CN108498463A - A kind of silymarin solubilising particle and its preparation method and application - Google Patents
A kind of silymarin solubilising particle and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of silymarin solubilising particles and its preparation method and application.The silymarin solubilising particle includes each component of following mass percent：Silymarin raw material 1%~6%, water-solubility carrier 20%~80%, solubilizer 10%~65% and fragrant corrigent 4%~10%.The present invention provides a kind of completely new solubilized formulation formula for silymarin, art technology blank is filled up, water-solubility carrier is determined by science, solubilizer, the proportion compatibility of fragrant corrigent and silymarin raw material, it significantly improves the solubility of slightly solubility silymarin and reaches Cmax, bioavilability is apparently higher than ordinary preparation, and its blood concentration is high, reduce dosage, palatability is good simultaneously, mobility good dispersion, property is stable and easy to preserve, preparation process is simple, mixed feeding dosing techniques are simple, it is efficient in veterinary medicine health care to be successfully realized silymarin, low toxicity, inexpensive medication target.
Description
Technical field
The invention belongs to the preparing technical fields of animal drug.More particularly, to a kind of silymarin solubilising particle and
Preparation method and application.
Background technology
Milk thistle originates in India and Pakistani Kashmir mountain area, and China introduces fine grinding in nineteen fifty-two from Britain
Ji, currently, the milk thistle as medicinal material plantation was by Tianjin local products branch company of China National Native Produce and Animal By-products Import and Export Corporation in 1972
It is introduced from Germany, has nowadays been widely applied plantation in China.
Milk thistle is a kind of medicinal material kind of domestic new development in recent decades, and there is pharmaceutical factory in the country treatment hepatopathy is made
Medicinal material.In Europe, has thousands of years of history using milk thistle treatment hepatopathy.And it is extracted from the kind skin of milk thistle seed
The main effective active composition silymarin arrived is a kind of flavonolignan class mixture, wherein mainly contain silibinin,
The ingredients such as Isosilybin, Silychristin and silydianin, wherein activity is most strong, highest content is silibinin.Now
There is multinomial pharmacological evaluation to prove that silymarin has the extensive pharmacological activity such as apparent anti-oxidant, anti-inflammatory.Inflammation is typically
One of the main reason for chronic liver disease occurrence and development, liver will produce a large amount of free radical in metabolic process, these are a large amount of certainly
Liver plasma membrane is damaged by peroxidatic reaction of lipid by base.Silymarin is similar to phenols in chemical constitution, with phenols
Chemical property can concede electronics, stabilized radical and active oxygen, thus with obviously antioxidant activity, it can
Directly reduce very much damage of the free radical to liver plasma membrane.Meanwhile silymarin is by influencing intracellular glutathione, it can
The phosphatide peroxidating for preventing cell membrane allows Hepatoxic substance to cannot be introduced into liver thin to reach the integrality for maintaining liver plasma membrane
Born of the same parents reach the protective effect to liver.In addition to this, metabolism of the silymarin in liver also can cell cultured supernatant.Activate ribosomes
The biosynthesis of RNA promotes the synthesis of memebrane protein, repairs impaired cell membrane in time.In short, silymarin draws many reasons
The hepar damnification risen has obviously protective effect, is a kind of hepatic injury repair medicine curative for effect.It is cured in people clinical
On be chiefly used in treating the hepatopathys such as acute, chronic hepatitis, various hepatic injuries, dry fibers and early-phase hepatocirrhosis, now there are some researches prove fine grindings
Silibin also has the pharmacological actions such as reducing blood lipid, anticancer, cardioprotective activity and neuroprotective activity.
Liver is maximum glandular organ in animal body, is also the metabolism center of animal body.It is to animal tissue cell
Absorption And Metabolism, hematopoiesis energy supply, maintain growth and development and health all play a crucial role.In addition, pork liver is as a kind of
Food materials are also deeply welcomed by the people, therefore the moment affects the dietetic life health of people whether the health of pig liver.And fine grinding
A kind of silibin efficient, extensive hepatinica of pharmacological action as low toxicity, also has very big Development volue on veterinary clinic.
It is fat-soluble also poor but at present since silymarin is practically insoluble in water, cause its oral absorption poor, bioavilability is low, work
The reasons such as skill is of high cost greatly limit application of the silymarin on animal clinical.
The dosage form that silymarin is clinically used in people doctor is mostly tablets and capsules, and silymarin faces in people doctor at present
It is used on bed, uses common pre-mixing agent more on veterinary clinic.But when using common pre-mixing agent, due to milk thistle poorly water-soluble,
Absorption difference, bioavilability is extremely low, half-life short, repeats and dosage is big, increase veterinary staff to a certain extent
Labor intensity and goods and materials cost, and common pre-mixing agent due to mobility dispersibility it is poor, cannot hold well with feed mixing
Easily cause the phenomenon of insufficiency of intake or excess due to premix is uneven.Therefore, the solubility for increasing silymarin, passes through dosage form
Changing improves its oral absorption, improves the bioavilability of silymarin, increase its blood concentration in animal body, reduce to
Dose, reduction drug cost are that current silymarin turns the main difficult technical for animals for needing to solve.
Invention content
The technical problem to be solved by the present invention is to overcome the deficiencies of existing silymarin preparation, provide a kind of manufacture craft letter
List can effectively improve silymarin solubility, increase oral absorbability, improve bioavilability and blood concentration, reduce
Silymarin dosage reduces the cost of animal-use drug and a kind of good silymarin solubilising particle of palatability, overcomes existing
Silymarin preparation poorly water-soluble, oral absorption is poor, and biological utilisation is low, and absolute bioavailability only has for 0.98% the deficiencies of.
The object of the present invention is to provide a kind of silymarin solubilising particles.
It is a further object to provide the preparation method of above-mentioned silymarin solubilising particle, manufacture craft letters
It is single.
It is a further object to provide the applications of above-mentioned silymarin solubilising particle.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：
A kind of silymarin solubilising particle, which is characterized in that include each component of following mass percent：Silymarin raw material 1%
~6%, water-solubility carrier 20%~80%, solubilizer 10%~65% and fragrant corrigent 4%~10%；
The water-solubility carrier be Macrogol 6000, hydroxypropyl-β-cyclodextrin, phosphatide, cholesterol, hypromellose,
D- alpha-tocopherols, FEG1000（Cetomacrogol 1000）, it is methyl-B-cyclodextrin, polyvinylpyrrolidone, PLURONICS F87, sweet
Reveal alcohol, succinate, cholate/one or more of phosphatide mixed micellazation or polyethyene diamine dendritic；It is used in mixed way
When, mixed proportion does not do considered critical；
Compared with other commonly use water-solubility carrier, water-solubility carrier provided by the invention can allow silymarin dissolubility significantly to carry
Height, quickly adequately release drug, dissolution in vitro can reach 97.0% or more；
The solubilizer is non-ionic solubilizer；Including polyethylene monostearate, sucrose fatty acid ester, Tween-20, spit
One or more of temperature -40, Tween-60, Tween-80, Emulsifier EL-60, Crodaret；Mixing makes
Used time, mixed proportion do not do considered critical；
Compared with other solubilizer, non-ionic solubilizer small toxicity is suitable for oral preparation, and solubilizer provided by the invention
After being mixed with other components of the present invention, the solubility of the significantly solubilized silymarin of energy makes drug quickly reach peak in vivo, and in vivo
Blood concentration is apparently higher than ordinary preparation, and the pharmacokinetic data available in pig body shows that silymarin reaches Cmax and can reach in vivo
1.2 μg/mL；
The fragrance corrigent is peppermint oil, wintergreen, caryophyllus oil, fennel oil, lemon oil, mandarin oil, sorbierite or mannitol
One or more of；When being used in mixed way, mixed proportion does not do considered critical.
Preferably, mass percent shared by the water-solubility carrier is 30%~50%.
Preferably, mass percent shared by the solubilizer is 20%~60%.
Preferably, mass percent shared by the fragrant corrigent is 4%~8%.
Preferably, mass percent shared by the silymarin raw material is 2%, 2.5%, 3%, 4% or 5%.
Present invention simultaneously provides a kind of preparation methods of optimization of the silymarin solubilising particle, using fluidization spray work
Skill is prepared, and includes the following steps：
S1. water-solubility carrier is proportionally weighed, heating and melting obtains mixture A；
S2. solubilizer is added after silymarin raw material being dissolved with ethyl alcohol, fully shaking is uniformly mixed, and obtains mixture B；
S3. mixture B obtained by step S2 is added in mixture A obtained by step S1, stirs evenly, obtains mixture C；
S4. fragrant corrigent is added in mixture C obtained by step S3, is stirred uniformly, is mixed under holding temperature
Object D；
S5. by mixture D heat preservation atomization obtained by step S4, through fluidized-bed spray granulation nodularization；
S6. it is sieved, collection cut size is in 40 mesh grain ball below, you can obtains the silymarin solubilising particle.
Preferably, the temperature of heating and melting described in step S1 is 80~120 DEG C.
Preferably, the temperature kept the temperature described in step S4 is 30~85 DEG C.
Preferably, the linear velocity of bed spray drop described in step S5 is in 30~135 meter per seconds；Fluidization air temperature is
15~25 DEG C.
Preferably, the grain size of grain ball described in step S6 is 80~450 μm.
The silymarin solubilising particle that is prepared using preparation method of the present invention, the preferably suitable system of science
Standby condition can guarantee optimal preparation effect.Gained silymarin solubilising particle appearance is in faint yellow or yellow, is in microballoon or micro-
The spherical fine particle of capsule, particle size are 80~450 μm, and mobility good dispersion, property is stable and easy to preserve, and mixed feeding is given
Medicine is easy to operate, is successfully realized efficient, less toxic, inexpensive medication target of the silymarin in veterinary medicine health care.
Correspondingly, the silymarin solubilising particle is preparing animal feed or is preparing silymarin oral preparation for animals
The application of aspect is also within protection scope of the present invention.Treatment pig relevant disease feed addition is prepared especially in aquaculture
Application well is obtained in terms of agent, drug or health products, such as including animal's liver injury repair, animal anticancer, anti-inflammatory, drop blood
The Animal diseases of fat, cardioprotective activity or neuroprotective activity etc..
The present invention has the advantages that：
The present invention achieves significant progress at three aspects：
The first, a kind of completely new solubilized formulation formula is provided for silymarin, has filled up art technology blank.Based on this hair
Bright formula, science determine the proportion compatibility of water-solubility carrier, solubilizer, fragrant corrigent and silymarin raw material, significantly improve
The solubility of slightly solubility silymarin, can fully discharge in vivo, to improving the bioavilability of silymarin, and
Its internal blood concentration is high, reduces dosage, has saved the drug cost in animal administration process, solves common pre-mixing agent
The problems such as oral administration biaavailability is low, internal blood concentration is low, drug cost is high, be successfully realized centralization-breeding factory treatment or
Health care medication utmostly reduces veterinary staff's labor intensity, reduces Animal stress degree, and silymarin solubilising
Particle toxic side effect is small, realizes application of the silymarin in Animal Medicine health care.
The second, preparation method of the invention, first passes through ethyl alcohol and dissolves drug, drug is made to exist in the form of molecule, then
The dissolubility that silymarin is increased by adding solubilizer, is combined with hydrophilic carrier with silymarin molecule, finally by adding
Add fragrant corrigent, increase the interest in fodder of animal, improve the palatability of drug, significantly improves silymarin oral bio
The stability of availability and preparation, by mixed feeding so that being rapidly achieved effective treatment concentration to blood concentration in animal body, from
And achieve the purpose that efficient, less toxic, silymarin is enhanced in animal's liver injury repair, anticancer, anti-inflammatory, reducing blood lipid, heart
The animal health of protection activity, neuroprotective activity etc. acts on.
Silymarin solubilising particle appearance prepared by third, the present invention is in the spherical shape of faint yellow or yellow, microballoon or micro-capsule
Fine particle, particle size are 80~450 μm, and mobility good dispersion, property is stable and easy to preserve, mixed feeding dosing techniques letter
It is single, it is successfully realized efficient, less toxic, inexpensive medication target of the silymarin in veterinary medicine health care.
On the basis of above-mentioned advantageous effect, preparation method of the present invention is simple for process, and cost is relatively low, it is easy to accomplish industry size
Production, application easy to spread.
From the point of view of summarizing, beneficial effects of the present invention are mainly reflected in：（1）Selected auxiliary material can dramatically increase silymarin
Solubility, bioavilability is high, and therapeutic effect is good, and to zootoxin pair very little, and auxiliary material is inexpensive, is easy to get, and animal is oral basic
It has no toxic side effect, industrialization production is suitble to use；（2）Silymarin solubilising grain diameter of the present invention is in 80~450 μ ms
Controllably, uniform particle sizes are distributed, and property is stablized, and is easy to preserve（3）Silymarin solubilising particle of the present invention has the smell of faint scent, increases
The interest in fodder for adding animal, solves the problems, such as palatability of drugs；（4）Grain good fluidity of the present invention, can mixed feeding administration, use prescription
Just；（5）Compared to traditional premix agent producing process, preparation process of the present invention avoids generating dust and electrostatic.
Description of the drawings
Fig. 1 is silymarin solubilising particle and silymarin pre-mixing agent the cumulative release curve graph in different medium.
Specific implementation mode
Further illustrated the present invention below in conjunction with specific embodiment, but embodiment the present invention is not done it is any type of
It limits.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagent, methods and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are purchased in market.
Embodiment 1 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）Proportionally weigh 2% silymarin bulk pharmaceutical chemicals, 25% hydroxypropyl-β-cyclodextrin, 35% PLURONICS F87,28% poly- second
Alkene monostearate and 10% peppermint oil；By load weighted PLURONICS F87 and hydroxypropyl-β-cyclodextrin in 90 DEG C of heating and meltings,
Obtain mixture A；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted polyethylene monostearate
Ester, fully shaking are uniformly mixed, and obtain mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted peppermint oil is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 20 DEG C, 60 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 2% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellowish
Chromosphere shape fine particle, grain size are 450 μm.
Embodiment 2 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）Proportionally weigh 2.5% silymarin bulk pharmaceutical chemicals, 20% phosphatide, 30%D- alpha-tocopherols, 40% Emulsifier EL-60
With 7.5% caryophyllus oil；By load weighted phosphatide and D- alpha-tocopherols in 90 DEG C of heating and meltings, mixture A is obtained；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted Emulsifier EL-60,
Fully shaking is uniformly mixed, and obtains mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted caryophyllus oil is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 15 DEG C, 80 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 2.5% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in light
Yellow spherical fine particle, grain size are about 450 μm.
Embodiment 3 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）It proportionally weighs 3% silymarin bulk pharmaceutical chemicals, 40% Macrogol 6000,20% hydroxypropyl-β-cyclodextrin, 30% spit
Temperature -80 and 7% sorbierite；By load weighted Macrogol 6000 and hydroxypropyl-β-cyclodextrin in 90 DEG C of heating and meltings, mixed
Close object A；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted Tween-80, fully shaking
It is uniformly mixed, obtains mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted sorbierite is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 18 DEG C, 135 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 3% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellowish
Chromosphere shape fine particle, grain size are about 90 μm.
Embodiment 4 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）It proportionally weighs 4% silymarin bulk pharmaceutical chemicals, 25% polyvinylpyrrolidone, 30% Macrogol 6000,36% spit
Temperature -40 and 5% lemon oil；By load weighted polyvinylpyrrolidone and Macrogol 6000 in 90 DEG C of heating and meltings, mixed
Object A；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted Tween-40, fully shaking
It is uniformly mixed, obtains mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted sorbierite is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 25 DEG C, 55 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 4% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellow
Spherical fine particle, grain size are about 400 μm.
Embodiment 5 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）Proportionally weigh 5% silymarin bulk pharmaceutical chemicals, 30% cholesterol, 30% succinate, 25% Tween-60 and 10% Chinese ilex
Oil；By load weighted cholesterol and succinate in 90 DEG C of heating and meltings, mixture A is obtained；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted Tween-60, fully shaking
It is uniformly mixed, obtains mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted wintergreen is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 20 DEG C, 50 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 5% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellow
Spherical fine particle, grain size are about 450 μm.
Embodiment 6 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）Proportionally weigh 6% silymarin bulk pharmaceutical chemicals, 60% polyvinylpyrrolidone, 20% Macrogol 6000,10% polyoxy
Ethylene hydrogenation castor oil and 4% mandarin oil；Load weighted polyvinylpyrrolidone and Macrogol 6000 are melted in 90 DEG C of heating
Change, obtains mixture A；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted polyethylene glycol hydrogenated castor-oil plant
Oil, fully shaking are uniformly mixed, and obtain mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted mandarin oil is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 25 DEG C, 30 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 6% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellow
Spherical fine particle, grain size are about 450 μm.
Embodiment 7 prepares silymarin solubilising granular preparation
Silymarin solubilising particle is prepared according to the following steps：
（1）It proportionally weighs 3% silymarin bulk pharmaceutical chemicals, 60% Macrogol 6000,20% hydroxypropyl-β-cyclodextrin, 10% spit
Temperature -80 and 7% sorbierite；By load weighted Macrogol 6000 and hydroxypropyl-β-cyclodextrin in 90 DEG C of heating and meltings, mixed
Close object A；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted Tween-80, fully shaking
It is uniformly mixed, obtains mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted sorbierite is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 18 DEG C, 135 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 3% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellowish
Chromosphere shape fine particle, grain size are about 90 μm.
The preparation of 1 existing silymarin pre-mixing agent of comparative example
1, preparation method prepares silymarin pre-mixing agent according to the following steps：
（1）3% silymarin, 40% zeolite powder, 35% silica and 22%L- carnitine hydrochlorides are accurately weighed by mass percentage；
（2）Take silymarin pretreating reagent, heating melting；Heating temperature is 90 DEG C, and zeolite powder is stirred evenly with silica；It is logical
No. 4 sieves are crossed, silymarin and l-carnitine hydrochloride is added, are uniformly mixed, control pulvis grain size is 90 μm, and fine grinding is made in sieving
Silibin pre-mixing agent.
The outer dissolution test of 8 silymarin solubilising granule of embodiment
1, for reagent product
Test medicine：The 3% silymarin solubilising slow-releasing granules that embodiment 3 is prepared；
Reference preparation：Commercially available 3.1% common silymarin pre-mixing agent（It is prepared with reference to the preparation method of comparative example 1）.
2, test method
According to《Republic of China Veterinary Pharmacopoeia》（Version in 2015）The first method of dissolution method（Basket method）It is measured.
（1）The accurate 3% silymarin solubilising particle and 3.1% common 0.5 g of silymarin pre-mixing agent for weighing equivalent respectively,
Drug loading digestion instrument is turned in basket, is referred to《Republic of China Veterinary Pharmacopoeia》、《United States Pharmacopeia》With《Japanese Pharmacopoeia》900
ML differences pH discharges buffer medium（The hydrochloric acid of pH=1.2, the acetate buffers of pH=4.3 salt, the phosphate-buffered salts of pH=6.8, water）Under the conditions of,
37 DEG C ± 0.5 DEG C of constant temperature, turns basket with 100 r/min；
（2）Respectively in 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6
H samples 5 mL, while the fresh dissolution mediums of 5 mL are added into stripping rotor；
（3）The sample of taking-up crosses 0.22 um filter membranes, and upper machine is detected；
（4）Silymarin content is measured with efficient liquid phase：Using high-efficient liquid phase technique under the chromatographic condition（C18 columns, mobile phase=
Methanol：Water=50：50,30 DEG C of column temperature, 0.9 mL/min of flow velocity, 288 nm of Detection wavelength）It is detected；
（5）Cumulative release percentage is calculated according to following formula, draws cumulative release percentage-time graph；
In formula：Cn is the mass concentration of solid content in n-th of time point samples taken, and V is dissolution medium total volume, Vi i-th
The sample volume at a time point, Ci are i-th of time point samples taken mass concentration, and W is microballoon gross mass, and DL is that microballoon carries medicine
The mass fraction of amount.
3, result
3% silymarin solubilising particle different time points Accumulation dissolution under different dissolution mediums is shown in Table 1；3.1% fine grinding
Silibin pre-mixing agent different time points Accumulation dissolution under different dissolution mediums is shown in Table 2；Silymarin solubilising particle and water
Fly silibin pre-mixing agent cumulative release curve graph under different dissolution mediums and sees Fig. 1.
1 silymarin solubilising particle of table Accumulation dissolution under different dissolution mediums
2 commercially available silymarin pre-mixing agent Accumulation dissolution under different dissolution mediums of table
Experiment finds, the existing silymarin pre-mixing agent of comparative example is in vitro in Dissolution Rate Testing, various dissolution mediums not
It can dissolve out completely.
The In Vitro Dissolution test data of table 1, table 2 and Fig. 1 shows that silymarin solubilising particle of the invention is situated between in different pH
Dissolution rate in matter is all remarkably higher than the common pre-mixing agent of silymarin, in silymarin solubilising particle in the media of pH=6.8 6 h
In Vitro Dissolution is up to 99.70%, and the common pre-mixing agent of silymarin In Vitro Dissolution in different medium only has 38.70%.It is external molten
Go out number it was demonstrated that the silymarin solubilising particle of the present invention can discharge completely in different medium, is moving when oral medication
It is discharged completely in object, can effectively improve blood concentration, enhanced clinical efficacy, significantly improve bioavilability.
9 silymarin solubilising particle pharmacokinetics of embodiment is tested
1, for reagent product
Test medicine：The 3% silymarin solubilising slow-releasing granules that embodiment 3 is prepared；
Reference preparation：The vigorous and graceful common 3.1% silymarin pre-mixing agent of meat（It is prepared with reference to the preparation method of comparative example 1）, commercially available
Product.
2, test method
（1）16 healthy white bi-crossbreedings of Yorkshire × length, male and female is fifty-fifty, 7 week old or so, conventinal breeding, free water
And feeding, adequate diet of the feeding without antibacterials, clinical manifestation health.Using own control, by 16 weanling pigs with
Machine is numbered, wherein 8 gavages take orally the solubilized particle of silymarin sustained release（Medicament 2）, it is vigorous and graceful that 8 gavages take orally meat（Reference）；
The preceding 16 h fasting of administration, free water.
（2）Test pig is administered only with single dose, and gavage qf oral administration dosage is 50 mg/kg.b.w.（With milk thistle
Guest counts）.
（3）Pig is lain on the back Baoding, is taken a blood sample from vena cava anterior；Primary blank blood is adopted before administration；5 after administration, 10,
15,20,30,45 min and 1,1.5,2,2.5,3,4,6 h acquire blood sample, detect plasma drug level.
3, result
The pharmacokinetic parameters of silymarin solubilising particle and silymarin pre-mixing agent in pig body are respectively as shown in table 3, table 4.
4 health pig single oral dose silymarin pre-mixing agent of table（50 mg/kg）Pharmacokinetic parameters
3, result
Experiment finds that pharmacokinetics experiment of the existing silymarin pre-mixing agent of comparative example in health pig body proves common pre-mixing agent
Blood concentration is low in vivo, absorption difference, quickly eliminates, and bioavilability is low.Silymarin solubilising particle of the present invention is in pig body
Pharmacokinetics experiment explanation, take orally silymarin solubilising particle 0.5 h or so in pig body and reach peak, up to Cmax up to 1585.74
Ng/mL, and it is 476.74 ng/ml that common pre-mixing agent, which reaches Cmax,；Compared with common pre-mixing agent, silymarin solubilising of the present invention
Blood concentration significantly improves in granule, and relative bioavailability is up to 246.62%.Illustrate compared to common pre-mixing agent, fine grinding
It discharges completely outside silibin solubilising granule, and is significantly improved up to Cmax, bioavilability obviously increases, and dosage is reduced, system
Agent is simple for process, and auxiliary material is inexpensively easily sought, and cost is relatively low, is successfully realized silymarin and switchs to veterinary clinic from people's doctor's clinical application
The purpose of medication.Pharmacokinetics of the silymarin in pig body has not been reported at home at present, and the present invention is follow-up milk thistle for animals
The exploitation of plain preparation and medication of the silymarin on animal clinical is instructed to be of great significance.
In addition, experiment also found that for the animals such as pig, silymarin solubilising particle of the invention can significantly improve
The interest in fodder of animal improves its foraging behaviour, improves the feed intake and production performance of animal, improves the palatability of drug.
The preparation of 2 silymarin solubilising particle of comparative example
1, preparation method prepares silymarin solubilising particle according to the following steps：
（1）Proportionally weigh 10% silymarin bulk pharmaceutical chemicals, 26% glycerin monostearate, 55% succinate, 3.5% sucrose
Higher fatty acids fat and 5.5% fennel oil；By load weighted glycerin monostearate and succinate in 90 DEG C of heating and meltings, obtain
To mixture A；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）The higher fatty acids of load weighted sucrose
Fat, fully shaking are uniformly mixed, and obtain mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted fennel oil is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 40 DEG C, 100 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains 10% silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in Huang
Chromosphere shape fine particle, grain size are about 90 μm.
2, experiment is found, the solubilizing effect unobvious for the silymarin solubilising particle being prepared, cumulative in vitro dissolution rate
Only 38.90%.
If in addition, by a large amount of Optimal Experimental studies have shown that silymarin bulk pharmaceutical chemicals content not 1%~6% model
When enclosing, the solubilizing effect unobvious for the silymarin solubilising particle being prepared, with the contents of silymarin bulk pharmaceutical chemicals be 1%~
The dissolution of its cumulative in vitro is compared up to 99.70% when 6%, and effect gap is very remote.
The preparation of 3 silymarin solubilising particle of comparative example
1, preparation method is same as above embodiment 3, the difference is that water-solubility carrier Macrogol 6000 and hydroxypropyl-β-cyclodextrin
Dosage it is different.
2, experimental study illustrated above is carried out to a series of silymarin solubilising particles of preparation, the results show that water-soluble
The dosage accounting of property carrier is preferably 20%~80%, and most preferably 30%~50%.
The preparation of 4 silymarin solubilising particle of comparative example
1, preparation method prepares silymarin solubilising particle according to the following steps：
（1）Proportionally weigh 5% silymarin bulk pharmaceutical chemicals, 30% hypromellose, 35% phosphatide, 25.5% polyoxyethylene castor
Sesame oil and 4.5% mannitol；By load weighted hypromellose and phosphatide in 150 DEG C of heating and meltings, mixture A is obtained；
（2）After load weighted silymarin raw material is dissolved with ethyl alcohol, step is added（1）Load weighted Emulsifier EL-60,
Fully shaking is uniformly mixed, and obtains mixture B；
（3）By step（2）Gained mixture B is added to step（1）In gained mixture A, stirring evenly makes silymarin molecule
It is combined with carrier, obtains mixture C；
（4）Load weighted mannitol is added to step（3）In gained mixture C, stirred under the conditions of 60 DEG C of holding temperatures equal
It is even, obtain mixture D；
（5）By step（4）Gained mixture D is cooled to 50~80 DEG C, then through fluidized-bed spray granulation nodularization；Wherein fluidization air
Temperature is 20 DEG C, 135 meter per second of linear velocity；
（6）Cooling, sieving, collection cut size obtains silymarin solubilising particle in 40 mesh grain ball below；Its appearance is in yellow ball
Shape fine particle, grain size are about 450 μm.
2, the content that raw material liquid medicine in obtained silymarin solubilising particle flies silibin, experiment hair are measured with HPLC methods
Now, when hypromellose and phosphatide are in 150 DEG C of heating and meltings, raw material liquid medicine flies Ji in finished product silymarin solubilising particle
The content of element is less than 5%.
It is found in addition, being investigated by a series of experiment of single factor, system of the heating and melting temperature to silymarin solubilising particle
Apparent influence is had, heating and melting temperature is best within the scope of 80~120 DEG C, and should strictly control heating during practical operation melts
The temperature of change avoids the degradation for causing bulk pharmaceutical chemicals silymarin.
Claims (10)
1. a kind of silymarin solubilising particle, which is characterized in that include each component of following mass percent：Silymarin raw material
1%~6%, water-solubility carrier 20%~80%, solubilizer 10%~65% and fragrant corrigent 4%~10%.
2. silymarin solubilising particle according to claim 1, which is characterized in that the water-solubility carrier is polyethylene glycol
6000, hydroxypropyl-β-cyclodextrin, phosphatide, cholesterol, hypromellose, D- alpha-tocopherols, PEG1000, methyl-β-ring
Dextrin, polyvinylpyrrolidone, PLURONICS F87, mannitol, succinate, cholate/phosphatide mixed micellazation or polyethyene diamine tree
One or more of dendritic polymer；
The solubilizer is non-ionic solubilizer；
The fragrance corrigent is peppermint oil, wintergreen, caryophyllus oil, fennel oil, lemon oil, mandarin oil, sorbierite or mannitol
One or more of.
3. silymarin solubilising particle according to claim 1, which is characterized in that quality hundred shared by the water-solubility carrier
Divide than being 30%~50%.
4. silymarin solubilising particle according to claim 1, which is characterized in that quality shared by the silymarin raw material
Percentage is 2%, 2.5%, 3%, 4% or 5%.
5. silymarin solubilising particle according to claim 1, which is characterized in that the non-ionic solubilizer is poly- second
Alkene monostearate, sucrose fatty acid ester, Tween-20, Tween-40, Tween-60, Tween-80, Emulsifier EL-60, polyoxy
One or more of ethylene hydrogenation castor oil.
6. the preparation method of any silymarin solubilising particle of Claims 1 to 5, which is characterized in that include the following steps：
S1. water-solubility carrier is proportionally weighed, heating and melting obtains mixture A；
S2. solubilizer is added after silymarin raw material being dissolved with ethyl alcohol, fully shaking is uniformly mixed, and obtains mixture B；
S3. mixture B obtained by step S2 is added in mixture A obtained by step S1, stirs evenly, obtains mixture C；
S4. fragrant corrigent is added in mixture C obtained by step S3, is stirred uniformly, is mixed under holding temperature
Object D；
S5. by mixture D heat preservation atomization obtained by step S4, through fluidized-bed spray granulation nodularization；
S6. it is sieved, collection cut size is in 40 mesh grain ball below, you can obtains the silymarin solubilising particle.
7. preparation method according to claim 6, which is characterized in that the temperature of heating and melting described in step S1 be 80~
120℃。
8. preparation method according to claim 6, which is characterized in that the temperature kept the temperature described in step S4 is 30~85 DEG C.
9. preparation method according to claim 6, which is characterized in that the linear velocity of bed spray drop described in step S5
In 30~135 meter per seconds；Fluidization air temperature is 15~25 DEG C.
10. any silymarin solubilising particle of Claims 1 to 5 is preparing animal feed or is preparing silymarin for animals
Application in terms of oral preparation.
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