CN1762347A - Andrographolide preparation and its production method - Google Patents
Andrographolide preparation and its production method Download PDFInfo
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Abstract
The invention discloses an andrographolide and preparation its preparing method, which can be used mainly for treating common cold, throat pain, aphtae, dysentery, and cerebrovascular diseases.
Description
Technical field: the present invention is a kind of andrographolide preparation and preparation method thereof, belongs to technical field of Chinese medicine.
Technical background: andrographolide is the extract of Chinese medicine Herba Andrographis; be used for cold, fever more; laryngopharynx swelling and pain, aphtha of the mouth and tongue, pertussis chronic cough; dysentery; the puckery pain of pyretic stranguria, carbuncle skin infection, the treatment of venom and cardiovascular and cerebrovascular disease; can activate and anti-fibrinolytic, antioxidation and protection vascular endothelial cell by antiplatelet, suppress vascular smooth muscle cell curing.A large amount of research has been done to it by many inventors and medicine enterprise, and the product of some treatments also is provided; As: andrographolide sheet, andrographolide capsule or the like, but the problem that they exist is: dosage form is too backward, and product quality is not ideal enough, and the dosage form kind is abundant inadequately, is suitable for crowd's narrow range; The what is more important andrographolide is insoluble in water, case of thermal instability, makes product bioavailability, medicine stability undesirable; It is that " 03110092 ", name are called the patent application of " dripping pills of andrographolide and preparation method thereof " that the Chinese patent communique discloses number of patent application, and number of patent application is that " 03141925 ", name are called the patent application of " andrographolide soft capsule formulation and preparation method thereof "; These two applications try hard to solve the deficiency that prior art, product exist, and the drug loading of its drop pill that provides, soft capsule preparation is smaller, supplementary product consumption big, taking dose is bigger, fail to solve fully the common problem of andrographolide product.
Summary of the invention: the objective of the invention is to: provide a kind of andrographolide preparation and preparation method thereof, to solve these problems that prior art exists; At prior art, the present invention is prepared into soft capsule, micropill, gel, dispersible tablet formulation with andrographolide.The gel mouthfeel is good, taking convenience, be beneficial to absorption; The drug loading of micropill is big, particle diameter is little, adopt packaging technique simultaneously, helps taste masking and improves the stability of product, is particularly suitable for the old people and swallow tablet or the inconvenient patient of capsule take; The disintegrative of dispersible tablet is good, has solved poorly soluble composition bioavailability problem; Andrographolide soft capsule formulation of the present invention, can cover poor taste, the abnormal smells from the patient of medicine, and play the effect that increases stability, improves bioavailability, preferred prescription drug loading is big on the basis of satisfying the moulding process requirement, supplementary product consumption is little, dose is few to the more important thing is product of the present invention; Simultaneously, the preparation technology's that the present invention finishes screening, make the preparation technology provide rationally, science, feasible, can directly instruct the production of enterprise, guarantee the product that obtains effectively.
The present invention constitutes like this: it mainly is the preparation that is formed by the andrographolide processing and fabricating, comprises all acceptable dosage forms on injection, powder pin, freeze-dried powder, gel and dispersible tablet, soft capsule, microcapsule, granule, pill, micropill, powder, drop pill, slow releasing preparation, controlled release preparation, gel, oral liquid, soft extract, extractum and the membrane pharmaceutics.
The preparation method of andrographolide preparation of the present invention: andrographolide, add suitable adjuvant, manufacture dispersible tablet, gel, soft capsule, drop pill, pellet preparations with diverse ways.Soft capsule in the preparation of the present invention prepares like this: gets andrographolide, crosses 100 mesh sieves, and standby; Get Cera Flava, put in the soybean oil, heating makes dissolving, puts to room temperature; Other gets soybean phospholipid, vitamin E, adds respectively in the above-mentioned oil solution, and mix homogeneously adds andrographolide, uses the colloid mill mix homogeneously, selects suitable softgel shell prescription for use, suppresses soft capsule under given conditions, drying, promptly.Described soybean oil is a diluent, and the part by weight of medicated powder and diluent is 1: 1.5; Described Cera Flava is as suspending agent, and consumption is 1.0%; Described soybean phospholipid is a wetting agent, and addition is 1.0%; Described vitamin E is an antioxidant, and consumption is 0.050%.The soft capsule shell prescription is made up of gelatin, purified water, glycerol, Polyethylene Glycol, Brown Ferric Oxide, ethyl hydroxybenzoate, propyl hydroxybenzoate, and weight proportion is a gelatin: purified water: glycerol: Polyethylene Glycol: Brown Ferric Oxide: ethyl hydroxybenzoate: propyl hydroxybenzoate=500: 500: 175: 25: 1: 1: 1.The colloid mill incorporation time is 10 minutes; Sprinkler body temperature in the soft capsule pressing process should be controlled at 42～46 ℃; Baking temperature is 24～30e, and relative humidity is 20～40%, and be 16～18 hours drying time.
Dispersible tablet in the preparation of the present invention prepares like this: get andrographolide, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a microcrystalline Cellulose, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a crospolyvinylpyrrolidone, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a low-substituted hydroxypropyl cellulose, add by adjuvant: the part by weight of medicated powder is 1: 1 a calcium hydrogen phosphate, add by adjuvant: the part by weight of medicated powder is 0.02: 1 a magnesium stearate mix homogeneously, make soft material with 2% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a carboxymethyl starch sodium, add by adjuvant: the part by weight of medicated powder is 0.03: 1 a steviosin, mix, tabletting, coating then, coating adopts top spray method: nozzle diameter 1mm, fluidisation air quantity 100m
3/ h, 50 ℃ of inlet temperature, 35 ℃ of bed body temperature degree, atomizing pressure 0.15MPa, hydrojet speed 5mL/min, promptly.
Pellet in the preparation of the present invention prepares like this: get andrographolide, add by adjuvant: the part by weight of medicated powder is 1: 1 a microcrystalline Cellulose, and mixing sieves, add an amount of alcoholic solution and make soft material, through the extruder sieve plate, aperture 0.9mm is extruded into fine strip shape, extrudes rotating speed 300rmin
-1, put in the spheronizator, regulate rotating speed 1000rmin
-1And round as a ball time 4min, make granule round as a ball fully, take out micropill in 50 ℃ of drying 3～4h, after the screening, carry out coating with 18～24 purpose micropills, the Radix Glycyrrhizae charcoal is a coating material, the coating pan rotating speed is 40r/min, promptly.
Gel in the preparation of the present invention prepares like this: get andrographolide, adding propylene glycol grinds evenly, it with weight ratio 2% carbomer, add a little distilled water and triethanolamine, stir and make gel, mix with the propylene glycol solution of above-mentioned andrographolide, grind well, then at 65 ℃ of 30min that sterilize down, cold putting promptly gets gel.
Compared with prior art, pharmaceutical preparation provided by the invention is used for cold, fever, laryngopharynx swelling and pain, aphtha of the mouth and tongue, the pertussis chronic cough, dysentery, the puckery pain of pyretic stranguria, carbuncle skin infection, the treatment of venom and cardiovascular and cerebrovascular disease, can activate and anti-fibrinolytic, antioxidation and protection vascular endothelial cell by antiplatelet, suppress vascular smooth muscle cell curing, its effect is remarkable; At prior art, the micropill that provides, dispersible tablet, gel, disintegrative is good, solved poorly soluble composition bioavailability problem, be particularly suitable for the old people and swallow tablet or the inconvenient patient of capsule take, adopted packaging technique, help stable components; The soft capsule that provides, dropping pill formulation have solved medicine and have met damp and hot problem of unstable, can also cover poor taste, the abnormal smells from the patient of medicine, and play the effect that increases stability, improves bioavailability, and supplementary product consumption is few, and dose is little; The gel of preparation, good mouthfeel, all-ages, enlarged use crowd scope, have the vast market potentiality; Reached the purpose of invention.
The applicant has carried out a series of experiments, with the supplementary product kind of the preparation technology that selects pharmaceutical preparation provided by the invention, use and consumption, ratio etc.; Guarantee its science, reasonable, feasible: the preparation that obtains has effective therapeutic effect.
Experimental example 1: Study on Forming
1.1 dispersible tablet Study on Forming
Dispersible tablet meet water rapidly disintegrate form the water dispersion tablet of uniform sticky suspension, it is poor to have solved former dosage form disintegrative, stripping is shortcoming slowly, and the dispersible tablet that the applicant makes is disintegrate fully in the 3min in 19 ℃～21 ℃ water, and suspension ability is good, bioavailability is high, dispersed homogeneous degree.Check disintegration: adopting changes the basket method, and the lift disintegration tester is got 6, observes the situation by screen cloth, and percent of pass height then disintegrative is good, more pleasant bulk absorption.
1.1.1 adjuvant screening
| Supplementary product consumption (adjuvant: medicated powder) | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Lactose microcrystal carboxymethyl cellulose Starch Sodium PVPP low-substituted hydroxypropyl cellulose dolomol Steviosin calcium monohydrogen phosphate disintegration time (minute) tablet weight variation | - 0.5∶1 0.5∶1 0.5∶1 0.5∶1 0.02∶1 0.03∶1 1∶1 2.3 ±3％ | 1∶1 1∶1 1∶1 1∶1 1∶1 0.05∶1 0.05∶1 2∶1 3.1 ±3％ | 1.5∶1 1.5∶1 1.5∶1 1.5∶1 2∶1 0.1∶1 0.1∶1 3∶1 2.8 ±6％ | 2∶1 - 2∶1 - 3∶1 - - 4∶1 3.5 ±8％ |
The result shows, optimum process condition is for adding by adjuvant: the part by weight of medicated powder is 0.5: 1 a microcrystalline Cellulose, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a crospolyvinylpyrrolidone, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a low-substituted hydroxypropyl cellulose, add by adjuvant: the part by weight of medicated powder is 1: 1 a calcium hydrogen phosphate, add by adjuvant: the part by weight of medicated powder is 0.02: 1 a magnesium stearate mix homogeneously, make soft material with 2% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a carboxymethyl starch sodium, add by adjuvant: the part by weight of medicated powder is 0.03: 1 a steviosin, mix tabletting.
1.1.2 art for coating
| Group | Inlet temperature ℃ | Atomisation pressure Mpa | Hydrojet speed mL/min | Coating effect |
| 1 2 3 4 5 6 7 8 | 45 45 45 45 50 50 50 50 | 0.15 0.15 0.20 0.20 0.15 0.15 0.20 0.20 | 5 10 5 10 5 10 5 10 | Generally, there are many glutinous companies better, seldom glutinous the company generally arranged, there are many glutinous companies better, having seldom, amount sticks even good, glutinous the company generally, there are many glutinous companies better, have and seldom measure glutinous the company better, have and seldom measure the company of sticking |
The result shows that best art for coating adopts top spray method: nozzle diameter 1mm, fluidisation air quantity 100m
3/ h, 50 ℃ of inlet temperature, 35 ℃ of bed body temperature degree, atomizing pressure 0.15MPa, hydrojet speed 5mL/min, promptly.
1.2 pellet Study on Forming
1.2.1 preparation technology: the plane critical angle of this measuring micropill, be about to a certain amount of micropill and put on the flat board, a dull and stereotyped side is lifted, to measure at micropill begin the to roll angle (φ) of top rake plane and horizontal plane, this angle is more little, and the roundness of micropill is good more.
| Group | Extrude rotating speed rmin -1 | Round as a ball rotating speed rmin -1 | Round as a ball time min | 2φ/° |
| 1 2 3 4 5 6 7 8 9 | 100 100 100 200 200 200 300 300 300 | 500 800 1000 500 800 1000 500 800 1000 | 2 4 6 4 6 2 6 2 4 | 36.7 34.4 28.5 36.0 39.2 36.6 37.8 31.8 27.8 |
The result shows that optimised process is for extruding rotating speed 300rmin
-1, put in the spheronizator, regulate rotating speed 1000rmin
-1And round as a ball time 4min.
1.2.2 art for coating
| Group | Coating pan rotating speed r/min | Coating effect |
| 1 2 3 4 5 6 | 25 30 35 40 45 50 | Generally, there are many glutinous companies better, micropill has seldom, and amount sticks even general, there are many glutinous companies good, substantially glutinous the company generally, there are many glutinous companies general, many glutinous companies are arranged |
The result shows that optimised process is 40r/min for the coating pan rotating speed.
1.3 gel forming technical study
The gel consumption: adopting carbomer in development is gel, than the fruit jelly that uses agar, starch to make, more high resilience, sustained when chewing, caloric value is little, be easy to digest and assimilate, experiment shows, adopts carbomer as gel, the product quality is even, transparency good, mouthfeel is crisp tough, but needs the control consumption, otherwise easily produces lamination or toughness is too strong, mouthfeel is bad.
| Consumption % | Product |
| 1％ 2％ 3％ | Quality is even, and transparency is good, and the layering quality is even, transparency is good, and quality is crisp tough moderate, and not stratified quality is even, transparency is good, and quality is tough, and is not stratified |
Determine that thus the optimum amount of carbomer is 2%.
1.4 soft capsule Study on Forming
Soft capsule dosage form is emerging dosage form, has characteristics such as impurity is few, Main Ingredients and Appearance is many, bioavailability is high, absorption is fast.Compare with common non-soft capsule dosage form such as hard capsule, tablet, can avoid adjuvant that non-soft capsule preparation contains the issuable side effect of human organ (as liver, kidney, heart, blood system etc.).Simultaneously, soft capsule has the characteristics identical with hard capsule again, as easy to carry, good stability etc.In addition, soft capsule external form slyness, high resilience when taking, can reduce the stimulation to esophageal wall, eliminate the damage that rigid friction is caused to the inboard mucosa of esophagus, thus the compliance when having improved the sufferer medication.The applicant finds that under study for action the kind of diluent and consumption directly have influence on the loading amount and the content uniformity of soft capsule.Because this product content of dispersion is more, diluent ratio is low excessively, and then medicinal liquid is mobile bad, and is also high to the production equipment requirement, can cause fill difficulty, content uniformity bigger.Diluent ratio is excessive, then can cause production cost to increase, and causes the patient to take too much adjuvant.Therefore screen the diluent of different proportion, thereby determined the optimal proportion scope.In addition, unstable because the two keys of the unsaturated lactone in less and its molecule of the dissolubility of andrographolide in oil are easily oxidized, so the selection of wetting agent, antioxidant is particularly important.
1.4.1 the prescription screening of soft capsule content
1.4.1.1 the selection of diluent
The diluent that soft capsule is commonly used has soybean oil and PEG400 etc., and the andrographolide water solublity is extremely low among the we, does not dissolve in PEG400, layering is separated out easily, and with the PEG400 is the soft capsule of substrate, and process conditions are required harshness, and its softgel shell is aging easily; Soybean oil is suitable for hydrophobic drug as disperse medium, and easy control of process conditions, and made capsule softgel shell is more stable.It is as follows that both are carried out medicine fusion comparative test.
Get two parts of andrographolide fine powders, add the soybean oil and the PEG400 of equivalent respectively, fully mix after colloid mill ground 10 minutes, placed 1,2,4,8 hour, the precipitation situation of observing two mixed liquors the results are shown in following table.
Different diluent medicine sedimentation situation result of the tests
| Diluent | Medicine sedimentation situation | |||
| 1 hour | 2 hours | 4 hours | 8 hours | |
| Soybean oil | Sedimentation does not appear | Sedimentation does not appear | Slightly sedimentation | A small amount of sedimentation is arranged |
| ? PEG-400 | A small amount of sedimentation | The more amount sedimentation | Most of sedimentation | Sedimentation fully, the obvious layering of medicine and diluent |
In sum, this product is the content good stability of diluent gained with the soybean oil, be difficult for layering and separate out, and be diluent so determine to select for use soybean oil.
1.4.1.2 the selection of diluent consumption
The consumption of diluent directly has influence on the loading amount and the content uniformity of soft capsule.Because this product content of dispersion is less, diluent ratio is low excessively, and then medicinal liquid is mobile bad, and is also high to the production equipment requirement, can cause fill difficulty, content uniformity bigger.Diluent ratio is excessive, then can cause production cost to increase, and causes the patient to take too much adjuvant.Therefore screen the diluent of different proportion, thereby determined the optimal proportion scope.Get andrographolide medicated powder, add not commensurability soybean oil respectively, fully mix, observe the medicinal liquid flowability after colloid mill ground 10 minutes, and encapsulated, investigate pouring process and the capsular content uniformity of gained, the results are shown in following table.
The selection result of the test of diluent ratio
| Medicated powder: diluent | The medicinal liquid flowability | Pouring process | Loading amount (g) | Content uniformity |
| 1: 1 | The medicinal liquid thickness, mobile relatively poor | The fill difficulty, sprinkler body easily stops up | 0.10 | 12% |
| 1: 1.2 | Medicinal liquid thickness, flowability are poor slightly | Fill is difficulty slightly, and idol has the sprinkler body clogging. | 0.11 | 9.5% |
| 1: 1.5 | The medicinal liquid denseness is suitable, and is better mobile | Fill is smooth, no sprinkler body clogging | 0.125 | 5.3% |
| 1: 2 | Medicinal liquid is rarer, good fluidity | Fill is smooth, no sprinkler body clogging | 0.15 | 5.5% |
By result in the table as can be known, when the part by weight of medicated powder and diluent is 1: 1.5 and 1: 2, the medicinal liquid denseness is suitable, better mobile, fill is smooth, and the soft capsule content uniformity is little, but does not have notable difference in 1: 1.5 and 1: 2, and the former supplementary product consumption is less, is 1: 1.5 so select the part by weight of medicated powder and diluent.
1.4.1.3 suspending agent Cera Flava consumption is selected
Because this product is the suspension type soft capsule, thus need to add an amount of suspending agent, to increase the stability of content.Select Cera Flava commonly used in the soft capsule as suspending agent, and investigate as follows its consumption:
Suspending agentThe Cera Flava consumption is selected
| Cera Flava consumption (%) | Medicinal liquid viscosity and flowability | Medicine sedimentation situation | ||||
| 4 hours | 8 hours | 16 hours | 24 hours | 36 hours | ||
| 0.0 | Medicinal liquid is thickness slightly, good fluidity | - | + | + | ++ | +++ |
| ? 0.5 | Medicinal liquid is thickness slightly, and is better mobile | ? - | ? - | ? - | ? - | ? + |
| ? 1.0 | Medicinal liquid is thickness slightly, and is better mobile | ? - | ? - | ? - | ? - | ? - |
| 1.5 | The medicinal liquid thickness, mobile relatively poor | - | - | - | - | - |
| 2.0 | The medicinal liquid thickness, mobile very poor | - | - | - | - | - |
Annotate: the not sedimentation of "-" expression medicine; The sedimentation of "+" expression medicine, "+" is many more, and the expression sedimentation is serious more.The Cera Flava consumption calculates with the consumption sum of andrographolide and soybean oil, and is as follows.
Last table shows, when the Cera Flava consumption is 1.0%, and the medicinal liquid good fluidity, medicine is free settling not.So selecting the Cera Flava consumption is 1.0%.
1.4.1.4 the wetting agent consumption is selected
Because the dissolubility of andrographolide in oil is less, thus add an amount of wetting agent, to increase its dissolubility.Wetting agent commonly used has tween, soybean phospholipid etc., because the tween price is higher and have certain toxicity, thus select inexpensive, safe soybean phospholipid as wetting agent, and its consumption is investigated, method is for getting 1 part of andrographolide, 1.5 parts of soybean oils, Cera Flava 1.0% adds not commensurability soybean phospholipid respectively, use the colloid mill mix homogeneously, left standstill 72 hours, and investigated the sedimentation situation of medicine, the results are shown in following table.
Wetting agentConsumption is selected
| Soybean phospholipid consumption (%) | Medicine sedimentation situation | |||
| 24 hours | 36 hours | 48 hours | 72 hours | |
| 0 | - | - | + | ++ |
| 0.5 | - | - | - | + |
| 1.0 | - | - | - | - |
| 1.5 | - | - | - | - |
Annotate: the not sedimentation of "-" expression medicine; The sedimentation of "+" expression medicine, "+" is many more, and the expression sedimentation is serious more.Last table shows, behind the adding soybean phospholipid, can obviously improve medicine sedimentation situation, and consumption 1.0% is similar to 1.5% effect, is 1.0% so select the soybean phospholipid addition.
1.4.1.5 antioxidant is selected
Because andrographolide is the diterpenoid-lactone class formation, the two keys of the unsaturated lactone in its molecule are easily oxidized, and are unstable, so need to add antioxidant in medicinal liquid.Because this product is diluent with the soybean oil, so antioxidant is good with oil-soluble.
Oil-soluble antioxidant commonly used has gallic acid, vitamin E etc.Gallic acid has the minimal irritation effect to human body, can cause chronic poisoning when taking multiple dose orally, and safety is relatively poor.Vitamin E is as antioxidant, and effect is strong, and is nontoxic, and to skin with organize nonirritant, dissolubility is good in oil.So select the antioxidant of vitamin E, and carry out influence factor's test to investigate its consumption as this product:
It is an amount of to get andrographolide, mixes evenly with soybean oil, Cera Flava, soybean phospholipid, is divided into 4 parts, and each adds vitamin E 0.0%, 0.025%, 0.050%, 0.075%, and is evenly mixed, makes for test agent.With prepared each put high temperature (60 ℃) respectively for test agent, high humidity (temperature is 25 ℃, and relative humidity is 90% ± 5%), illumination (under the condition of 4500lx ± 500lx), in sampling in 0,5,10 day, detects every index and changes, the results are shown in Table down.
The result shows, after using vitamin E,, but can obviously strengthen the stability of andrographolide in medicinal liquid to the character and the not obviously influence of hydroscopicity of medicinal liquid, its consumption 0.050% and 0.075% effect do not have significant difference, are 0.050% so select the vitamin E consumption.
The medicinal liquid influence factor result of the test of different vitamin E ratios
| Vitamin E consumption (%) | Time | The influence factor | The medicinal liquid character | Hydroscopicity (%) | Other lactone | Andrographolide content (%) |
| 0.0 | 0 day | --------- | The white homogeneous latex emulsion | ---- | Up to specification | 38.5 |
| 5 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 36.7 | |
| High humidity | The white homogeneous latex emulsion | 0.13 | Up to specification | 38.4 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Against regulation | 35.5 | ||
| 10 days | High temperature | The white homogeneous latex emulsion | ---- | Against regulation | 35.9 | |
| High humidity | The white homogeneous latex emulsion | 0.18 | Up to specification | 38.1 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Against regulation | 34.5 | ||
| 0.025 | 0 day | -------- | The white homogeneous latex emulsion | ---- | Up to specification | 38.6 |
| 5 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 37.8 | |
| High humidity | The white homogeneous latex emulsion | 0.17 | Up to specification | 38.4 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Up to specification | 36.9 | ||
| 10 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 36.5 | |
| High humidity | The white homogeneous latex emulsion | 0.15 | Up to specification | 38.2 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Against regulation | 35.6 | ||
| 0.050 | 0 day | -------- | The white homogeneous latex emulsion | ---- | Up to specification | 38.3 |
| 5 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 38.5 | |
| High humidity | The white homogeneous latex emulsion | 0.15 | Up to specification | 38.4 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Up to specification | 38.0 | ||
| 10 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 37.8 | |
| High humidity | The white homogeneous latex emulsion | 0.17 | Up to specification | 38.4 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Up to specification | 37.5 |
| 0.075 | 0 day | -------- | The white homogeneous latex emulsion | ---- | Up to specification | 38.6 |
| 5 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 38.3 | |
| High humidity | The white homogeneous latex emulsion | 0.16 | Up to specification | 38.4 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Up to specification | 37.9 | ||
| 10 days | High temperature | The white homogeneous latex emulsion | ---- | Up to specification | 37.8 | |
| High humidity | The white homogeneous latex emulsion | 0.20 | Up to specification | 38.1 | ||
| Illumination | The white homogeneous latex emulsion | ---- | Up to specification | 37.4 |
Above-mentioned investigation result shows, when medicine and soybean oil ratio be 1: 1.5, Cera Flava consumption be 1.0% and the soybean phospholipid consumption be 1%, when the vitamin E consumption is 0.050%, the medicinal liquid good fluidity, stablize not stratified, can satisfy the requirement of soft capsule pressing, can make the content of dispersion of finished product suitable again, the single dose of this moment is 0.128g, make things convenient for the patient to take, be so determine this product prescription:
Andrographolide 50g soybean oil 75g Cera Flava 1.25g soybean phospholipid 1.25g
Vitamin E 0.0625g makes 1000
1.4.2 soft capsule shell prescription screening
1.4.2.1 softgel shell basis prescription is selected
Softgel shell basis prescription adopts soft capsule gelatin, purified water prescription commonly used, and both usage ratio are gelatin: water=100: 100
1.4.2.2 plasticizer is selected
The purpose that adds plasticizer is to increase the plasticity of soft capsule, guarantees the good stretchability of soft capsule goods; Long-term its hardness that keeps makes it not yielding.Document shows that glycerol does not almost have influence as plasticizer to dissolution rate.And a stable thermal reversibility gel network can be formed, thereby be suitable for use as the plasticizer of soft capsule most.
The consumption of glycerol and gelatin is selected commonly used 0.35: 1, and the too little then softgel shell of consumption is hard, crisp, poor plasticity, and too greatly then softgel shell is softer for consumption, than being easier to the moisture absorption and extrusion, and the soft capsule drying time of can extending.
1.4.2.3 disintegrating agent is selected
Studies show that the PEG 400 of adding gelatin amount 5% can shorten disintegration time effectively as auxiliary disintegrating agent in the softgel shell prescription, so be chosen in the auxiliary disintegrating agent of PEG 400 conducts that adds gelatin amount 5% in the softgel shell prescription.
1.4.2.4 screening agent is selected
Because andrographolide is unstable, be screening agent so add 0.2% Brown Ferric Oxide of gelatin amount, make cyst membrane opaque, to reduce the soft capsule shell transmittance, the increase stability of drug.
1.4.2.5 antiseptic is selected
Owing to gelatin is come by animal bone preparation, when soft capsule leaves in the bigger ring moat of excess moisture or humidity, can cause putrid and deteriorated, so adding ethyl hydroxybenzoate and propyl hydroxybenzoate as antiseptic, consumption is respectively 0.2% of gelatin amount.
Lab scale and middle trial production show that with the made softgel shell compacting soft capsule of above-mentioned composition, production process is smooth, and product design is attractive in appearance; Stability test shows, consists of the soft capsule of softgel shell with this, and at duration of storage, content is stable, and the product disintegrate is good.
In sum, the soft capsule shell prescription is made up of gelatin, purified water, glycerol, Polyethylene Glycol, Brown Ferric Oxide, ethyl hydroxybenzoate, propyl hydroxybenzoate, and weight proportion is a gelatin: purified water: glycerol: Polyethylene Glycol: Brown Ferric Oxide: ethyl hydroxybenzoate: propyl hydroxybenzoate=500: 500: 175: 25: 1: 1: 1.
1.4.3 preparations shaping technical study
1.4.3.1 the medicine degree of grinding is investigated
Medicine degree of grinding too Xiao Yi causes the obstruction of equipment sprinkler body, soft capsule oil impregnate etc., and degree of grinding is excessive then has relatively high expectations to disintegrating apparatus, and energy consumption increases, and production efficiency reduces, and production cost is increased.For this reason, it is an amount of to get andrographolide respectively, and pulverize separately becomes varigrained fine powder, by method for making, is pressed into capsule, investigates the influence of medicine degree of grinding to production process and finished product, the results are shown in following table.
The medicine degree of grinding is investigated
| The medicine degree of grinding | The medicinal liquid situation | Production process and finished product situation |
| 60 orders | The medicinal liquid Chinese medicine is than free settling | The equipment sprinkler body easily stops up, and finished product has the oil impregnate phenomenon |
| 80 orders | The medicinal liquid Chinese medicine is than free settling | Idol has sprinkler body to stop up generation, and the oil impregnate phenomenon is arranged during finished product |
| 100 orders | The medicinal liquid Chinese medicine is more stable, does not find medicine sedimentation situation | Produce smoothly, do not see the sprinkler body clogging, finished product is not seen oil impregnate |
| 120 orders | The medicinal liquid Chinese medicine is more stable, does not find medicine sedimentation situation | Produce smoothly, do not see the sprinkler body clogging, finished product is not seen oil impregnate |
Above-mentioned result of the test shows, medicine pulverizing medicinal liquid Chinese medicine between 100～120 orders is more stable, do not find medicine sedimentation situation, produce smoothly, do not see the sprinkler body clogging, finished product is not seen oil impregnate, because the medicine degree of grinding is 100 mesh sieves and the not obviously difference of 120 mesh sieves, so select medicine is crossed 100 mesh sieves.
1.4.3.2 the colloid mill incorporation time selection
It is an amount of to get andrographolide, adds each adjuvant by method for making, makes medicinal liquid, and put and mix 5,10,15 minutes in the colloid mill, colloid mill mill spacing 5um, is the control temperature 50 during grinding? below, relatively gained medicinal liquid situation the results are shown in following table.
By the result as can be known, mixed 10 minutes and 15 minutes medicinal liquid situation zero differences, but all be better than mixing 5 minutes.So determine to mix 10 minutes with colloid mill.
The selection of incorporation time
| Incorporation time | The medicinal liquid situation |
| 5 minutes | Medicinal liquid has granular sensation, mixes inhomogeneous |
| 10 minutes | Medicinal liquid is even, the feel exquisiteness |
| 15 minutes | Medicinal liquid is even, the feel exquisiteness |
1.4.3.3 the selection of sprinkler body temperature
In the pressing process of soft capsule, the sprinkler body temperature is the key factor that influences soft capsule content uniformity and yield rate, and the sprinkler body temperature is low excessively, and the capsule pressing is bad, leakage easily; The sprinkler body temperature is too high, can influence the outward appearance of soft capsule.Investigate the pressing situation and the yield rate of soft capsule under the different temperatures for this reason, the results are shown in following table.
The selection result of the test of sprinkler body temperature
| The sprinkler body temperature | Soft capsule finished product situation |
| 38～42℃ | Pressing is bad, leakage easily |
| 42～46℃ | The yield rate height, content uniformity is little |
| 46～48℃ | The soft capsule appearance poor, the out-of-flatness of pressing position |
As seen from the experiment, the sprinkler body temperature should be controlled at 42～46 ℃ and is advisable.
1.4.3.4 dry humiture is selected
Get soft capsule, use the rotating cage seasoning,, investigate product bone dry required time (routinely, being dried to softgel shell water content 12～14%) and dry back finished product situation (disintegrate, outward appearance), the results are shown in following table respectively with different humiture dryings:
Dry humiture, selection of time
| Baking temperature (ε) | Relative humidity | Drying time (h) | The finished product outward appearance | Disintegration time (branch) |
| 24～27 | 20～30％ | 17 | Finished product is attractive in appearance | 15 |
| 30～40 ％ | 18 | Finished product is attractive in appearance | 13 | |
| 40～60 ％ | 26 | Finished product is attractive in appearance | 14 | |
| 27～30 | 20～30％ | 16 | Finished product is attractive in appearance | 13 |
| 30～40 ％ | 18 | Finished product is attractive in appearance | 15 | |
| 40～60 ％ | 24 | Finished product is attractive in appearance | 14 | |
| ? 30～33 | ? 20～30％ | ? 23 | The false phenomenon of doing is arranged, and the ball type is relatively poor,Finished product generation sunken inside ball | ? 30 |
| ? 30～40 ％ | ? 26 | The false phenomenon of doing is arranged, and the ball type is relatively poor,Finished product generation sunken inside ball | ? 32 | |
| ? 40～60 ％ | ? 30 | The false phenomenon of doing is arranged, and the ball type is relatively poor,Finished product generation sunken inside ball | ? 31 |
Last table shows, when baking temperature is 24～30e, and relative humidity 20～40%, product bone dry required time is shorter, the finished product good looking appearance, and disintegration time is shorter, so selecting baking temperature is 24～30e, relative humidity is 20～40%, and be 16～18 hours drying time.
Experimental example 2: contrast experiment
2.1 check disintegration
Adopting changes the basket method, and the lift disintegration tester is got 6, observes the situation by screen cloth, and percent of pass height then disintegrative is good, more pleasant bulk absorption.
| Group | Disintegration time |
| Andrographolide capsule micropill of the present invention | 25min 2.40min |
2.2 release experiment
Simulated gastric fluid-95% ethanol (3: 2) is solvent, 37 ± 0.5 ℃ 100 rev/mins.Get andrographolide sheet, soft capsule of the present invention, drop pill of the present invention, put and get the 6ml solvent when changeing in the basket respectively at 5min, 10min, 20min, 30min, 40min, 50min, 60min, 90min, put immediately in the centrifuge tube with 4,000 rev/mins of centrifugal 5min, get supernatant 5ml, thin up is to 10ml, content with high-efficient liquid phase technique mensuration andrographolide lactone calculates the cumulative percentage rate that discharges.
| Discharge cumulative percentage rate % | ||
| The andrographolide sheet | Dispersible tablet of the present invention | |
| 5min 10min 20min 30min 40min 50min 60min 90min | 5.34 41.22 62.50 68.86 78.53 87.55 89.56 92.37 | 83.05 92.18 95.62 97.75 98.52 100.00 100.10 102.30 |
2.3 stability experiment
| Group | Andrographolide % | ||
| 0 month | March | June | |
| Andrographolide sheet andrographolide capsule dispersible tablet of the present invention micropill of the present invention | 0.84 0.83 0.82 0.83 | 0.77 0.79 0.81 0.82 | O.74 0.76 0.80 0.81 |
The result shows that preparation of the present invention is functional.
Experimental example 3: pharmacodynamic experiment is grabbed antibacterial anti-inflammatory effect experiment
1. antiinflammatory action: mice dimethylbenzene is brought out the influence of mice auricle swelling
Get body weight 20-26g mice, be divided into 3 groups at random, irritate stomach respectively and give different preparations, the administration capacity is the 0.25g/kg body weight, 2 times/day, successive administration 6d was coated with dimethylbenzene 0.1ml in the Mus auris dextra back of the body after the last administration in 30 minutes, and mice is put to death in the cervical vertebra dislocation after 2 hours, lay round auricle with card punch in left and right sides ear same area, weighing, is contrast with left auricle, calculates left and right sides ear method of double differences value as the swelling degree.Experimental result shows that product xylol of the present invention brings out mice auricle swelling all the obvious suppression effect, sees the following form.
| Group | Dosage | Number of animals | Swelling degree (mg) |
| Capsule matched group gel experimental group soft capsule experimental group | 0.8g/kg 0.8g/kg 0.8g/kg | 10 10 10 | 3.25±0.03 3.32±0.02 3.01±0.03 |
2. external bacteriostasis research
The preparation of ordinary culture medium: escherichia coli, staphylococcus aureus, bacillus pyocyaneus are inoculated into common Nutrient medium surface with getting the collarium densification respectively, the filter paper that will contain the diameter 0.4cm of formulation soln with the sterile working is attached on the culture medium, cultivates 24h for 37 ℃ and observes the measurement inhibition zone diameter.The preparation of blood plate culture medium: behind autoclave sterilization on the ordinary nutrient agar medium base, add 5%～10% aseptic defiber sheep blood mixing when being cooled to 56 ℃, pour in the culture dish standby.Bacteriostatic experiment: with alpha streptococcus, group B streptococcus with get collarium respectively densification be inoculated on the blood plate nutrition base, after the filter paper that will contain the diameter 0.4cm of formulation soln with the sterile working is attached on the culture medium, cultivates 24h for 37 ℃ and observe and measure inhibition zone diameters.
| Group | Strain | Inhibition zone diameter meansigma methods d/cm |
| Tablet control group micropill preparation experimental group is disperseed the tablet experimental group | Escherichia coli and staphylococcus aureus Pseudomonas aeruginosa alpha streptococcus beta streptococcus escherichia coli and staphylococcus aureus Pseudomonas aeruginosa alpha streptococcus beta streptococcus escherichia coli and staphylococcus aureus | 0.765 0.816 0.802 1.476 1.418 0.876 0.910 0.815 1.486 1.426 0.879 0.920 |
| Bacillus pyocyaneus alpha streptococcus group B streptococcus | 0.819 1.482 1.423 |
The result shows that preparation antiinflammatory fungistatic effect of the present invention is good, is not less than tablet, capsule.
Concrete embodiment:
Embodiments of the invention 1: get andrographolide 50g, cross 100 mesh sieves, standby; Get Cera Flava as suspending agent, consumption is 1.0%, puts in the diluent, and soybean oil is a diluent, and the ratio of medicated powder and diluent is 1: 1.5, and heating makes dissolving, puts to room temperature; Other gets 1.0% soybean phospholipid is that wetting agent, 0.050% vitamin E are antioxidant, add respectively in the above-mentioned oil solution, mix homogeneously, add andrographolide, use the colloid mill mix homogeneously, the softgel shell prescription is made up of gelatin, purified water, glycerol, Polyethylene Glycol, Brown Ferric Oxide, ethyl hydroxybenzoate, propyl hydroxybenzoate, weight proportion is a gelatin: purified water: glycerol: Polyethylene Glycol: Brown Ferric Oxide: ethyl hydroxybenzoate: propyl hydroxybenzoate=500: 500: 175: 25: 1: 1: 1, and suppress soft capsule under given conditions: the colloid mill incorporation time is 10 minutes; Sprinkler body temperature in the soft capsule pressing process should be controlled at 42～46 ℃; Baking temperature is 24～30e, and relative humidity is 20～40%, and be 16～18 hours drying time, promptly gets soft capsule, oral, a 0.1～0.15g, 3～4 times on the one.
Embodiments of the invention 2: get andrographolide 50g, add in adjuvant: the ratio of medicated powder is 0.5: 1 a microcrystalline Cellulose, add in adjuvant: the ratio of medicated powder is 0.5: 1 a crospolyvinylpyrrolidone, add in adjuvant: the ratio of medicated powder is 0.5: 1 a low-substituted hydroxypropyl cellulose, add in adjuvant: the ratio of medicated powder is 1: 1 a calcium hydrogen phosphate, add in adjuvant: the ratio of medicated powder is 0.02: 1 a magnesium stearate mix homogeneously, make soft material with 2% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, add in adjuvant: the ratio of medicated powder is 0.5: 1 a carboxymethyl starch sodium, add in adjuvant: the ratio of medicated powder is 0.03: 1 a steviosin, mix, tabletting, coating then, coating adopts a spray method: nozzle diameter 1mm, fluidisation air quantity 100m
3/ h, 50 ℃ of inlet temperature, 35 ℃ of bed body temperature degree, atomizing pressure 0.15MPa, hydrojet speed 5mL/min promptly gets dispersible tablet.
Embodiments of the invention 3: get andrographolide 50g, add in adjuvant: the ratio of medicated powder is 1: 1 a microcrystalline Cellulose, and the mixing that sieves adds an amount of alcoholic solution and makes soft material, and through the extruder sieve plate, aperture 0.9mm is extruded into fine strip shape, extrudes rotating speed 300rmin
-1, put in the spheronizator, regulate rotating speed 1000rmin
-1And round as a ball time 4min, make granule round as a ball fully, take out micropill in 50 ℃ of drying 3～4h, after the screening, carry out coating with 18～24 purpose micropills, the Radix Glycyrrhizae charcoal is a coating material, the coating pan rotating speed is 40r/min, promptly gets pellet.
Embodiments of the invention 4: get andrographolide 50g, adding propylene glycol grinds evenly, it with weight ratio 2% carbomer, add a little distilled water and triethanolamine, stir and make gel, mix with the propylene glycol solution of above-mentioned andrographolide, grind well, then at 65 ℃ of 30min that sterilize down, cold putting promptly gets gel.
Embodiments of the invention 5: get andrographolide 10g, add 15g Macrogol 4000 and 5g polyoxyethylene monostearate (S-40), at 80～90 ℃ of fusion mixings, splash in the dimethicone and cool off, drip apart from being 4cm, low speed is controlled at 30～40/min, promptly gets drop pill.
Embodiments of the invention 6: get andrographolide 100g, add starch 300g, stevioside 3g, microcrystalline Cellulose 10g with the alcoholic solution system soft material of an amount of polyvinylpyrrolidone k30, granulates, and 70 ℃ of forced air dryings are granulated, and granulate promptly gets granule.
Claims (9)
1. andrographolide preparation, it is characterized in that: it mainly is the preparation that is formed by the andrographolide processing and fabricating, comprises all acceptable dosage forms on injection, powder pin, freeze-dried powder, gel and dispersible tablet, soft capsule, microcapsule, granule, pill, micropill, powder, drop pill, slow releasing preparation, controlled release preparation, gel, oral liquid, soft extract, extractum and the membrane pharmaceutics.
2. according to the preparation method of the described andrographolide preparation of claim 1, it is characterized in that: get andrographolide, add suitable adjuvant, manufacture dispersible tablet, gel, soft capsule, drop pill or pellet preparations with diverse ways.
3. according to the preparation method of claim 1 or 2 described andrographolide preparations, it is characterized in that: the soft capsule in the described preparation prepares like this: get andrographolide, cross 100 mesh sieves, and standby; Get Cera Flava, put in the soybean oil, heating makes dissolving, puts to room temperature; Other gets soybean phospholipid, vitamin E, adds respectively in the above-mentioned oil solution, and mix homogeneously adds andrographolide, uses the colloid mill mix homogeneously, selects suitable softgel shell prescription for use, suppresses soft capsule under given conditions, drying, promptly.
4. according to the preparation method of the described andrographolide preparation of claim 3, it is characterized in that: soybean oil is a diluent, and the part by weight of medicated powder and diluent is 1: 1.5; Cera Flava is as suspending agent, and consumption is 1.0%; Soybean phospholipid is a wetting agent, and addition is 1.0%; Vitamin E is an antioxidant, and consumption is 0.050%.
5. according to the preparation method of the described andrographolide preparation of claim 3, it is characterized in that: the soft capsule shell prescription is made up of gelatin, purified water, glycerol, Polyethylene Glycol, Brown Ferric Oxide, ethyl hydroxybenzoate, propyl hydroxybenzoate, and weight proportion is a gelatin: purified water: glycerol: Polyethylene Glycol: Brown Ferric Oxide: ethyl hydroxybenzoate: propyl hydroxybenzoate=500: 500: 175: 25: 1: 1: 1.
6. according to the preparation method of the described andrographolide preparation of claim 3, it is characterized in that: the colloid mill incorporation time is 10 minutes; Sprinkler body temperature in the soft capsule pressing process should be controlled at 42～46 ℃; Baking temperature is 24～30e, and relative humidity is 20～40%, and be 16～18 hours drying time.
7. according to the preparation method of claim 1 or 2 described andrographolide preparations, it is characterized in that: the dispersible tablet in the described preparation prepares like this: get andrographolide, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a microcrystalline Cellulose, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a crospolyvinylpyrrolidone, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a low-substituted hydroxypropyl cellulose, add by adjuvant: the part by weight of medicated powder is 1: 1 a calcium hydrogen phosphate, add by adjuvant: the part by weight of medicated powder is 0.02: 1 a magnesium stearate mix homogeneously, make soft material with 2% polyvinylpyrrolidone aqueous solution, by No. 2 sieve series grains, 50～60 ℃ of forced air dryings, dry granular is after No. 3 sieve granulate, add by adjuvant: the part by weight of medicated powder is 0.5: 1 a carboxymethyl starch sodium, add by adjuvant: the part by weight of medicated powder is 0.03: 1 a steviosin, mix, tabletting, coating then, coating adopts top spray method: nozzle diameter 1mm, fluidisation air quantity 100m3/h, 50 ℃ of inlet temperature, 35 ℃ of bed body temperature degree, atomizing pressure 0.15MPa, hydrojet speed 5mL/min, promptly.
8. according to the preparation method of claim 1 or 2 described andrographolide preparations, it is characterized in that: the pellet in the described preparation prepares like this: get andrographolide, add by adjuvant: the part by weight of medicated powder is 1: 1 a microcrystalline Cellulose, mixing sieves, add an amount of alcoholic solution and make soft material, through the extruder sieve plate, aperture 0.9mm is extruded into fine strip shape, extrude rotating speed 300rmin-1, put in the spheronizator, regulate rotating speed 1000rmin-1 and round as a ball time 4min, make granule round as a ball fully, take out micropill in 50 ℃ of drying 3～4h, after the screening, carry out coating with 18～24 purpose micropills, the Radix Glycyrrhizae charcoal is a coating material, the coating pan rotating speed is 40r/min, promptly.
9. according to the preparation method of claim 1 or 2 described andrographolide preparations, it is characterized in that: the gel in the described preparation prepares like this: get andrographolide, adding propylene glycol and grind evenly, is 2% carbomer with weight ratio, adds a little distilled water and triethanolamine, stirring makes gel, mix with the propylene glycol solution of above-mentioned andrographolide, grind well, then at 65 ℃ of 30min that sterilize down, cold putting promptly gets gel.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2005102005477A CN1762347A (en) | 2004-09-24 | 2005-09-22 | Andrographolide preparation and its production method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200410040765.4 | 2004-09-24 | ||
| CNA2004100407654A CN1634032A (en) | 2004-09-24 | 2004-09-24 | Andrographolide preparation and its production method |
| CNA2005102005477A CN1762347A (en) | 2004-09-24 | 2005-09-22 | Andrographolide preparation and its production method |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101439062B (en) * | 2007-11-22 | 2012-07-18 | 天津天士力制药股份有限公司 | Chinese medicine granule containing andrographolide and preparation method thereof |
| CN102652762A (en) * | 2012-05-14 | 2012-09-05 | 浙江大学 | Application of effective parts of common andrographis herbs |
| CN103265510A (en) * | 2013-06-09 | 2013-08-28 | 珠海金鸿药业股份有限公司 | Andrographolide crystal, soft capsule containing andrographolide crystal, and preparation method of soft capsule |
| CN104138361A (en) * | 2014-07-31 | 2014-11-12 | 南京正科制药有限公司 | Andrographolide dispersible tablet and preparation method thereof |
| CN104688676A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Andrographolide concentrated liquid and medical application thereof |
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2005
- 2005-09-22 CN CNA2005102005477A patent/CN1762347A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101439062B (en) * | 2007-11-22 | 2012-07-18 | 天津天士力制药股份有限公司 | Chinese medicine granule containing andrographolide and preparation method thereof |
| CN102652762A (en) * | 2012-05-14 | 2012-09-05 | 浙江大学 | Application of effective parts of common andrographis herbs |
| CN103265510A (en) * | 2013-06-09 | 2013-08-28 | 珠海金鸿药业股份有限公司 | Andrographolide crystal, soft capsule containing andrographolide crystal, and preparation method of soft capsule |
| CN103265510B (en) * | 2013-06-09 | 2014-09-10 | 珠海金鸿药业股份有限公司 | Andrographolide crystal, soft capsule containing andrographolide crystal, and preparation method of soft capsule |
| CN104688676A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Andrographolide concentrated liquid and medical application thereof |
| CN104688676B (en) * | 2013-12-10 | 2018-03-30 | 沈阳药科大学 | Andrographolide concentrated type liquid formula and its medical usage |
| CN104138361A (en) * | 2014-07-31 | 2014-11-12 | 南京正科制药有限公司 | Andrographolide dispersible tablet and preparation method thereof |
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