CN102614133A - Andrographolide ground suspending liquid, preparation method thereof, and application of pharmaceutical preparation - Google Patents
Andrographolide ground suspending liquid, preparation method thereof, and application of pharmaceutical preparation Download PDFInfo
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Abstract
The invention relates to andrographolide ground suspending liquid, a preparation method thereof, and the application of pharmaceutical preparation, which belongs to the field of pharmaceutical preparation. The preparation method comprises the steps of adding andrographolide into hydrophilic accessory solution with certain concentration, and grinding the andrographolide in a basket grinder to prepare suspending liquid with particle sizes smaller than 3000 nm. Liquid layers of pharmaceutical suspending liquid are laminated onto blank pellet cores with certain particle size range, to prepare andrographolide immediate-release pellets. After grinding, by reducing pharmaceutical particle sizes, increasing particle surface areas and improving the wettability of pharmaceutical particles, the dissolution in vitro of the drug is improved, and hydrophilic carriers are adopted to effectively prevent the aggregation of pharmaceutical particles so as to improve the stability of the pharmaceutical preparation. The preparation method is simple and easy for industrialized production, and the dissolving-out speed of the prepared andrographolide immediate-release pellets is high, so that the bioavailability is obviously improved.
Description
Technical field
The present invention relates to the application of andrographolide grinding suspension and preparation method thereof and pharmaceutical preparation, belong to field of pharmaceutical preparations.
Background technology
Andrographolide (Andrographolide) is the diterpene ginkgolide that extraction obtains in acanthaceous plant Herba Andrographis, is one of main effective ingredient of Chinese medicine Herba Andrographis, has effects such as heat-clearing and toxic substances removing, removing heat from blood detumescence.Be widely used in treatment of diseases such as upper respiratory tract infection, bacillary dysentery clinically.Characteristics such as as the Chinese medicine antimicrobial drug, determined curative effect has untoward reaction and toxic and side effects is few, and toleration is little.The terpenoid that the andrographolide chemical compound is made up of lactone ring five membered and diterpene bicyclic mother nucleus basic structure thereof; Water-soluble hardly and aqueous medium; Oral administration biaavailability is lower; The refined directly oral solid formulation of preparation of andrographolide chemical compound of pointing out of the Yang Jing of Chinese Medical Sciences University, bioavailability is merely 44.06% in its body.
Andrographolide is a kind of poorly water-soluble and medicine with high osmosis, belongs to second type of medicine of classification biology.The absorption of such medicine in digestive tract mainly is subject to its lower dissolubility, and stripping is the systemic speed limit process of its oral back body, improves therefore that dissolubility can improve the interior bioavailability of its body effectively with dissolution rate in its water.At present existing the whole bag of tricks improves the dissolution and the dissolution rate of andrographolide, and is of following document:
CN03130434.6 discloses a kind of method for preparing of dripping pills of andrographolide; It is characterized in that andrographolide and Macrogol 4000; Or polyethylene glycol 6000, or Macrogol 4000 and polyethylene glycol 6000 mixture be carrier, 90 ℃ of fusion methods make the solid dispersion drop pill.Compare with traditional tablet, the andrographolide dissolution rate improves.
CN200610104591.2 discloses a kind of method for preparing of andrographolide nanometer oral liquid; It is characterized in that selecting for use the liquid nonionic surfactant of HLB between 10-15; Perhaps < 10 non-ionic surface active agent is composite with HLB; Andrographolide is dissolved in the cosurfactant ethanol, finally makes 10-100nm andrographolide nanometer emulsion.This oral fluid power increases the dissolubility of andrographolide, improves the bioavailability of andrographolide, reduces its GI irritation property, strengthens patient's compliance.
CN200310121183.4 discloses a kind of andrographolide chemical compound solubilising method for preparing and pharmaceutical preparation; It is characterized in that andrographolide thing and some solubilize compound; For example cyclodextrin, aminoacid, phospholipid, gathering property of water high polymer, vegetable oil are adding an amount of organic cosolvent; Vacuum state adopts the method for mechanical lapping down, is that andrographolide chemical compound and solubilize compound reach superfine mechanism, and then handles through the high frequency ultrasound wave oscillator; Make andrographolide and molecule solubilize compound realize that self-identifying and assembling form a kind of new andrographolide coordination compound, thus preparation have good stripping andrographolide preparation.
The present invention aims to provide a kind of pretreatment technology that has industrial prospect concurrently and improve andrographolide stripping problem, promptly adopts the suspension grinding technique that andrographolide is handled.With the suspension adding lapping device of andrographolide with hydrophilicity condiment with certain viscosity; For example be equipped with in the grinding container of mill ball; In mill basket, carry out superfine grinding by mill ball; Produce dispersion, mixing, cyclical effect at the dispersion impeller high speed rotating, form the high efficiency circulation of suction, grinding, discharging thus, just can obtain outstanding grinding effect in the short time.The effect of the centrifugal force that grinding suspension produces when receiving high speed rotating simultaneously, the abrasive power of mill ball and shearing force; Three power are cooperated the abundant micronization of medicine jointly; Particle diameter can reach micron order even nanoscale; Medicine behind the micronization is wrapped by hydrophilic high molecular material immediately and keeps apart, and prevents small drug particle coalescence and possible surface adsorption, thereby increases the dissolution of medicine; Finally form the medicine aqueous dispersion as the micron particle aqueous colloidal dispersion, further process the preparation of various route of administration then.Via above method, the particle diameter through reducing medicine, increase surface area, improve the stripping that effect such as wettability promotes medicines, be to increase the very effective approach of insoluble drug dissolution rate.
Summary of the invention
The invention provides the application that a kind of andrographolide grinding suspension and preparation method thereof and pharmaceutical preparation are provided; Said method comprises andrographolide is joined in the aqueous solution of hydrophilicity condiment; And in containing the grinder that grinds bead, grind, said grinding bead is processed by glass, zirconium oxide or such as the polymer of polystyrene derivative.With respect to general drug micronization technology, this liquid feeding is sheared grinding technique can let micronized medicine have more superior stability.Simultaneously, the medicinal liquid after liquid feeding grinds can directly carry out downstream processing, as processes multiple dosage forms such as fast-release tablet, fast release micropill.Grinding suspension after directly liquid feeding being ground carries out downstream processing, and to have a processing step simple, easy to operate superiority such as save time.
The andrographolide grinding suspension, it is to be made in basket grinding machine for grinding by andrographolide crude drug and hydrophilicity condiment aqueous solution.
Described hydrophilicity condiment is selected from one or more in cellulose derivative (like HPMC, HPC, HMC), polyvinylpyrrolidone (PVP), Polyethylene Glycol, gelatin and the xanthan gum, preferred HPMC.
The mass percent concentration of the aqueous solution of described hydrophilicity condiment is 3%-15% (w/v), preferred 5%.
Based on the andrographolide grinding suspension gross weight meter that finally makes, andrographolide content is 15-30% (w/w), preferred 20-25% (w/w).
Preferably, in the andrographolide grinding suspension after the grinding, andrographolide particle diameter < 3000nm.
Preferably, described grinding is in the basket grinder that runs up that grinds frequency 35Hz, to carry out, and milling time is 1-4 hour, preferred 3 hours.
The invention provides through a kind of said andrographolide grinding suspension of the andrographolide grinding suspension of method for preparing and acceptable accessories and be combined in the application on the useful in preparing drug formulations.
The present invention also provides described application, is the andrographolide grinding suspension is processed fast release micropill.
Described application; Be selected from a kind of or its mixture of sucrose, microcrystalline Cellulose, lactose; Select for use 5% hydroxypropyl emthylcellulose to prepare celphere as binding agent, in the celphere surface, drug loading is controlled at 5-20% with andrographolide grinding suspension lamination; Adopt the fluidized-bed coating machine lamination, obtain the andrographolide grinding suspension and process fast release micropill.
The air blast flux of described fluidized-bed coating machine is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.
The particle size range of described celphere is that 16-24,24-32 or 32-40 purpose are a kind of,
Described particle size range is preferably 32-40 order celphere.
Described drug loading is 10-15%.
The present invention have following characteristics and effect following:
The present invention relates to the application of andrographolide grinding suspension, method for preparing and pharmaceutical preparation; Said method comprises the andrographolide crude drug is joined in the aqueous solution of certain density hydrophilicity condiment; And in containing the basket grinder of grinding bead, grind, described grinding bead is processed by glass, zirconium oxide or such as the polymer of polystyrene derivative.With respect to the drug micronization technology of routine, this liquid feeding that the present invention adopted is sheared grinding technique can let micronized medicine have more superior stability.Simultaneously, the medicinal liquid after liquid feeding grinds can directly carry out downstream processing, as processes multiple dosage forms such as fast release micropill, fast-release tablet, slow releasing capsule.Grinding suspension after directly liquid feeding being ground carries out downstream processing, and to have a processing step simple, easy to operate superiority such as save time.Preparation technology of the present invention is simple, is easy to suitability for industrialized production, and the andrographolide fast release micropill dissolution rate of preparation is fast, and its bioavailability is improved significantly.
The present invention provides a kind of employing suspension grinding technique that andrographolide is handled.With the suspension adding lapping device of andrographolide with hydrophilicity condiment with certain viscosity; For example be equipped with in the grinding container of grinding bead; Produce powerful suction force and eddy current through self-priming impeller high speed rotating, suspension is sucked be equipped with in the mill basket of abrasive media; By the high speed rotating of mixing arm and distribution blade, give abrasive media enough kinetic energy, material is applied shearing force, frictional force and impulsive force, medicine fully disperses, refinement thereby make; The dispersion impeller high speed rotating of mill basket bottom forms negative pressure and powerful suction force, with the suspension sucking-off of refinement in the basket; Drug suspension is thrown away from mill basket by the powerful centrifugal force of high speed rotating dispersion impeller immediately, promotes the dispersion of suspension.Grinding suspension carries out superfine grinding by mill ball in mill basket, produce dispersion, mixing, cyclical effect at the dispersion impeller high speed rotating, forms the high efficiency circulation of suction, grinding, discharging thus, just can obtain outstanding grinding effect in the short time.The effect of the centrifugal force that grinding suspension produces when receiving high speed rotating simultaneously, the abrasive power of mill ball and shearing force; Three power are cooperated the abundant micronization of medicine jointly; Particle diameter can reach micron order even nanoscale; Medicine behind the micronization is wrapped by hydrophilic high molecular material immediately and keeps apart, and prevents small drug particle coalescence and possible surface adsorption, thereby increases the dissolution of medicine; Finally form the medicine aqueous dispersion as the nano-particle aqueous colloidal dispersion, further process the preparation of various route of administration then.The inventive method is to increase the very effective approach of insoluble drug dissolution rate.
Description of drawings
Fig. 1 is the releasing curve diagram of andrographolide in the different pH dissolution mediums of the present invention.
Fig. 2 is the releasing curve diagram of dripping pills of andrographolide in the different pH dissolution mediums of the present invention.
Fig. 3 is the releasing curve diagram of andrographolide fast release micropill in the different pH dissolution mediums of the present invention.
The specific embodiment
Below in conjunction with embodiment the present invention is described further.Following examples are merely several specific embodiment of the present invention, but design concept of the present invention is not limited thereto, and allly utilize this design that the present invention is carried out the change of unsubstantiality, all should belong to the behavior of invading protection domain of the present invention.
Method among the following embodiment if no special instructions, is conventional method.
Percentage composition among the following embodiment is quality percentage composition (w/w) if no special instructions.
(1) method for preparing of andrographolide grinding suspension:
Take by weighing the andrographolide crude drug; Prepare the hydrophilicity condiment aqueous solution of finite concentration (w/v) respectively; The hydrophilicity condiment aqueous solution of andrographolide with above-mentioned variable concentrations is positioned in the grinding cup; Grinding frequency is the basket grinding machine for grinding 1-5h that 35Hz runs up, and the grinder model is that the SOWER laboratory produced of Shanghai Suowei Electromechanical Equipment Co., Ltd. is with basket grinder SMA-0.75 type.
(2) method for preparing of andrographolide fast release micropill:
Be selected from a kind of or its mixture of sucrose, microcrystalline Cellulose, lactose; Select for use 5% hydroxypropyl emthylcellulose to prepare celphere as binding agent; The particle size range of celphere is that 16-24,24-32 or 32-40 purpose are a kind of, the preferred 32-40 order of particle size range celphere.Drug loading is controlled at 5-20%, and the Herba Andrographis suspension lamination of method for preparing is surperficial in celphere, the preferred 10-15% of drug loading; Adopt the fluidized-bed coating machine lamination; Air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.
The preparation process:
(1) preparation of celphere: take by weighing a kind of or its mixture of an amount of sucrose, microcrystalline Cellulose, lactose, as binding agent, prepare soft material with the 5%HPMC aqueous solution; Soft material is added the feedstuff mouth, and extruded velocity is 30rpm, round as a ball speed 900rpm; Round as a ball 15min; Make celphere, place 40 ℃ of oven dry 12 hours, the ball nuclear of screening targeted particle size.
(2) medicine lapping liquid lamination to celphere prepares the pastille micropill.Drug loading is controlled at 5-20%, and the Herba Andrographis suspension lamination of method for preparing is surperficial in celphere, the preferred 10-15% of drug loading.Air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Get 32-40 order celphere, place fluid bed, start hot blast, micropill is preheating to 30 ℃; Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes; Air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed; Continue fluidized drying 10min, take out finished product, place 40 ℃ of oven dry.
The screening of hydrophilicity condiment solution concentration:
Embodiment 1
(1) the andrographolide grinding suspension is to have following feedstock production to form:
Andrographolide 120g, polyvinylpyrrolidone (PVP-K30) hydrophilic carrier concentration of aqueous solution are respectively 5% (w/v), 10% (w/v), 15% (w/v), 500ml distilled water;
The andrographolide crude drug of said consumption and the PVP-K30 hydrophilicity condiment aqueous solution of above-mentioned variable concentrations are evenly placed in the basket grinding cup mix homogeneously.The grinding frequency setting is 35Hz, and milling time 3h obtains corresponding andrographolide grinding suspension;
(2) preparation of Herba Andrographis fast release micropill:
The andrographolide suspension lamination of getting above-mentioned 5%, 10% and 15% PVP-K30 aqueous solution preparation respectively is in 32-40 order celphere surface, and drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
(3) dissolution determination method:
Adopt 2005 editions two appendix XD dissolution determination methods of Chinese Pharmacopoeia, second method, water is a dissolution medium, and bath temperature is (37 ± 0.5) ℃, and rotating speed is 50rmin
-1Respectively at 5,10,20,30; 45,60 with 90min time sampling 5mL, add synthermal medium 5mL simultaneously; 0.45 μ m filtering with microporous membrane is got subsequent filtrate and is diluted to suitable concentration, according to 2005 editions appendix IVA-of Chinese Pharmacopoeia UV-VIS spectrophotometry; Measure absorbance at the 240nm place, and compare, calculate the dissolution of each time point of andrographolide with contrast solution.
(4) experimental result and analysis:
Grind the influence of liquid altogether according to what above-mentioned dissolution determination method was investigated variable concentrations PVP-K30 and medicine to the andrographolide dissolution; The result shows that the stripping quantity that liquid makes andrographolide fast release micropill 30min that grinds altogether of 5%, 10% and 15% PVP-K30 and medicine is followed successively by: 75%; 92%, 91%.This instance shows that PVP-K30 has remarkable increase effect to the dissolubility of andrographolide; But lapping liquid is in long-term put procedure; Occur tangible lamination with PVP-K30 as the grinding suspension of carrier, drug particle is flocked on container bottom, and the upper strata is a settled solution; Maybe be because the PVP-K30 viscosity in aqueous solution be lower, the suspending weak effect.
Embodiment 2
(1) the andrographolide grinding suspension is to have following feedstock production to form:
Andrographolide 120g, Polyethylene Glycol hydrophilic carrier concentration of aqueous solution are respectively 10% (w/v), 15% (w/v), 20% (w/v), 500ml distilled water;
The andrographolide crude drug of said consumption and the Polyethylene Glycol hydrophilic carrier aqueous solution of above-mentioned variable concentrations are evenly placed in the basket grinding cup mix homogeneously.The grinding frequency setting is 35Hz, and milling time 3h obtains corresponding andrographolide grinding suspension;
(2) preparation of Herba Andrographis fast release micropill:
The andrographolide suspension lamination of getting above-mentioned 10%, 15% and 20% Polyethylene Glycol hydrophilic carrier aqueous solution preparation respectively is in 32-40 order celphere surface, and drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
(3) dissolution determination method:
Adopt 2005 editions two appendix XD dissolution determination methods of Chinese Pharmacopoeia, second method, water is a dissolution medium, and bath temperature is (37 ± 0.5) ℃, and rotating speed is 50rmin
-1Respectively at 5,10,20,30; 45,60 with 90min time sampling 5mL, add synthermal medium 5mL simultaneously; 0.45 μ m filtering with microporous membrane is got subsequent filtrate and is diluted to suitable concentration, according to 2005 editions appendix IVA-of Chinese Pharmacopoeia UV-VIS spectrophotometry; Measure absorbance at the 240nm place, and compare, calculate the dissolution of each time point of andrographolide with contrast solution.
(4) experimental result and analysis:
Grind the influence of liquid altogether according to what above-mentioned dissolution determination method was investigated variable concentrations Polyethylene Glycol and medicine to the andrographolide dissolution; The result shows that the stripping quantity that liquid makes andrographolide fast release micropill 30min that grinds altogether of 10%, 15% and 20% Polyethylene Glycol and medicine is followed successively by: 75%; 80%, 85%.
Embodiment 3
(1) the andrographolide grinding suspension is to have following feedstock production to form:
Andrographolide 120g, gelatin hydrophilic carrier concentration of aqueous solution are respectively 3% (w/v), 5% (w/v), 8% (w/v), 10% (w/v), 500ml distilled water;
The andrographolide crude drug of said consumption and the gelatin hydrophilicity condiment aqueous solution of above-mentioned variable concentrations are evenly placed in the basket grinding cup mix homogeneously.The grinding frequency setting is 35Hz, and milling time 3h obtains corresponding andrographolide grinding suspension;
(2) preparation of Herba Andrographis fast release micropill:
The andrographolide suspension lamination of getting above-mentioned 3%, 5%, 8% and 10% aqueous gelatin solution preparation respectively is in 32-40 order celphere surface, and drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
(3) experimental result and analysis:
Grind the influence of liquid altogether according to what the dissolution method of embodiment 1 was investigated variable concentrations gelatin and medicine to the andrographolide dissolution; The result shows that the stripping quantity that liquid makes andrographolide fast release micropill 30min that grinds altogether of 3%, 5%, 8% and 10% gelatin and medicine is followed successively by: 81%; 90%; 91%, 89%.
Embodiment 4
(1) the andrographolide grinding suspension is to have following feedstock production to form:
Andrographolide 120g, xanthan gum hydrophilic carrier concentration of aqueous solution are respectively 3% (w/v), 5% (w/v), 8% (w/v), 10% (w/v), 500ml distilled water;
The andrographolide crude drug of said consumption and the xanthan gum hydrophilicity condiment aqueous solution of above-mentioned variable concentrations are evenly placed in the basket grinding cup mix homogeneously.The grinding frequency setting is 35Hz, and milling time 3h obtains corresponding andrographolide grinding suspension;
Above-mentioned xanthan gum can be by gelatin and Polyethylene Glycol mixture replacing;
(2) preparation of Herba Andrographis fast release micropill:
The andrographolide suspension lamination of getting above-mentioned 3%, 5%, 8% and 10% xanthan gum solution preparation respectively is in 32-40 order celphere surface, and drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
(3) experimental result and analysis:
Grind the influence of liquid altogether according to what the dissolution method of embodiment 1 was investigated variable concentrations xanthan gum and medicine to the andrographolide dissolution; The result shows that the stripping quantity that liquid makes andrographolide fast release micropill 30min that grinds altogether of 3%, 5%, 8% and 10% xanthan gum and medicine is followed successively by: 79%; 82%, 85%, 83%.
(1) the andrographolide grinding suspension is to have following feedstock production to form:
Andrographolide 120g, HPMC hydrophilic carrier concentration of aqueous solution are respectively 3% (w/v), 5% (w/v), 8% (w/v), 15% (w/v), 500ml distilled water;
The andrographolide crude drug of said consumption and the HPMC hydrophilicity condiment aqueous solution of above-mentioned variable concentrations are evenly placed in the basket grinding cup mix homogeneously.The grinding frequency setting is 35Hz, and milling time 3h obtains corresponding andrographolide grinding suspension;
Above-mentioned HPMC can be substituted by HPC or HMC;
(2) preparation of Herba Andrographis fast release micropill:
The andrographolide suspension lamination of getting above-mentioned 3%, 5%, 8% and 15% HPMC aqueous solution preparation respectively is in 32-40 order celphere surface, and drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
(3) experimental result and analysis:
Grind the influence of liquid altogether according to what the dissolution method of embodiment 1 was investigated variable concentrations HPMC and medicine to the andrographolide dissolution; The result shows that the stripping quantity that liquid makes andrographolide fast release micropill 30min that grinds altogether of 3%, 5%, 8% and 15% HPMC and medicine is followed successively by: 72%; 90%; 91%, 85%.When this instance show to adopt the 3%HPMC aqueous solution as carrier, dissolution rate was obviously on the low side in the medicine 45min, and 5% with 8%HPMC dissolution rate indifference almost, all reach 90% in the 30min.When the carrier ratio was hanged down, lapping liquid was rarer, failed to make medicine and grinding bead fully to act on, and grinding efficiency is low to cause 3%HPMC to the medicament solubilization poor effect.In addition, the medicine high degree of dispersion is in carrier, and through mechanical force and HPMC interaction, hydrophilic HPMC is wrapped in outside the drug particle, if carrier concn is low excessively, this surface coating rate of possibility is low, and hydrophilic is low, and solubilizing effect is poor; Concentration further increases, and drug particle possibly reach capacity, and no longer includes remarkable solubilizing effect; When carrier concn was too high, the viscosity of carrier also can increase thereupon, can form gel layer at medical surfaces simultaneously and suppressed the release of medicine.Therefore select for use in the lapping liquid prescription HPMC concentration as 5%.Therefore prepare the final hydrophilicity condiment solution of confirming that 5 (w/v) %HPMC solution grinds as andrographolide in the experiment of andrographolide fast release micropill at the application embodiment.
Among the present invention in the experiment of following andrographolide fast release micropill used grinding suspension all be that the dissolution determination condition that is adopted is identical with present embodiment with the common abrasive material of 5 (w/v) %HPMC with the andrographolide crude drug.
Embodiment 6
(1) preparation of andrographolide grinding suspension:
Andrographolide 90g, 120g, 150g and 180g (based on andrographolide grinding suspension gross weight meter, andrographolide content is 15%, 20%, 25% and 30%), the HPMC hydrophilic carries concentration of aqueous solution and is respectively 5% (w/v), 500ml distilled water;
The andrographolide crude drug (15-30%) of said different amounts is evenly placed in the basket grinding cup mix homogeneously with 5%HPMC hydrophilicity condiment aqueous solution.The grinding frequency setting is 35Hz, and milling time 3h obtains corresponding andrographolide grinding suspension;
(2) preparation of Herba Andrographis fast release micropill:
Get above-mentioned andrographolide content respectively and be 15%, 20%, 25% and 30% grinding suspension lamination in 32-40 order celphere surface, drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
Andrographolide grinding suspension and fast release micropill method for preparing, stripping assay method are together.
(3) experimental result and analysis
The andrographolide of investigating different content according to the dissolution determination method of embodiment 1 grinds the dissolution influence of liquid to the andrographolide fast release micropill altogether; The result shows that andrographolide content is that 15%, 20%, 25% and 30% the stripping quantity that grinds the andrographolide fast release micropill 30min that liquid gets altogether is followed successively by: 93%; 91%, 89% and 77%.In hydrophilic support, carrier and medicine can interact through hydrophobic bond and insoluble drug under the high-strength mechanical abrasive action, and hydrophilic HPMC is wrapped in dispersibility and the wettability that drug particle strengthens medicine outward.If drug level is too high, surface coating rate is low, and hydrophilic is low, and solubilizing effect is poor.Consider the drug loading that finished product preparation is final and the rate of release of andrographolide, select therefore that andrographolide content is 20-25% in the lapping liquid prescription for use.
Embodiment 7
(1) andrographolide grinding suspension:
With embodiment 5.
(2) preparation of Herba Andrographis fast release micropill:
With the andrographolide suspension of above-mentioned 5% HPMC aqueous solution preparation respectively lamination be 32-40 purpose sucrose in equal in quality, size, lactose-microcrystalline Cellulose 1:4 and microcrystalline Cellulose celphere surface, drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
Andrographolide grinding suspension and fast release micropill method for preparing, stripping assay method are together.
(3) experimental result and analysis
Investigate of the influence of different types of ball core according to determination of dissolution rate method among the embodiment 1 to the andrographolide dissolution; The result shows with sucrose; The stripping quantity that lactose-microcrystalline Cellulose 1:4 and microcrystalline Cellulose celphere make andrographolide quick-release and slow-release micropill 30min is followed successively by: 95%; 94%, 95%.This instance shows that the drug release of sucrose ball core is the fastest, is lactose-microcrystalline Cellulose ball core secondly, and celphere is the dissolution rate that water soluble adjuvant can increase medicine, and medicine dissolution after 20min is basic identical, does not have notable difference.But in the lamination process; Sucrose ball core and lactose ball core can be dissolved in the lamination liquid, and at the lamination process initial stage, blank pill nuclear can adhesion occur because of dissolving; Wall sticking phenomenon is serious; Need in the lamination process, constantly to end feed liquor, ball sandwich layer layer is dry, wrap up then this phenomenon disappearance of micropill surface fully to the later stage medicine.In view of andrographolide is the thermal sensitivity medicine, should reduce the medicine heated time as far as possible, to sum up factor selects microcrystalline Cellulose ball core as celphere.
(1) andrographolide grinding suspension
With embodiment 5.
(2) preparation of Herba Andrographis fast release micropill
The andrographolide suspension of above-mentioned 5% HPMC aqueous solution preparation is distinguished lamination in the 16-24 order, 24-32 order and 32-40 order microcrystalline Cellulose celphere surface, drug loading is controlled at 10-15%.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
Andrographolide grinding suspension and fast release micropill method for preparing, stripping assay method are together.
(3) experimental result and analysis
Investigate of the influence of varigrained celphere according to determination of dissolution rate method among the embodiment 1 to the andrographolide dissolution; The result shows the 16-24 order; The stripping quantity that 24-32 order and 32-40 order microcrystalline Cellulose celphere make andrographolide quick-release and slow-release micropill 30min is followed successively by: 92%; 91%, 95%.The demonstration of this instance is along with the celphere particle diameter reduces, and the dissolution rate of medicine obviously increases, and ball core particle diameter is more little, and surface area is big more, and the contact area of medicine and dissolution medium increases, and dissolution rate is accelerated.Therefore, microcrystalline Cellulose celphere granularity is confirmed as the 32-40 order.
Embodiment 9
(1) andrographolide grinding suspension
With embodiment 5.
(2) preparation of Herba Andrographis fast release micropill
With 10g, 20g, the andrographolide suspension difference lamination of 20g and 40g is on the 32-40 of equal in quality order microcrystalline Cellulose celphere.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
Andrographolide grinding suspension and fast release micropill method for preparing, stripping assay method are together.
(3) experimental result and analysis
Investigate of the influence of different drug loading according to determination of dissolution rate method among the embodiment 1 to the andrographolide dissolution; The result shows 10g, 20g, and 30g and 40g andrographolide suspension lamination are on the 32-40 of equal in quality order microcrystalline Cellulose celphere; Making different drug loading andrographolide quick-release and slow-release micropill 30min stripping quantities is followed successively by: 99%; 93%, 94%, 91%.This instance shows the increase along with the micropill drug loading, and the dissolution rate of medicine obviously slows down.The celphere of equal in quality, drug loading are high more, and medicine is big more at the thickness that the ball wicking surface coats, and the speed that medicine contacts with dissolution medium is slow more.This phenomenon can be offset through reducing the celphere particle diameter.Drug loading meeting on the low side causes volumes of formulation excessive, reduces the compliance of medicine.Take all factors into consideration and confirm that drug loading is controlled at about 13%.
(1) andrographolide grinding suspension
With embodiment 1.
(2) preparation of Herba Andrographis fast release micropill
Is that drug loading is controlled at about 13% on the 32-40 order microcrystalline Cellulose celphere with the andrographolide suspension lamination of above-mentioned 5% HPMC aqueous solution preparation in granularity.The fluidized bed granulation parameter: air blast flux is 45-50Hz, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.Young blow speed is slower, and along with time lengthening, the medicine of lamination is many more on the micropill, and it is heavy that micropill becomes, and air blast will increase gradually, guarantees the fluidized state of micropill, till lapping liquid has sprayed, continues fluidized drying 10min, takes out finished product, places 40 ℃ of oven dry.
Andrographolide grinding suspension and fast release micropill method for preparing, stripping assay method are together.
(3) experimental result and analysis
Investigated the optimum prescription of fast release micropill according to determination of dissolution rate method among the embodiment 1; Andrographolide crude drug and the commercially available drop pill dissolution in five kinds of media such as 0.1mol/L HCl, pH 4.5 acetate buffers, pH 6.8 phosphate buffers, distilled water, pH 7.2 phosphate buffers, the result sees accompanying drawing 1, Fig. 2 and Fig. 3.
This instance shows: the andrographolide crude drug, the dissolution of dripping pills of andrographolide and andrographolide fast release micropill does not all have the pH dependency.The dissolution of andrographolide more commercially available drop pill and crude drug under various pH conditions all is significantly increased in the self-control micropill, and dissolution is 3 times of commercially available drop pill in the 30min, is 9 times of crude drug dissolution.
Claims (13)
1. the andrographolide grinding suspension is characterized in that it being to be made in basket grinding machine for grinding by andrographolide crude drug and hydrophilicity condiment aqueous solution.
2. andrographolide grinding suspension according to claim 1, described hydrophilicity condiment is selected from one or more in cellulose derivative, polyvinylpyrrolidone, Polyethylene Glycol, gelatin and the xanthan gum.
3. andrographolide grinding suspension according to claim 1 and 2, based on andrographolide grinding suspension gross weight meter, andrographolide content is 15-30% (w/w).
4. andrographolide grinding suspension according to claim 3, based on andrographolide grinding suspension gross weight meter, andrographolide content is 20-25% (w/w).
5. andrographolide grinding suspension according to claim 1 and 2, the concentration that it is characterized in that described hydrophilicity condiment aqueous solution are 3-15% (w/v), preferred 5% (w/v).
6. andrographolide grinding suspension according to claim 1 is characterized in that described andrographolide particle diameter < 3000nm.
7. andrographolide grinding suspension according to claim 1 is characterized in that described grinding is in the basket grinder that runs up that grinds frequency 35Hz, to carry out, and milling time is 1-4 hour.
8. andrographolide grinding suspension according to claim 7 is characterized in that described milling time is 3 hours.
9. said andrographolide grinding suspension of claim 1 and acceptable accessories are combined in the application on the useful in preparing drug formulations.
10. pharmaceutical preparation according to claim 9 is characterized in that being selected from one or more of sucrose, microcrystalline Cellulose, lactose, selects for use 5% hydroxypropyl emthylcellulose to prepare celphere as binding agent; Adopt fluidized-bed coating machine, andrographolide grinding suspension lamination in the celphere surface, is made the andrographolide fast release micropill.
11. pharmaceutical preparation according to claim 9 is characterized in that said andrographolide fast release micropill prepares that the fluidized-bed coating machine air blast flux is 45-50Hz in the process, spray gun whiff pressure 1.0kgf/cm, and drug solution speed is 0.5-0.8mL/min.
12. pharmaceutical preparation according to claim 9, the particle size range that it is characterized in that said celphere are that 16-24,24-32 or 32-40 purpose are a kind of.
13. pharmaceutical preparation according to claim 9 is characterized in that said andrographolide fast release micropill drug loading is 10-15%.
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| CN104274440A (en) * | 2013-07-11 | 2015-01-14 | 成都中医药大学 | Andrographolide composite particles and preparation method thereof |
| WO2015018344A1 (en) * | 2013-08-06 | 2015-02-12 | 天士力制药集团股份有限公司 | Application of andrographolide in the preparation of a pharmaceutical for treatment of inflammatory bowel disease, andrographolide enteric targeting micropellet, and method for preparation thereof |
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| CN104274440A (en) * | 2013-07-11 | 2015-01-14 | 成都中医药大学 | Andrographolide composite particles and preparation method thereof |
| CN104274440B (en) * | 2013-07-11 | 2017-04-26 | 成都中医药大学 | Andrographolide composite particles and preparation method thereof |
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| US9889093B2 (en) * | 2013-08-06 | 2018-02-13 | Tasly Pharmaceutical Group Co., Ltd. | Application of andrographolide in the preparation of a pharmaceutical for treatment of inflammatory bowel disease, andrographolide enteric targeting micropellet, and method for preparation thereof |
| CN106913527A (en) * | 2015-12-28 | 2017-07-04 | 江苏先声药业有限公司 | A kind of Rui Gefeini fast release micropills and preparation method thereof |
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| CN113730588B (en) * | 2020-09-30 | 2022-11-29 | 成都中医药大学 | Hydrophilic natural indigo and preparation method thereof |
| CN112426410A (en) * | 2020-12-08 | 2021-03-02 | 黄山中皇制药有限公司 | Potassium dehydroandrographolide succinate enteric dry suspension |
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Application publication date: 20120801 |