1.2 take off liquid shrinkage factor and transparency raising rate
Card handkerchief type carrageenan % amidatioon low methoxyl pectin % sucrose % takes off liquid shrinkage factor % transparency raising rate % mouthfeel
0.6 7.98-little hardship
0.6 0.2 4.87-10.2 little hardship
0.6 8 7.88 10.25 is moderate
0.6 0.2 8 4.67 10.17 is moderate
0.7 0.1 5.64-10.1 little hardship
0.7 6 7.56 5.42 is moderate
0.7 0.1 6 5.53 5.38 is moderate
0.8 0.2 4.90-10.33 little hardship
0.8 9 8.11 10.23 is sweet excessively
0.8 0.2 9 4.91 10.30 is sweet excessively
The result shows: the gel that card handkerchief type carrageenan forms is strong and crisp, and mouthfeel elasticity deficiency adds the good amidatioon low methoxyl pectin of retentiveness and can reduce fragility, improves elasticity, and reduce and take off the liquid shrinkage factor, but poor transparency; Adding high solid content sucrose can enhance the transparency, but best composite condition is 0.6% card handkerchief type carrageenan, 0.2% amidatioon low methoxyl pectin, 8% sucrose.
1.2 gel (fluid or semi-fluid build)
1.2.1 kind screening
We have screened the effect of gel-carbomer, agar, gelatin, chitosan, tragacanth and compatibility of drugs, and the result shows that the preparation viscosity of agar and glycyrrhiza compound prescription compatibility is the most moderate.
Kind consumption viscosity
Gelatin 0.5% viscosity is excessive
Carbomer 0.5% viscosity is excessive
Agar 0.5% modest viscosity
Chitosan 0.5% viscosity is too small
Tragacanth 0.5% viscosity is too small
1.2.2 consumption screens preparation viscosity and stability that we have investigated following agar consumption, the result shows that the preparation stability of 0.3%-0.5% agar and glycyrrhiza compound prescription compatibility is best.
The character of consumption viscosity illumination after 10 days
The too small liquefaction of 0.1% viscosity
0.3% modest viscosity no change
0.5% modest viscosity no change
0.8% modest viscosity is partly dry
1% viscosity is excessive dry
1.3 tablet coating technology
Paregoric is volatile, and in order to keep stability of formulation, we carry out coating to tablet.
Group inlet temperature ℃ atomisation pressure Mpa hydrojet speed mL/min coating effect
1 45 0.18 8 is general, and many glutinous companies are arranged
2 45 0.18 10 is better, and having seldom, amount sticks even
3 45 0.15 8 is general, and many glutinous companies are arranged
4 45 0.15 10 is better, and having seldom, amount sticks even
5 50 0.18 8 is better, and having seldom, amount sticks even
6 50 0.18 10 is general, and many glutinous companies are arranged
7 50 0.15 8 is good, between glutinous the company
8 50 0.15 10 is better, and having seldom, amount sticks even
The result shows that optimised process is 50 ℃ of inlet temperature, atomizing pressure 0.15MPa, hydrojet speed 8mL/min.
1.4 micropill art for coating
Paregoric is volatile, and in order to keep stability of formulation, we carry out coating conditions and grope.
Group inlet temperature ℃ atomisation pressure Mpa hydrojet speed mL/min coating effect
1 50 0.15 10 is better, and micropill has seldom to be measured glutinous the company
2 50 0.15 15 is better, and micropill has seldom to be measured glutinous the company
3 50 0.20 10 is general, and many glutinous companies are arranged
4 50 0.20 15 is general, and many glutinous companies are arranged
5 55 0.15 10 is better, and micropill has seldom to be measured glutinous the company
6 55 0.15 15 is general, and many glutinous companies are arranged
7 55 0.20 10 is good, not glutinous company the between the micropill
8 55 0.20 15 is general, and many glutinous companies are arranged
The result shows that optimised process is 55 ℃ of inlet temperature, atomizing pressure 0.2MPa, hydrojet speed 10mL/min.
1.5 drop pill preparation technology
1.5.1 the proportioning of medicine and substrate
Medicine and substrate (Macrogol 4000) proportioning
Medicine and substrate composition merge the situation denseness and drip the system situation
1: 1 difficult thick difficulty
1: 2 easily moderate easy
1: 3 easily moderate easy
1: 4 easily moderate easy
Medicine and substrate ratio are between 1: 2～4 as can be known from the above table, and all plastic, still in order to use adjuvant less to the greatest extent, we determine that medicine and substrate ratio are 1:2.
1.5.2 the coolant and the type of cooling are selected
The coolant and the type of cooling are selected: with methyl-silicone oil, liquid paraffin is coolant, and medicine and substrate were dripped system in 1: 2 behind the ratio mixing.Drip the system condition: system is dripped in (80 ± 2) ℃ insulation, and the drip internal diameter is 4.0mm, external diameter 6.0mm.Coolant temperature adopts gradient or non-gradient mode, and the gradient chilling temperature is distributed as: 40 ℃～50 ℃, 10 ℃～30 ℃, 0 ℃～4 ℃ (3 temperature-averagings are cut apart the length of cooling column), non-gradient is cooled to 0 ℃～10 ℃.Dripping speed is 20～30/min.Evaluation index: the roundness of drop pill (the minor axis of drop pill/major diameter〉0.8) qualification rate.
Group coolant cools post height/cm roundness qualification rate/%
1 methyl-silicone oil 120 91.2 90.2
2 methyl-silicone oils 140 85.7 80.3
3 liquid paraffin 120 76.9 78.8
4 liquid paraffin 140 75.8 72.4
From above table as can be seen, use methyl-silicone oil and liquid paraffin all can make the drop pill molding, but by contrast, when using methyl-silicone oil, the qualification rate of drop pill is higher, therefore definite optimum coolant is selected methyl-silicone oil for use.
1.5.3 drip distance, drip selection fast, temperature
Drip distance, drip selection fast, temperature: the interior external diameter of drip is fixed as 4.1,6.1mm.Evaluation index: the heavy qualification rate of ball is by mass discrepancy requirement of Pharmacopoeia of the People's Republic of China version in 2000: meet ± 7.5% within.
Group temperature/℃ drip a distance/cm drips the ball weight qualification rate/% of speed/(dmin-1)
1 80 4 15～25 78.6
2 80 6 25～35 85.7
3 80 10 35～55 81.9
4 70 4 25～35 96.5
5 70 6 35～55 91.3
6 70 10 15～25 93.2
7 60 4 35～55 91.4
8 60 6 15～25 95.5
9 60 10 25～35 87.1
The result shows, the optimum condition of preparation drop pill of the present invention: with the Macrogol 4000 is substrate, according to medicine: the part by weight of substrate=1: 3 adds Macrogol 4000, mixing, the employing internal diameter is that 4.0mm, external diameter are the dropper of 6.0mm, dripping system temperature 70 ℃, droplet speed is that 25～35d/min, a distance are 4cm, splash in the long cooling column of 120cm, and be the liquid coolant pill again with the methyl-silicone oil.
1.6 soft capsule technology examination
1.6.1 substrates quantity examination
Substrates quantity examination table
| Medication amount (g): substrate (g) | Quality of liquid medicine |
| 1：1 | Viscosity is big, and is mobile poor |
| 1：1.2 | Viscosity, flowability are all good |
| 1：2 | Differences in viscosity is mobile big |
From above table as can be seen, when substrates quantity was 1.2 times of medicine, the viscosity of medicinal liquid, flowability were all better, are beneficial to the molding of soft capsule, determined that therefore optimum substrates quantity is 1.2 times of medication amount.
1.6.2 capsule shells prescription screening
In the batching of ratio shown in the table, put into the 500ml bottle,suction, 65 water-baths are dissolved, automatic stirringization glue, evacuation about vacuum 0.095Mpa, was incubated after 5 hours and placed 1 hour simultaneously, filter glue, get a part of glue and measure viscosity and other performance, a part of glue evenly is paved into skim on iron plate, is positioned over to observe the rubber performance next day and judge, use " +++", " ++ ", "+", "-" to represent by good successively to difference the examination result of each index, the results are shown in following table.
Rubber batching screening table
Through screening, overall merit, prescription 2,8.11 prepared film qualities are good, consider the characteristics of fill material and reduce supplementary product consumption as far as possible, select prescription 2, i.e. gelatin: glycerol: water 1:0.5:0.7.
1.7 oral cavity disintegration tablet disintegrating agent screening
Disintegrating agent screening table
| Prescription | Microcrystalline Cellulose (%) | Polyvinylpolypyrrolidone (%) | Hydroxypropyl cellulose (%) | Disintegration time (s) |
| 1 | 4 | 8 | 0 | 12 |
| 2 | 4 | 8 | 1 | 10 |
| 3 | 4.5 | 8 | 2 | 6 |
| 4 | 4.5 | 8 | 0 | 5 |
| 5 | 5 | 8 | 1 | 7 |
| 6 | 5 | 8 | 2 | 8 |
1.8 dispersible tablet disintegrating agent screening:
A leading indicator that influences the quality of the pharmaceutical preparations in the dispersible tablet is exactly a dispersing uniformity, i.e. sample fully disintegrate and being uniformly dispersed in 3min.And influence sample dispersion inhomogeneity mainly is the kind and the consumption of disintegrating agent, for this reason the inventor that disintegrating agent is carried out The selection result is as follows.
| Ointment (g) | Crospolyvinylpyrrolidone | Low-substituted hydroxypropyl cellulose | Carboxymethyl starch sodium | Disintegration time (min) |
| 10 | 15 | - | - | 3.0 |
| 10 | - | 15 | - | 3.7 |
| 10 | - | - | 15 | 3.5 |
| 10 | 12 | 5 | - | 2.3 |
| 10 | - | 12 | 5 | 3.4 |
| 10 | 12 | - | 5 | 2.8 |
| 10 | 12 | - 5 | 5 | 2.3 |
From top result of the test as can be seen, be 1.2 times of ointment when selecting crospolyvinylpyrrolidone for use, the disintegrate effect was the most desirable when low-substituted hydroxypropyl cellulose was 0.5 times of ointment, so we make up this as optimal conditions.
Experimental example 2: to the pharmacodynamic experiment of the antitussive effect of experimental cough
2.1 mice ammonia is drawn the antitussive effect of the method for coughing
The antitussive effect that mice ammonia is drawn the method for coughing: get 105 of mices, male and female half and half are divided into 7 groups, i.e. model group (H at random
2O), positive drug control group (codeine), treatment A group (gel of the present invention), treatment B group (tablet of the present invention), treatment C group (drop pill of the present invention), treatment D group (dispersible tablet of the present invention), treatment E group (FUFANG GANCAO KOUFUYE).Every group 15.Gastric infusion, 1h after the administration, it is in the glass bell jar of 1L that 1 mice is placed volume, put a cotton balls in it, each 25%～28% ammonia 0.2ml of suction injects on the cotton balls with the 1ml syringe, the also incubation period of record mouse cough and the cough number of times in the 3min are observed in the experiment that hockets at random of each treated animal.
Mice ammonia is drawn the antitussive effect of coughing
Cough number of times in group dosage (mg/kg) n incubation period (s) 3min
Model group-15 21.6 ± 12.4 118.5 ± 18.2
Positive controls 10 15 30.7 ± 14.3 85.8 ± 17.4
Treatment A organizes 10 15 33.2 ± 10.2 81.6 ± 12.5
Treatment B organizes 10 15 33.9 ± 21.1 81.8 ± 23.6
Treatment C organizes 10 15 34.2 ± 18.5 80.5 ± 17.5
Treatment D organizes 10 15 35.1 ± 19.6 79.4 ± 25.1
Treatment E organizes 10 15 32.9 ± 10.0 82.0 ± 11.7
2.2 the Cavia porcellus acrylic aldehyde is drawn the antitussive effect of the method for coughing
Get 70 of the Cavia porcelluss of acrylic aldehyde sensitivity, male and female half and half are divided into 7 groups, i.e. model group (H at random
2O), positive drug control group (codeine), treatment A group (gel of the present invention), treatment B group (drop pill of the present invention), treatment C group (drop pill of the present invention), treatment D group (dispersible tablet of the present invention), treatment E group (FUFANG GANCAO KOUFUYE).Every treated animal dosage is that 3.5ml/250g irritates stomach.Matched group irritates stomach for distilled water 3.5ml/250g.1h after the administration, with each 1 of administration group and blank group Cavia porcellus, inserting volume is in the airtight bell jar of 8L, injects previously prepared acrylic aldehyde 8ml (gas) by the bottom, observes each Mus number of times of coughing in 5min.
The Cavia porcellus acrylic aldehyde is drawn the antitussive effect of coughing
Cough number of times in the group n 5min
Model group 10 30.6 ± 10.2
Positive controls 10 15.0 ± 7.4
Treatment A organizes 10 14.0 ± 1.9
Treatment B organizes 10 14.2 ± 4.6
Treatment C organizes 10 13.8 ± 2.6
Treatment D organizes 10 13.5 ± 3.1
Treatment E organizes 10 15.2 ± 2.3
The result shows that preparation of the present invention can suppress mice effectively to be stimulated the cough that causes and suppressed the experimental cough that Cavia porcellus is caused by acrylic aldehyde and electricity irritation by ammonia, and effect is better than FUFANG GANCAO KOUFUYE.
Concrete embodiment
Embodiments of the invention 1: Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g
By mass percentage,, put into cold water, stir, make it to disperse, soak 20～30min, make the abundant water absorption and swelling of substrate, stir then, heat, filter 0.6% card handkerchief type carrageenan, 0.2% amidatioon low methoxyl pectin, 8% sucrose; Extracting liquorice fluid extract, paregoric, guaifenesin add matrix solution, mix homogeneously adds sodium bicarbonate, transfers pH8.0～9.0, join rapidly in the disinfecting container, seal, sterilization is cooled to rapidly about 30 ℃, condensation, drying promptly gets gel, this product oral, three times on the one, each 2 bags, every bag 15g.
Embodiments of the invention 2: Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g
Get above-mentioned recipe quantity Radix Glycyrrhizae fluidextract, paregoric, guaifenesin, mixing, add sodium bicarbonate adjust pH 8.0～9.0, with the Macrogol 4000 is substrate, part by weight according to medicine: substrate=1:2 adds Macrogol 4000, mixing, the employing internal diameter is that 4.0mm, external diameter are the dropper of 6.0mm, dripping system temperature 70 ℃, droplet speed is that 25～35d/min, a distance are 4cm, splashing in the long cooling column of 120cm, is liquid coolant again with the methyl-silicone oil, cooling, pill promptly gets dropping pill formulation.
Embodiments of the invention 3: Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g
Get above-mentioned recipe quantity Radix Glycyrrhizae fluidextract, guaifenesin, adding is the amylum pregelatinisatum of 1:3 with drug ratios, with drug ratios be the crospolyvinylpyrrolidone mix homogeneously of 1:3, make soft material with 3% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, adding is the carboxymethyl starch sodium of 1:1.5 with drug ratios, mixes, and sprays into paregoric, tabletting, coating then, Opadry 2 is a coating material, coating adopts top spray method: nozzle diameter 1mm, fluidisation air quantity 100m3/h, 50 ℃ of inlet temperature, 30 ℃ of bed body temperature degree, atomizing pressure 0.15MPa, hydrojet speed 8mL/min promptly gets tablet.
Embodiments of the invention 4: Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g
Get above-mentioned recipe quantity Radix Glycyrrhizae fluidextract, paregoric, guaifenesin, add with drug ratios be 1:3 amylum pregelatinisatum, with drug ratios be the microcrystalline Cellulose of 1:3, mix homogeneously, make soft material with 3% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, encapsulated, promptly get capsule preparations.
Embodiments of the invention 5: Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g
Extracting liquorice fluid extract, paregoric, guaifenesin, press medicine: substrate=1:1.2, the mixed-matrix of adding soybean oil, soybean lecithin, heating and melting, mixing gets soft capsule content; The preparation of glue: with gelatin: glycerol: water=1:0.5:0.7, get gelatin and add an amount of distilled water and make its imbibition, glycerol and remaining water are put be heated to 70～80 ℃ in the glue pot in addition, mix homogeneously adds expansible gelatin and stirs, and makes it to dissolve into uniform glue, in 70 ℃ of insulations 1～2 hour, leave standstill, remove the come-up foam, filter with cloth bag, in encapsulating machine, be pressed into soft capsule, put in the drum drying machine and finalize the design, whole ball, drying promptly gets soft capsule.
Embodiments of the invention 6: Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml, guaifenesin 5g
Extracting liquorice fluid extract, guaifenesin; adding is the citric acid of 3:2 with drug ratios, and mix homogeneously adds dehydrated alcohol and makes wetting agent system soft material; cross 24 mesh sieves and make wet granular; dropping into rotating speed immediately is in the semi-automatic coating granulator of 80～100r/min, prepared 10～12 hours, and after placing 40 ℃ of baking oven dryings; spray into paregoric; take out, coating is in the coating process: fluidisation air quantity: 125～135m
3H
-1, inlet temperature: 55 ℃, temperature of charge: 45 ℃, atomizing pressure: 0.2Mpa, nozzle diameter: 1.4mm, hydrojet speed: 10mLmin-1, leaving air temp: 35 ℃; Coating, drying promptly gets pellet.
Embodiments of the invention 7: Radix Glycyrrhizae fluidextract 100ml, paregoric 150ml, guaifenesin 3g
The extracting liquorice fluid extract is dried and crushed into fine powder, with guaifenesin, calcium hydrogen phosphate, the crospolyvinylpyrrolidone ratio mixing in 1:1.5:1.2, again by said medicine: it is evenly mixed that adjuvant is pressed 2:1 adding low-substituted hydroxypropyl cellulose, cross sieve No. 5, make wetting agent system soft material, cross No. 2 sieve series grains with the 5%PVP alcoholic solution, 60 ℃ of oven dry, No. 2 sieve granulate, simultaneously in medicine: the adjuvant ratio is that 1:1 adds steviosin, sprays into paregoric, compacting promptly gets dispersible tablet in flakes.
Embodiments of the invention 8: Radix Glycyrrhizae fluidextract 150ml, paregoric 200ml, guaifenesin 8g
The extracting liquorice fluid extract, be dried and crushed into fine powder, with guaifenesin, 8% polyvinylpolypyrrolidone, 4.5% microcrystalline Cellulose, 4% citric acid, 3% sodium bicarbonate, an amount of mannitol mixing sprays into paregoric, and compacting promptly gets oral cavity disintegration tablet in flakes.
Embodiments of the invention 9: Radix Glycyrrhizae fluidextract 150ml, paregoric 200ml, guaifenesin 8g
Get 0.5% agar, add appropriate amount of fluid glucose and distilled water, stir evenly, add Radix Glycyrrhizae fluidextract, paregoric, guaifenesin and an amount of stevioside, mix homogeneously joins in the disinfecting container, seals, and promptly gets gel.
Claims (3)
1,1, a kind of compound licorice medicine preparation, it is to add appropriate amount of auxiliary materials with Radix Glycyrrhizae fluidextract 120ml, paregoric 180ml and guaifenesin 5g to make oral gel, it is characterized in that: by mass percentage,, put into cold water 0.6% card handkerchief type carrageenan, 0.2% amidatioon low methoxyl pectin, 8% sucrose, stir, make it to disperse, soak 20～30min, make the abundant water absorption and swelling of substrate, stir then, heat, filter; Extracting liquorice fluid extract, paregoric, guaifenesin add matrix solution, and mix homogeneously adds liquor ammoniae fortis and sodium bicarbonate, transfers pH8.0～9.0, join rapidly in the disinfecting container, seal, be cooled to rapidly about 30 ℃, condensation, drying promptly gets gel.
2, according to the described compound licorice medicine preparation of claim 1, it is characterized in that: by mass percentage, with 0.3～0.5% agar as thickening agent and stabilizing agent, add appropriate amount of fluid glucose and distilled water, stir evenly, add Radix Glycyrrhizae fluidextract, paregoric, guaifenesin and an amount of stevioside, mix homogeneously, join in the disinfecting container, seal, promptly get gel.
3, according to the described compound licorice medicine preparation of claim 1, it is characterized in that: paregoric is preparation like this: get benzoic acid 5g, Camphora 3g, Oleum Anisi Stellati 3ml, adding concentration is after 56% ethanol 900ml dissolves, slowly add tinctura opii 50ml and 56% ethanol 3ml, make full dose become 1000ml, stir evenly, filter, promptly.
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| CNB2005101197535A CN100496459C (en) | 2004-11-05 | 2005-11-04 | Compound licorice root medicinal preparation and preparing method thereof |
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| CN 200410081236 CN1634373A (en) | 2004-11-05 | 2004-11-05 | Compound licorice root medicinal preparation and preparing method thereof |
| CN200410081236.9 | 2004-11-05 | ||
| CNB2005101197535A CN100496459C (en) | 2004-11-05 | 2005-11-04 | Compound licorice root medicinal preparation and preparing method thereof |
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| CN1994285B (en) * | 2006-01-04 | 2011-03-16 | 上海医药工业研究院 | Sustained release micro-pellet of guaifenesin and preparation process thereof |
| CN102274157A (en) * | 2010-06-10 | 2011-12-14 | 北京润德康医药技术有限公司 | Medicinal gel preparation suitable for old people and preparation method for medicinal gel preparation |
| CN102743443B (en) * | 2012-07-13 | 2014-04-02 | 福州海王金象中药制药有限公司 | Compound glycyrrhiza oral solution preparation technology |
| CN109316509A (en) * | 2018-11-02 | 2019-02-12 | 云南康创生物医药科技孵化有限公司 | Relieving cough and reducing sputum oral solution and preparation method thereof |
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Non-Patent Citations (2)
| Title |
|---|
| 国家药品西药标准（化学药品地标升国标第16册）. 国家药典委员会，228，国家药典委员会. 2001 |
| 国家药品西药标准（化学药品地标升国标第16册）. 国家药典委员会，228，国家药典委员会. 2001 * |
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