CN109568264A - A kind of andrographolide nano suspension - Google Patents
A kind of andrographolide nano suspension Download PDFInfo
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- CN109568264A CN109568264A CN201710894010.8A CN201710894010A CN109568264A CN 109568264 A CN109568264 A CN 109568264A CN 201710894010 A CN201710894010 A CN 201710894010A CN 109568264 A CN109568264 A CN 109568264A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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Abstract
The present invention provides a kind of andrographolide nano suspension, the andrographolide nano suspension includes: effective andrographolide particle of the average grain diameter less than 1000 nm and at least one anionic surface stabilizer.The nano suspension prescription is simple, preparation process simplify it is controllable, be easy to industrialization, be high-efficient, better stability of preparation, dilution-resistant.
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, are related to a kind of andrographolide nano suspension and its preparation
Methods and applications.
Background technique
Andrographolide is the diterpenic lactone that extracts in acanthaceous plant Herba Andrographitis, anti-inflammatory, antibacterial,
Antiviral and antitumor, immunological regulation, treatment cardiovascular and cerebrovascular disease, Hepatoprotective cholagogue etc. have fabulous application value.Clinic is used
In treatment bacillary dysentery, leptospirosis, meningitis, pneumonia, infection of the upper respiratory tract etc., because it feels bacterium or virus
It is good to contaminate disease therapeuticing effect, enjoys the good reputation of " Chinese medicine antibiotic ".
The peroral dosage forms such as the andrographolide tablet of CFDA approved production at present, capsule, dripping pill.These preparations to bacterium,
Although virus has certain inhibiting effect, bioavilability is limited.Injection is form of medication the most direct, but due to wearing
Heart lotus lactone itself has water-soluble low, fusing point height, and the low property of drugloading rate in lipid drug-loading system, the note listed at present
Penetrating agent is its hydrophilic derivant, but as the application range of andrographolide hydrophilic derivant injection constantly expands, about
The report of its adverse reaction also gradually increases.Recently, Xiyanping (andrographolide soluble derivative) injection is in Gansu, black
The serious adverse reactions such as the shiver with cold of ten many cases, fever occur altogether for Longjiang, Jiangsu.Adverse reaction and drug combination, steady occur for injection
Qualitative, particulate matter, adjunct ingredient and production technology have substantial connection.
Therefore nano suspension directly is made as optimal selection in andrographolide.Nano suspension is with surface-active
Agent is stabilizer, the dispersion system of colloid being made of drug microparticles.With drug concentration height, administered volume is small, supplementary product consumption is few,
The advantages such as toxicity is low, prescription is simple, technology of preparing is mature.It can be made into different preparations as intermediate dosage form, oral significantly to mention
High bioavilability, injection can reduce administration frequency or realize the advantages such as target administration.Therefore nano suspension technology can mention
High drug effectiveness, safety and stability, meet it is clinical there is an urgent need to.
Currently, the preparation method of nano suspension has two kinds of technologies of bottom up and top down, the former includes precipitating
Method, supercritical fluid technique, emulsion process etc., the latter include media milling process, high pressure homogenization method, additionally can two kinds of technologies connection
It closes and uses.Only patent " andrographolide nano suspension composition and its preparation method and application " (CN at present
105726494 A) prepare andrographolide nano suspension, but its ball-milling method for using or high pressure homogenization method milling time compared with
Long, efficiency is lower.The closed system that ball mill uses, can not achieve continuous operation；Without filtration system, manual separation is needed after grinding
Material and abrasive media；And needing bulk pharmaceutical chemicals are pre-dispersed in aqueous systems, technique is not easy enough, and amplification production is limited.
Simultaneously it is noted that nano-colloid system of the nano suspension as high degree of dispersion, system free energy is higher,
Aggregation, sedimentation, curing equistability problem easily occur in aqueous medium, becomes an important factor for limiting its application.
Summary of the invention
It is an object of the present invention to provide the andrographolide nano suspension and its preparation process of a kind of injectable and applications.It should
Nano suspension prescription is simple, preparation process simplify it is controllable, be easy to industrialization, be high-efficient, better stability of preparation, dilution-resistant.
For achieving the above object, technical scheme is as follows:
A kind of andrographolide nano suspension, which is characterized in that composition includes: effective average grain diameter less than 1000 nm
Andrographolide particle and at least one stabilizer.
Andrographolide nano suspension of the present invention, which is characterized in that the andrographolide amount is 0.05%
~ 8%(w/v)；In some technical solutions, Determination of Andrographolide is 0.05% ~ 5%(w/v)；In some technical solutions, punching
Lotus lactone content is 5% ~ 8%(w/v)；In some technical solutions, Determination of Andrographolide is 0.5% ~ 5%(w/v), it does not include 5%
(w/v)；In some technical solutions, Determination of Andrographolide is 0.5% ~ 4%(w/v)；In some technical solutions, in Herba Andrographitis
Ester content is 5%(w/v), in some technical solutions, Determination of Andrographolide 6%(w/v), in some technical solutions, wear
Heart lotus lactone content is 8%(w/v).
Andrographolide nano suspension of the present invention, which is characterized in that prepared andrographolide nanometer is mixed
Suspension average grain diameter is less than about 1000 nm, is less than about 900 nm, is less than about 800 nm, is less than about 700 nm, is less than about 650
Nm, it is less than about 600 nm, is less than about 550 nm, is less than about 500 nm, is less than about 450 nm, small about 400 nm, boy about 350
Nm, it is less than about 300 nm, is less than about 250 nm, is less than about 200 nm, is less than about 150 nm, is less than about 100 nm.
Andrographolide nano suspension of the present invention, which is characterized in that the stabilizer is cholic acid and cholic acid
Salt: deoxycholic acid and its sodium salt, neocholan and its sodium salt, hyodesoxycholic acid and its sodium salt, taurocholate and its sodium salt, ox
Sulphur ursodesoxycholic acid and its sodium salt, Taurochenodeoxycholic Acid and its sodium salt；Sulfates: lauryl sodium sulfate；Sulfonates:
Neopelex, dioctyl succinate disulfonate acid；Odium stearate salt；Triethanolamine salt；Meglumine salt；Trihydroxy methyl
The mixture of one of aminomethane salt or alkaline amino acid salt or any combination thereof.Preferably cholic acid salt, dosage are
0.05% ~ 1%(w/v).Pre-stage test of the present invention shows to be added stabilizer before grinding for maintaining nano suspension in process of lapping
Stability plays a significant role.
A kind of preparation method of andrographolide nano suspension, which comprises the following steps: 1) by stabilizer
It completely dissolves in water；2) aqueous solution containing stabilizer is transferred in the grinder for having installed abrasive media, is brought into operation,
Andrographolide bulk pharmaceutical chemicals are added after solution forms circulation in instrument to be ground；3) grinding is after a certain period of time from discharge port
Obtain milky nanosuspension；4) the andrographolide nano suspension composition for dispensing stable.Pre-stage test of the present invention
It is middle to prepare nano suspension, including planetary ball mill using a variety of instruments, high pressure homogenizer, microjet instrument, wet grinding mill,
It is preferred that wet grinding mill.
In some technical solutions of the present invention, andrographolide bulk pharmaceutical chemicals can directly prepare nano suspension.
In some technical solutions of the invention, andrographolide bulk pharmaceutical chemicals can prepare nanometer suspension after micronization processes
Agent.Preferably bulk pharmaceutical chemicals are through micronization processes.
The preparation method of andrographolide nano suspension of the present invention, which is characterized in that the abrasive media of use
For zirconium oxide bead, partial size is 0.1 ~ 0.8 mm, and abrasive media filling rate is 50% ~ 85%(v/v), i.e., abrasive media volume with grind
Mill chamber volume ratio is 50% ~ 85%.
In some technical solutions of the invention, when the abrasive media used is 0.1 mm zirconium oxide bead, andrographolide
Bulk pharmaceutical chemicals need to be through micronization processes.Because the filter screen aperture accordingly used is smaller since abrasive media partial size is smaller, if
Not carrying out micronization processes to drug will cause sieve blocking.
The preparation method of andrographolide nano suspension of the present invention, which is characterized in that grinder running parameter
To grind 1500 ~ 4000 rpm of revolving speed, runing time is 0.25 ~ 4 h, and grinding chamber temperature is controlled 10 ~ 50oC。
Freeze drying protectant appropriate can be also added in andrographolide nano suspension of the present invention, freeze-drying
It stores in solid form afterwards or is further made other dosage formulations as intermediate dosage form.Selectable freeze drying protectant is sugarcane
Sugar, trehalose, maltose, mannitol, glycerol, distearoylphosphatidylethanolamine -- polyethylene glycol (PEG) 2000, poly- second two
Or mixtures thereof one of alcohol 2000, polysorbas20, Tween 80, vitamin E polyethylene glycol succinic acid ester.Single freeze drying protectant
Preferably sucrose, trehalose, preferable amount are 3 ~ 10%(w/v)；Combination freeze drying protectant preferably sucrose is combined with mannitol or seaweed
Sugar is combined with mannitol, and preferable amount is 1 ~ 5%(of sucrose or trehalosew/v) (w/v), 1 ~ 5%(of mannitolw/v).Frozen-dried protective
The selection of agent is for maintaining property, the state of drug to play a key effect.Suitable freeze drying protectant can guarantee the outer of dried frozen aquatic products
It sees, redissolve state and change of size, therefore suitable freeze drying protectant need to be selected for different pharmaceutical.In the present invention, use is excellent
The dried frozen aquatic products smooth in appearance that the single or combination freeze drying protectant of choosing obtains is complete, the redissolution time is shorter, redissolution state is preferable, grain
Diameter increases smaller.
The preparation method of andrographolide nano suspension of the present invention, which is characterized in that in the Herba Andrographitis
Ester nano suspension can store in solid form by spray dried form or further be made as intermediate dosage form other dosage forms
Preparation.Spray drying supporting agent include one of dextrin, starch, microcrystalline cellulose, silica, mannitol, lactose, maltose or
Its any mixture.
After the freeze-drying of andrographolide nano suspension or spray drying of the present invention, wearing after solid-state or redissolution
Ester nanoparticles average grain diameter is less than about 1000 nm, is less than about 900 nm, is less than about 800 nm, is less than about 700 nm, is small in heart lotus
In about 650 nm, be less than about 600 nm, be less than about 550 nm, be less than about 500 nm, be less than about 450 nm, be less than about 400 nm,
About 350 nm of boy, it is less than about 300 nm, is less than about 250 nm, is less than about 200 nm, is less than about 150 nm, is less than about 100
nm。
A kind of application of andrographolide nano suspension, which is characterized in that the andrographolide nano suspension group
Parental injection (for example, vein, muscle is subcutaneous) can be formulated for by closing object, be taken orally (with solid, liquid or suction form),
Vagina, nose, rectum, eye, oral cavity, in brain pond, in peritonaeum or the preparation of the different way of administration such as local administration.
The application of andrographolide nano suspension composition of the present invention, which is characterized in that in the Herba Andrographitis
Ester nano suspension can be prepared into following dosage form by the conventional method of preparation: solid or semisolid preparation includes but unlimited
In tablet, capsule, gel, ointment, creme etc.；Liquid preparation includes but is not limited to liquid dispersant, suspension etc..
Andrographolide nano suspension of the present invention, also include when being used as solid or semisolid preparation it is a kind of or
Multiple auxiliary materials, such as: filler, binder, lubricant, disintegrating agent, gas-producing disintegrant, corrigent, preservative or other auxiliary materials,
Depending on final dosage form.The filler includes but is not limited to that starch, sucrose, dextrin, lactose, pregelatinized starch, crystallite are fine
Tie up element, mannitol, sorbierite etc.；The binder includes but are not limited to, cellulose family, polyvinylpyrrolidone, gelatin,
Polyethylene glycol etc.；The lubricant includes but are not limited to, colloidal silicon dioxide, talcum powder, stearic acid, magnesium stearate, hard
Resin acid calcium, silica gel, lauryl sodium sulfate etc.；The disintegrating agent includes but are not limited to, crosslinked polyvinylpyrrolidone, carboxylic
Methyl starch sodium, potato starch, cornstarch, modified starch, croscarmellose sodium etc.；The gas-producing disintegrant
It includes but are not limited to, organic acid plus carbonate or bicarbonate.Suitable organic acid includes citric acid, tartaric acid, apple
Acid, fumaric acid, adipic acid, succinic acid and alginic acid and acid anhydrides and hydrochlorate；Suitable carbonate and bicarbonate include such as carbon
Sour sodium, calcium carbonate, zinc carbonate, sodium bicarbonate.Or the presence of only sodium bicarbonate；The corrigent includes but are not limited to,
Sucrose, xylitol, saccharin, cyclamate, Aspartame, acesulfame potassium etc.；The preservative includes but is not limited to,
Potassium sorbate, methyl p-hydroxybenzoate, ethyl-para-hydroxybenzoate, propylparaben, butyl p-hydroxybenzoate,
Benzoic acid and its salt etc..
Andrographolide nano suspension of the present invention, which is characterized in that nanometer suspension preparation, freeze-drying system
Agent, spray dried formulations or the solid being prepared into, semisolid, liquid preparation can be used before when as liquid preparation medication
Water redissolves, and can be redissolved and be diluted with 5% glucose solution when necessary, andrographolide nanosuspension is average after redissolving and diluting
Partial size be less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 650 nm, be less than about
600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about about 350 nm of 400 nm, boy, be less than
About 300 nm, it is less than about 250 nm, is less than about 200 nm, is less than about 150 nm, is less than about 100 nm.
Present invention has an advantage that
(1) prescription is simple, and stabilizing agent dosage is few, highly-safe.And in the present invention, it can be solved simultaneously using at least one stabilizer
Certainly prepare and dilution in preparation stability problem, and dosage is small, and safety is higher.
(2) technique is simplified controllably, high-efficient, is easy to industrialization.Compared with prior art, wet grinding mill is open system
System, can carry out continuity operation, batch size is controllable；Material can be achieved and abrasive media is automatically separated；It can adjust and grind at any time
It consumes time, at any time sample detection；Grinding efficiency significantly improves, and in identical milling time, particle average grain diameter is smaller in preparation, point
Scattered coefficient is smaller；Equipment meets GMP requirement, is easy to industrialization.
(3) stability is good.Temperature is controlled in process of lapping by the way of condensate water circulatory, avoids high temperature to preparation stabilization
Property impacts；Preparation solves the stability problem in nano suspension storing process using freeze-drying mode, and uses
Single or joint freeze drying protectant utmostly avoids the growth of preparation partial size in freeze-drying process, and the stability of preparation is more preferable.
Detailed description of the invention
Fig. 1 is that Herba Andrographitis nano suspension partial size prepared by the different grinding bead partial sizes of embodiment 4 changes with milling time
Curve；
Fig. 2 is andrographolide nano suspension average grain diameter (Particle prepared by the different milling times of embodiment 5
) and the coefficient of dispersion (PI) size；
Fig. 3 is andrographolide nano suspension average grain diameter (Particle prepared by the different grinding revolving speeds of embodiment 6
) and the coefficient of dispersion (PI) size；
Fig. 4 is 10 andrographolide nanometer suspension dried frozen aquatic products of embodiment, redissolves liquid and dilution appearance；
Fig. 5 is 10 andrographolide nanometer suspension dried frozen aquatic products transmission electron microscope photo of embodiment；
Fig. 6 is 10 andrographolide nanometer suspension dried frozen aquatic products stereoscan photograph of embodiment；
Fig. 7 is average grain diameter (Particle size) and dispersion after 11 andrographolide dried frozen aquatic products of embodiment are redissolved and diluted
Coefficient (PI) changes over time situation；
Fig. 8 is the nanometer suspension freeze-dried product accelerated test medicament contg of andrographolide (drug content) and average grain diameter
(Particle size)；
Fig. 9 is the nanometer suspension freeze-dried product long term test medicament contg of andrographolide (drug content) and average grain diameter
(Particle size)；
Figure 10 is the nanocrystalline spray powder stereoscan photograph of 15 andrographolide of embodiment；
Figure 11 is andrographolide nano suspension intravenous Drug-time curve；
Figure 12 is that andrographolide nano suspension takes orally Drug-time curve.
Specific embodiment
The contents of the present invention are further illustrated with specific embodiment below, but are not meant in any way to this hair
It is bright to be limited.
In following embodiments, the andrographolide bulk pharmaceutical chemicals come from Sichuan Province Yu Xin pharmaceutcal corporation, Ltd, and purity is greater than
99%；Partial size andzetaPotential measurement is examined using Nicomp-380 dynamic light scattering laser particle analyzer (PSS company, the U.S.)
It surveys.
The unit of percentage composition is in addition to especially indicating in the present inventionw/v, indicate to contain the component in every 100 mL water
Grams.
1 andrographolide nano suspension of embodiment preparation --- different instruments compare
Prescription:
Technique:
(1) ATS high pressure homogenizer: being dissolved in distilled water for 0.2 g NaTDC, and 6g andrographolide is added after being completely dissolved,
Drug is fully dispersed in the aqueous solution containing stabilizer using shearing dispersing mode.Mixed liquor is passed through into high pressure homogenizer,
400, each circulation primary of 800 bar, then 1200 bar are recycled 20 times, are taken out appropriate andrographolide suspension measurement partial size and are
1.1 μm, nanoscale is not achieved.Prescription andrographolide amount is down to 0.6%, is recycled using same way by high pressure homogenizer
20 times, taking out appropriate andrographolide suspension measurement average grain diameter is 532 nm.
(2) drug microjet instrument: is fully dispersed in the aqueous solution containing stabilizer using with identical prescription in (1) and method
In.By mixed liquor by microjet instrument, 25000 psi are recycled 20 times, are taken out appropriate andrographolide suspension measurement partial size and are
1.5 μm.Prescription andrographolide amount is down to 0.6%, is recycled 20 times using same way by microjet instrument, taking-up is worn in right amount
It is 1.4 μm that heart lotus lactone suspension, which measures average grain diameter, and micron order is still not achieved.
(3) planetary ball mill: use that (preparation amount is that drug is completely dispersed by 40 mL) and method with prescription identical in (1)
In the aqueous solution containing stabilizer.Mixed liquor is packed into the planetary ball mill containing 80 g partial sizes for 0.4 mm zirconium oxide abrasive pearl
In, 10 min are run, rest 2 min, working altogether 16 recycles or 20 circulations or 24 circulations.It is taken out after grinding suitable
It measures andrographolide suspension and measures average grain diameter, respectively 630.0 nm, 367.0 nm and 367.1 nm, partial size is up to nanometer
Grade, but grinding efficiency is lower.
(4) MiniCer wet grinding mill: using with identical prescription in (1), shifted after stabilizer is completely dissolved in water
500 g partial sizes are had been loaded with as 0.2 ~ 0.3 mm zirconium oxide abrasive pearl MiniCer wet grinding mill to having installed, and are brought into operation, to
Andrographolide bulk pharmaceutical chemicals are added after forming circulation in instrument in solution, in 30 oC, 3500 rpm grind 1.5 h, take out appropriate
It is 214 nm that andrographolide suspension, which measures average grain diameter, and grinding efficiency is apparently higher than planetary ball mill.
Therefore finally determine that milling apparatus is MiniCer grinder (NETZSCH, Shanghai Nai Chi mechanical device Co., Ltd).
The preparation of 2 andrographolide nano suspension of embodiment --- bulk pharmaceutical chemicals are without micronization or through micronization processes
It takes and is not micronized andrographolide bulk pharmaceutical chemicals, distinguished using (4) method in prescription in the same manner as in Example 1 and embodiment 1
Andrographolide nano suspension is prepared, before grinding, 0.5 h, 1 h take out appropriate andrographolide suspension and measure partial size.
With embodiment 1(4), i.e., the nano suspension prepared after bulk pharmaceutical chemicals micronization compares.It the results are shown in Table 1.
Nano suspension average grain diameter of the 1 andrographolide bulk pharmaceutical chemicals of table through micronization or without micronization preparation
As shown in Table 1, it is smaller to grind same time partial size after being micronized for bulk pharmaceutical chemicals.But meanwhile the method for the present invention is for partial size
The grinding efficiency of larger particle is higher, and preceding 0.5 h can make particle diameter be decreased to 0.386 μm from 39.8 μm, it is seen that this method
Grinding efficiency it is very high.
The preparation of 3 andrographolide nano suspension of embodiment --- it is added or is added without stabilizer
Prescription:
Technique:
Andrographolide nano suspension is prepared using (4) technique in embodiment 1, before grinding, 0.5,1.0,1.5 h is from discharging
Mouth takes out appropriate andrographolide nanosuspension and measures partial size.The andrographolide that stabilizer preparation is added with embodiment 2 is received
Rice suspension compares.It the results are shown in Table 2.
The andrographolide nano suspension average grain diameter prepared when containing or not contain stabilizer in 2 prescription of table
As shown in Table 2, after stabilizer being added, drug particle partial size can be made, which to increase with milling time, constantly to be reduced, but is added without
Stabilizer, drug particle does not decline not only when grinding 1 h, increases instead.It can be seen that stabilizer is added for maintaining process of lapping
Middle nano suspension stability plays a significant role.
The preparation of 4 andrographolide nano suspension of embodiment --- different grinding bead partial sizes
Prescription:
Technique:
1g hyodesoxycholic acid is dissolved in distilled water, this solution is transferred to and has been charged into 450 g, 0.1 mm(or 0.2,0.3,0.4,
0.6,0.8 mm) zirconium oxide bead wet grinding mill, bring into operation, after solution formed in instrument circulation after 8 g punchings are added
Lotus lactone bulk pharmaceutical chemicals are ground；Under 3600 rpm revolving speeds, work 1 h.During work, in 0.25,0.5,0.75,1.0 h
Appropriate andrographolide nanosuspension, which is taken out, from discharge port measures partial size, the result is shown in Figure 1.
As seen from Figure 1, with the reduction of grinding bead partial size, the nano suspension partial size that identical milling time obtains is got over
It is small.It therefore, can be by adjusting nano suspension average grain diameter prepared by grinding bead size controlling.
5 andrographolide nano suspension of embodiment preparation --- different milling times
Prescription:
Technique:
It 0.8g natrium dehydrocholicum is dissolved in distilled water is transferred to this solution and have been charged into 500 g, the wet process of 0.1 mm zirconium oxide bead
In grinder, 8g andrographolide bulk pharmaceutical chemicals are added after solution forms circulation in instrument and are ground；Turn in 3900 rpm
Under speed, work 3.5 h.During work, appropriate Herba Andrographitis is taken out from discharge port in 0.5,1.0,1.5,2.0,2.5,3.0,3.5 h
Lactone nanosuspension measures partial size, as a result sees Fig. 2.
As seen from Figure 2, with the increase of milling time, nano suspension partial size is gradually decreased, but partial size reduces speed
Rate is gradually reduced；The coefficient of dispersion is always between 0.1 ~ 0.25.Therefore, prepared nanometer can be controlled by adjusting milling time
Suspension average grain diameter.
6 andrographolide nano suspension of embodiment preparation --- difference grinding revolving speed
Prescription:
Technique:
0.1g taurine sodium deoxycholate is dissolved in distilled water, this solution is transferred to and has been charged into 350 g, 0.4 mm zirconium oxide bead
Wet grinding mill in, after solution formed in instrument circulation after be added 1g andrographolide bulk pharmaceutical chemicals ground；In 1500
The rpm of rpm(or 2000,2500,3000,3600,3900) under revolving speed, work 0.5 h.After grinding, worn from discharge port taking-up
Heart lotus lactone nanosuspension measures partial size, as a result sees Fig. 3.
As seen from Figure 3, increase with grinding revolving speed, identical milling time nano suspension partial size reduces, the coefficient of dispersion
Reduce.Therefore, prepared nano suspension average grain diameter can be controlled by adjusting milling time.
7 andrographolide nano suspension of embodiment preparation --- different stabilizers
Prescription:
Technique:
The variety classes stabilizer of recipe quantity is dissolved in distilled water, this solution is transferred to and has been charged into 450 g, 0.6 mm zirconium oxide
In the wet grinding mill of pearl, 4g andrographolide bulk pharmaceutical chemicals are added after solution forms circulation in instrument and are ground；In
Under 3500 rpm revolving speeds, work 1.5 h.After grinding, andrographolide nanosuspension is taken out from discharge port and measures partial size,
It the results are shown in Table 3.
The andrographolide nano suspension of the different types of stabilizer of table 3 preparation
As shown in Table 3, andrographolide nano suspension can be prepared using various stabilizers, under same process, using gallbladder
The nano suspension average grain diameter of Barbiturates preparation is smaller, and the coefficient of dispersion is smaller.
8 andrographolide nano suspension of embodiment preparation --- freeze-drying
Prescription:
Be added after preparation preparation freeze drying protectant it is appropriate (%,w/v, freeze drying protectant quality/preparation gross mass)
Technique:
2g sodium taurochenodeoxycholate is dissolved in distilled water, this solution is transferred to and has been charged into 400 g, 0.2 mm zirconium oxide bead
In wet grinding mill, 5 g andrographolide bulk pharmaceutical chemicals are added after solution forms circulation in instrument and are ground；In 3400
Under rpm revolving speed, work 3 h, obtains milky nanosuspension from discharge port；Appropriate freeze drying protectant is added thereto, dispenses
It is put into afterwards and carries out the nanometer suspension freeze-dried product that 45 h of freeze-drying must be stable in freeze drier.Herba Andrographitis is nanometer suspension freeze-dried
Product redissolve liquid particle size results with distilled water and are shown in Table 4 and table 5.
Andrographolide nano suspension after the different amounts of single freeze drying protectant of variety classes is added in table 4
Dried frozen aquatic products redissolve liquid average grain diameter (average grain diameter is 155.9 nm before being lyophilized)
Appearance: muffin is lyophilized when sucrose and trehalose group 1% and omits atrophy；3%, 5%, 10% when smooth in appearance it is complete, be in round pie；
15%, 20% when dried frozen aquatic products top at round pie, lower part atrophy or fusing.The time is redissolved within 10s；Maltose group dried frozen aquatic products
In bulk, there is a needle-shaped or crystalline particulate, and unite situation aggravation with germinatus sugar amount increase, redissolves the time within 5s；It is sweet
It is smooth complete to reveal alcohol group overall appearance, is in round pie, redissolves the time within 5 s.
In conjunction with dried frozen aquatic products appearance, size results after redissolving the time and redissolving, preferably sugarcane when single freeze drying protectant
Sugar or trehalose, preferred amount ranges are 3% ~ 10%.
Andrographolide nano suspension freezes after the different amounts of combination freeze drying protectant of variety classes is added in table 5
Dry product redissolves liquid average grain diameter (average grain diameter is 155.9 nm before being lyophilized)
Note: "-" expression does not carry out this experiment.
The nanometer suspension freeze-dried product of andrographolide redissolve shape after the different amounts of combination freeze drying protectant of variety classes is added in table 6
State and time
In conjunction with dried frozen aquatic products appearance, size results after redissolving the time and redissolving can choose sucrose, trehalose or mannitol point
Not with glycerol, polysorbas20, Tween 80, distearoylphosphatidylethanolamine-PEG2000, vitamin E polyethylene glycol succinic acid ester
Or PEG2000 forms freeze drying protectant, but partial size has different degrees of growth after preparation freeze-drying.
9 andrographolide nano suspension of embodiment preparation --- different freeze drying protectants
Prescription:
| Andrographolide | 5%(w/v) |
| Natrium taurocholicum | 0.2%(w/v) |
| Distilled water adds to | 200 mL |
Be added after preparation preparation freeze drying protectant it is appropriate (%,w/v, freeze drying protectant quality/preparation gross mass)
Technique:
0.4g natrium taurocholicum is dissolved in distilled water, this solution is transferred to and has been charged into 500 g, the wet process of 0.1 mm zirconium oxide bead
In grinder, 10g andrographolide bulk pharmaceutical chemicals are added after solution forms circulation in instrument and are ground；Turn in 3900 rpm
Under speed, work 2.5 h, obtains milky nanosuspension from discharge port；Appropriate freeze drying protectant is added thereto, is put after packing
Enter to carry out the nanometer suspension freeze-dried product that 45 h of freeze-drying must be stable in freeze drier.By the nanometer suspension freeze-dried product of Herba Andrographitis with
Distilled water redissolves, and redissolves liquid particle size results and is shown in Table 7.
The nanometer suspension freeze-dried product of andrographolide are multiple after the different amounts of combination freeze drying protectant of variety classes is added in table 7
Solution average grain diameter (partial size is 142.3 nm before being lyophilized)
Phenomena such as all groups of dried frozen aquatic products smooth surfaces, no layering, bubble, atrophy.The time is redissolved within 10 s.In conjunction with
The combination freeze drying protectant preferably sucrose of embodiment 8 is combined with mannitol or trehalose is combined with mannitol, and preferable amount is sucrose
Or 1 ~ 5%(of trehalosew/v), 1 ~ 5%(of mannitolw/v).
The appearance and form of 10 andrographolide nano suspension of embodiment
According to andrographolide nano suspension prepared by embodiment 9, when freeze drying protectant is 5% sucrose, when 3% mannitol, wear
Heart lotus lactone dried frozen aquatic products, redissolution liquid and dilution are shown in attached drawing 4.As shown in figure 4, the white pie of andrographolide dried frozen aquatic products, table
Phenomena such as face is flat and smooth, no layering, bubble, atrophy.After being redissolved with distilled water, redissolution liquid is uniform milky nanometer suspension
Liquid；After the dilution of 5% glucose solution, dilution shows slightly blue-opalescent.
Transmission electron microscope (TEM) photo of dried frozen aquatic products is shown in Fig. 5.As shown in figure 5, it is in irregular six side that andrographolide is nanocrystalline
Shape, close to round or ellipse.
Scanning electron microscope (SEM) photo of dried frozen aquatic products is shown in Fig. 6.As shown in fig. 6, andrographolide dried frozen aquatic products appearance is in irregular
Sheet.
11 andrographolide nano suspension dilution stability of embodiment
Prescription:
| Andrographolide | 3%(w/v) |
| NaTDC | 0.6%(w/v) |
| Distilled water adds to | 200 mL |
It is added after preparation preparation
| Sucrose | 3%(w/v) |
| Mannitol | 3%(w/v) |
Technique:
1.2g NaTDC is dissolved in distilled water, this solution is transferred to and has been charged into 500 g, the wet process of 0.4 mm zirconium oxide bead
In grinder, 6g andrographolide bulk pharmaceutical chemicals are added after solution forms circulation in instrument and are ground；Turn in 3200 rpm
Under speed, work 2 h, obtains milky nanosuspension from discharge port；6g sucrose and 6g mannitol are added thereto, is put after packing
Enter to carry out the nanometer suspension freeze-dried product that 45 h of freeze-drying must be stable in freeze drier.By the nanometer suspension freeze-dried product of Herba Andrographitis with
Distilled water redissolves, and dilutes 20 times with 5% glucose solution, and static placement measures average grain in 0,1,2,4,6,8,12,24 h
Diameter, the results are shown in attached figure 7.
The result shows that andrographolide nano suspension redissolves and dilution rear stability is good.
12 Determination of Andrographolide measuring method of embodiment
Agilent1260 Infinity high performance liquid chromatograph and DAD detector (Agilent company of the U.S.)；Chromatographic column:
Thermo C18(250 mm × 4.6 mm, 5 μm, power & light company)；Detection wavelength: 225 nm；Mobile phase: methanol-water (60:
40,v/v)；Column temperature: 35oC；Flow velocity: 1.0 mL/min；Sample volume: 10 μ L.
The nanometer suspension freeze-dried product study on the stability of 13 andrographolide of embodiment --- accelerated test
The nanometer suspension freeze-dried product of Herba Andrographitis are prepared using the prescription and technique of embodiment 11 and carry out accelerated test.By dried frozen aquatic products pressure
Lid is placed in BIC-250 growth cabinet (Shanghai is rich to prove to be true after interrogation the limited medical company of industry).It is 40 ± 2 that temperature, which is arranged,oC, humidity
It is 75 ± 5%, is sampled in 0,1,2,3 the end of month, partial size and Andrographolide in Medicinal Preparations changes of contents after measurement preparation redissolves.Knot
Fruit sees Fig. 8.
As shown in Figure 8, the nanometer suspension freeze-dried product of Herba Andrographitis are in 40 ± 2oC, humidity are 75 ± 5% placement 3 months, drug
Content is substantially unchanged, and average grain diameter has and increases to a certain degree, but growth degree is within 70 nm.
The nanometer suspension freeze-dried product study on the stability of 14 andrographolide of embodiment --- long term test
The nanometer suspension freeze-dried product of Herba Andrographitis prepared using embodiment 13 carry out long term test.By dried frozen aquatic products gland, Yu Wendu
25±2 oC is placed under the conditions of humidity 60 ± 5%, is sampled in 0,1,2,3 the end of month, after measurement preparation redissolves in partial size and preparation
Determination of Andrographolide variation.As a result see Fig. 9.
As shown in Figure 9, the nanometer suspension freeze-dried product of Herba Andrographitis are in 25 ± 2oC, humidity are 60 ± 5% placement 3 months, drug
Content is substantially unchanged, and average grain diameter is substantially without growth, and integrated embodiment 13 and 14 is as a result, the nanometer suspension freeze-dried product of Herba Andrographitis
High temperature should be avoided, place physics at room temperature and chemical property is stablized.
The preparation of the nanocrystalline capsule of 15 andrographolide of embodiment
Spray drying technique:
| Instrument parameter | Value |
| Inlet air temperature (oC) | 120 |
| Charging rate (%) | 15 |
| Atomizing pressure (mmHg) | 50 |
| Dry air flow (%) | 100 |
Prescription (the nanocrystalline capsule of andrographolide):
| Andrographolide is nanocrystalline | 54.2%(w/w) |
| Crosslinked polyvinylpyrrolidone | 5%(w/w) |
| Microcrystalline cellulose | 20%(w/w) |
| Cornstarch | 20.8%(w/w) |
| It is made | 10 g(every, 50 mg containing andrographolide) |
Nanosuspension is prepared using 4 formulation and technology of embodiment, 2%(is added into suspensionw/v) after mannitol, by B-290
Small-sized spray drier (Bu Qi company, Switzerland) obtains solid powder, the as nanocrystalline spray powder of andrographolide.Nanocrystalline spray drying
Powder stereoscan photograph is shown in Figure 10, and as shown in Figure 10, nanocrystalline andrographolide is in spherical or near-spherical.
The nanocrystalline spray powder of andrographolide and recipe quantity auxiliary material are weighed, is filled in capsule shells to get andrographolide
Nanocrystalline capsule.
16 andrographolide nano suspension of embodiment (other ingredients of prescription and preparation method thereof are with embodiment 4) rat
Medicine dynamic test
Herba Andrographitis nano injection agent used in this test is prepared by the prescription and technique of embodiment 4, and wherein partial size is 312 nm
Herba Andrographitis nano injection agent preparation using 0.3 mm zirconium oxide bead, grind 1 h；Partial size is that the Herba Andrographitis of 152 nm is received
The preparation of rice injection grinds 1 h using the zirconium oxide bead of 0.1mm.
Dosage regimen: the Wistar rat 15 of 12 h of fasting is taken only to be randomly divided into 5 groups, tail vein injection dosage is 240
mg·kg-1Partial size be 152,312nm andrographolide nano injection agent；The Andro of 152 nm, 312 nm is administered orally in stomach-filling
Nanometer suspension preparation, physical mixed group, intravenous injection group after administration 1,5,15,30,60,120,240min eye socket take blood,
Stomach-filling take orally group with after being administered 5,15,30,60,120,240min eye socket take blood, be collected in 1.5mL centrifuge tube, rapidly into
The processing of promoting circulation of blood slurry samples, sample is in 4oC saves stand-by.
The processing method of plasma sample: precision pipettes 200 μ L of blood sample in 1.5mL centrifuge tube, and internal standard (card is added
Horse Xiping methanol solution, 0.01mgmL-1) 50 μ L, 800 μ L of 200 μ L of methanol and acetone, be vortexed 15 min extract after in
10000 rpm are centrifuged 10min, pipette 600 μ L of acetone layer, and room temperature under nitrogen volatilizes, and the drug volatilized is multiple with 100 μ L of mobile phase
Molten, be vortexed 5 min, is centrifuged 10 min in 10000 rpm, precision pipettes 20 μ L of supernatant, and sample introduction is analyzed.
Chromatographic condition:
Chromatographic column: Hypersil BDS C18(200 mm × 4.6 mm, 5 μm, Dalian Yi Lite)；
Detection wavelength: 225 nm；
Column temperature: 35oC；
Flow velocity: 1.0 mL/min；
Sample volume: 10 μ L；
Mobile phase: methanol-water (60:40,v/v).
The mean blood plasma concentration by test preparation is measured as shown in Figure 11, Figure 12.
8 medicine of table moves parameter
| Group | AUC0-t(μ g/mLmin) | t1/2(min) | tmax(min) | Cmax(μ g/mL) |
| Intravenous (152 nm of nanometer suspension) | 3012.4 | 7.5 | 1 | 135.6 |
| Intravenous (312 nm of nanometer suspension) | 2808.7 | 1.9 | 1 | 166.9 |
| Oral (nanometer suspension) | 9821.6 | 101.5 | 15 | 50.9 |
| Oral (commercial preparation) | 8742.9 | 110.9 | 240 | 41.9 |
| Oral (physical mixed) | 2334.1 | 21.6 | 120 | 20.0 |
By Figure 11,12 and table 8 it is found that nanometer suspension intravenous injection group is eliminated comparatively fast.Oral group is compared, nanometer suspension tmaxMinimum,
AUC is maximum, can embody its advantage with commercial dispersants piece and bulk pharmaceutical chemicals physics mixed phase ratio.
Claims (14)
1. a kind of andrographolide nano suspension, which is characterized in that the Herba Andrographitis including effective average grain diameter less than 1000 nm
Lactone particle and at least one stabilizer.
2. andrographolide nano suspension as described in claim 1, which is characterized in that the Determination of Andrographolide is
0.05% ~ 8%(w/v).
3. andrographolide nano suspension as claimed in claim 2, which is characterized in that the Determination of Andrographolide is
0.05% ~ 5%(w/v).
4. andrographolide nano suspension as claimed in claim 2, which is characterized in that the Determination of Andrographolide is
5% ~ 8%(w/v).
5. andrographolide nano suspension as claimed in claim 2, which is characterized in that the Determination of Andrographolide is
0.5% ~ 5%(w/v), it does not include 5%(w/v).
6. andrographolide nano suspension as claimed in claim 2, which is characterized in that the Determination of Andrographolide is
0. 5% ~ 4%(w/v).
7. andrographolide nano suspension as claimed in claim 2, which is characterized in that the Determination of Andrographolide is
5%(w/v).
8. andrographolide nano suspension as claimed in claim 4, which is characterized in that the Determination of Andrographolide is
6%(w/v).
9. andrographolide nano suspension as claimed in claim 4, which is characterized in that the Determination of Andrographolide is
8%(w/v).
10. andrographolide nano suspension as described in claim 1, which is characterized in that the stabilizer be cholic acid and
Cholic acid salt: deoxycholic acid and its sodium salt, neocholan and its sodium salt, hyodesoxycholic acid and its sodium salt, taurocholate and its sodium
Salt, Tauro ursodesoxy cholic acid and its sodium salt, Taurochenodeoxycholic Acid and its sodium salt；Sulfates: lauryl sodium sulfate；Sulfonic acid
Salt: neopelex, dioctyl succinate disulfonate acid；Odium stearate salt；Triethanolamine salt；Meglumine salt；Three
The mixture of one of hydroxymethyl aminomethane salt or alkaline amino acid salt or any combination thereof.
11. andrographolide nano suspension as claimed in claim 10, which is characterized in that the stabilizer is cholate
Class, dosage are 0.05% ~ 1%(w/v).
12. andrographolide nano suspension as described in claim 1, which is characterized in that the andrographolide nanometer is mixed
Suspension average grain diameter is less than about 1000 nm, is less than about 900 nm, is less than about 800 nm, is less than about 700 nm, is less than about 650
Nm, it is less than about 600 nm, is less than about 550 nm, is less than about 500 nm, is less than about 450 nm, is less than about 400 nm, boy about 350
Nm, it is less than about 300 nm, is less than about 250 nm, is less than about 200 nm, is less than about 150 nm, is less than about 100 nm.
13. the application of andrographolide nano suspension as claimed in claim 1, which is characterized in that the punching
Lotus lactone nano suspension can be prepared to following dosage form: solid, semisolid preparation or liquid preparation.
14. the application of andrographolide nano suspension as claimed in claim 13, which is characterized in that it is as liquid preparation
When medication, it can be redissolved and be diluted with water or 5% glucose solution before, andrographolide nanosuspension after redissolving and diluting
Average grain diameter is less than about 1000 nm, is less than about 900 nm, is less than about 800 nm, is less than about 700 nm, is less than about 650 nm, is small
In about 600 nm, be less than about 550 nm, be less than about 500 nm, be less than about 450 nm, be less than about 400 nm, about 350 nm of boy,
Less than about 300 nm, be less than about 250 nm, be less than about 200 nm, be less than about 150 nm, be less than about 100 nm.
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