CN103637994A - A premix auxiliary material and a preparation technology thereof - Google Patents
A premix auxiliary material and a preparation technology thereof Download PDFInfo
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- CN103637994A CN103637994A CN201310547067.2A CN201310547067A CN103637994A CN 103637994 A CN103637994 A CN 103637994A CN 201310547067 A CN201310547067 A CN 201310547067A CN 103637994 A CN103637994 A CN 103637994A
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Abstract
The invention discloses a premix auxiliary material. The premix auxiliary material comprises polyvinylpyrrolidone, glyceryl behenate, and a pharmaceutical adjuvant filler and a pharmaceutical adjuvant disintegrant, wherein the weight ratio of the filler, the disintegrant, the polyvinylpyrrolidone and the glyceryl behenate is (80-98.5):(10-0.5):(5-0.5):(5-0.5). The premix auxiliary material comprising the polyvinylpyrrolidone and the glyceryl behenate is good in fluidity, strong in compressibility and good in lubricating effect. The mixing uniformity, the medicine content, the tablet hardness, and the like would not change with prolongation of the total mixing time. The premix auxiliary material is prone to enlargement. Indexes comprising fluidity, the Carr's index, compressibility, friability, etc. of the premix auxiliary material provided by the invention are superior to corresponding indexes of auxiliary materials mixed physically. Uncontrollable factors of the technology are reduced, thus facilitating large-scale production. The premix auxiliary material can be used for direct compression of tablets or encapsulation of capsules.
Description
Technical field
The present invention relates to a kind of premixing auxiliary material and preparation technology thereof who can be used for the direct compression of tablet or the fill of capsule, belong to field of pharmaceutical preparations.
Background technology
The preparation technology of tablet is divided into wet granulation, dry granulation and direct powder compression technology conventionally.An investigation of Shangraw etc. shows, direct powder compression technology has become the preferred production technology of most of makeies.Technique of direct powder compression research starts from the late period of the 1950's.Compare with wet granulation, technique of direct powder compression can improve the stability of damp and hot sensitive medicaments; Compare with dry granulation, simplified processing step, avoided loaded down with trivial details technological parameter, there is simple, the time saving and energy saving and low consumption of technique.But technique of direct powder compression is higher with the requirement of material to tabletting, all adjuvants must have good mobility, good compressibility, good lubricity and larger medicine carrying capacity, also must have adaptability and preferably repeatability widely.Common single adjuvant is difficult to meet above-mentioned requirements simultaneously.Except single adjuvant is modified and reached vertical compression requirement, premixed type adjuvant in technique of direct powder compression, shown good superiority (Zhang Yilan, etc. Acta Pharmaceutica Sinica .2012,47 (5): 640-645).
Premixed type adjuvant (co-processedexcipent) refers to by two kinds or two or more single adjuvant according to a certain percentage, with certain production technology (as common dry, hot-melt extruded, lyophilization, co-precipitation etc.), evenly mix in advance, become a kind of new adjuvant that has the apparent homogeneous of multi-functional or specific function concurrently.Premixed type adjuvant keeps or has improved the advantage of single adjuvant, has also made up weak point simultaneously, and often the performance in technique of direct powder compression is better than the physical mixture of single adjuvant or adjuvant.The research and development impetus of premixed type adjuvant is powerful, constantly there is new product to come out, as commodity Ludipress(Germany BASF AG, containing lactose 93%, PVP K30 3.5%, crospovidone 3.5%), LudipressLCE(Germany BASF AG, containing lactose 96.5%, PVP K30 3.5%), AvicelRC-581(U.S. FMC Corp., containing microcrystalline Cellulose 89%, sodium carboxymethyl cellulose 11%), StarLac(Germany Meggle company, containing lactose 85%, corn starch 15%), MicroceLac(Germany Meggle company, containing lactose 75%, microcrystalline Cellulose 25%), Cellactose(Germany Meggle company, containing lactose 75%, cellulose 25%), ProSolv(Germany JRS company, containing microcrystalline Cellulose 98%, colloidal silica 2%), LubritoseMCC(U.S. Kerry company, containing microcrystalline Cellulose 98%, glyceryl monostearate 2%), LubritoseAN(U.S. Kerry company, containing lactose 96%, glyceryl monostearate 4%) and AdavantoseFS95(U.S. SPI company, containing fructose 95%, starch 5%) etc.
Premixing auxiliary material patent is disclosed more, as Wujiang Dixing Technologies Co., Ltd. discloses a kind of mannitol, the premixing auxiliary material of lactose and polyvinylpolypyrrolidone (CN200910052769), the mannitol of Hunan Xiang Yao pharmaceutical Co. Ltd, the premixing auxiliary material of sorbitol and microcrystalline Cellulose (CN200910180030), the mannitol of Shanghai Huamao Pharmaceutical Co, the premixing auxiliary material of isosorbide and polyvinylpolypyrrolidone (CN201010184194), the microcrystalline Cellulose of the mountains and rivers, Anhui pharmaceutic adjuvant limited company, the premixing auxiliary material of polyvinylpolypyrrolidone and silicon dioxide (CN201210097822), the hyprolose of Tianjin Aileyi Medicine Materials Co., Ltd., premixing auxiliary material of lactose (CN201210332700) etc.
Polyvidone, has another name called polyvinyl pyrrolidone, and as water miscible macromolecular material, its effect extensively, has good colloid protective effect, film property, caking property, hygroscopicity, solubilising or cohesion.Can be used as high molecular surfactant, in different dispersions, also can be used as dispersant, emulsifying agent, thickening agent, levelling agent, granularity regulator, anti-precipitant, flocculating agent, cosolvent and detergent again, therefore, polyvidone is widely used on pharmaceutics.Conventional polyvidone by American I SP company (trade name:
) and German BASF AG (trade name:
) produce.
Patent about the premixing auxiliary material containing polyvidone is more, as Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong discloses a kind of lactose-polyvidone-crospolyvidone premixed agent and preparation method thereof (Granted publication CN101664556B), this patent Introduction composition and the technique of lactose-polyvidone-polyvinylpolypyrrolidone premixing auxiliary material, its proportion of composing is lactose: polyvidone: polyvinylpolypyrrolidone=(93～93.8): (3.0～3.4): (3.2～3.6).But this proportion of composing and German BASF AG produce
basically identical, disclosed
lactose in its specification of quality (specification): polyvidone: the ratio of polyvinylpolypyrrolidone is (93 ± 2): (3.5 ± 0.5): (3.5 ± 0.5), its disclosed patent is shown in DE-3505433 and US5006345.Germany BASF AG also produces
lCE, it is comprised of lactose and polyvidone, and its ratio is 96.5:3.5.
Remove
with
outside two kinds of BASF products of LCE, in US5840769 patent, German BASF AG also discloses the premixing auxiliary material of microcrystalline Cellulose, polyvidone and polyvinylpolypyrrolidone.In EP0487774 patent, Taiwan Huimin pharmaceutical Co. Ltd discloses the premixing auxiliary material containing mannitol and polyvidone, and this adjuvant now goes on the market, and commodity are by name
mannitolTAG, the ratio of its mannitol and polyvidone is 90:10, has also added a small amount of anticaking agents calcium phosphate dibasic anhydrous (0.3%).France ScoraSA. company produces two kinds containing the premixing auxiliary material of polyvidone, and its commodity are by name
dC97PVPTDS,
lL250DC97PVPTDS, is the premixing auxiliary material of calcium carbonate and polyvidone, and its proportion of composing is 97:3, and both differences are the latter lead content≤250ppm.
Behenic acid is behenic acid, and Glyceryl Behenate is mixture (accounting for respectively 18%, 52% and 28%) single, two, three Glyceryl Behenates, and melting range is 69-74 ℃, oral nontoxic non-stimulated, Oral Administration in Rats LD
50be greater than 5g/kg.Because its fusing point is suitable, amphipathic, with pressed powder form, exist, there is preferably lubricated, emulsifying and skeleton slow release and form.Compare with alkaline magnesium stearate lubricant, Glyceryl Behenate is inertia, is applicable to most of medicine, improves the compressibility of powder, insensitive to incorporation time, on disintegration time without impact (WangJ, WenH, DesaiD.EurJPharmBiopharm, 2010,75 (1): 1-15).But in quick or high speed tabletting process, owing to producing a large amount of heat in tabletting process, and the inhomogeneities of physical mixed causes tablet to produce sticking phenomenon, affects its use.By French Gattefosse company, produced, commodity are by name
888ATO.
Summary of the invention
For above-mentioned prior art, the invention provides a kind of premixing auxiliary material, its preparation technology is also provided.The present invention is the excellent bonds characteristic of utilizing polyvidone, and Glyceryl Behenate is all the feature of inertia to most of material, and absorb fillers and a small amount of disintegrating agent are prepared into premixing auxiliary material simultaneously, have further opened up the application of polyvidone and Glyceryl Behenate.
The present invention is achieved by the following technical solutions:
A kind of premixing auxiliary material, by polyvidone, Glyceryl Behenate, and pharmaceutic adjuvant filler, disintegrating agent form, wherein, the weight ratio of filler, disintegrating agent, polyvidone and Glyceryl Behenate is: (80～98.5): (10～0.5): (5～0.5): (5～0.5), preferably, the weight ratio of filler, disintegrating agent, polyvidone and Glyceryl Behenate is: (85～98): (10～0.5): (3～1): (2～0.5).
Described filler is selected from any in microcrystalline Cellulose, mannitol, lactose, or the mixture of any two or more compositions.
Described disintegrating agent is selected from any in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, or the mixture of any two or more compositions.
Described low-substituted hydroxypropyl cellulose is cellulosic low substituted hydroxy-propyl ether, and it contains hydroxypropyl (-OCH
2cHOHCH
3) amount 7.0%～16.0%.
The preferred low viscous polyvidone of described polyvidone [10%(W/V) 20 ℃ of the dynamic viscosities of polyvidone aqueous solution be 5.5～8.5mPas], as BASF AG produces
k30, or the production of American I SP company
k30.
Described premixing auxiliary material, preferred, be composed of the following components: microcrystalline Cellulose 95kg, low-substituted hydroxypropyl cellulose 9.6kg, polyvidone 1kg and Glyceryl Behenate 0.7kg.
Described premixing auxiliary material, preferred, be composed of the following components: microcrystalline Cellulose 95kg, cross-linking sodium carboxymethyl cellulose 2kg, polyvidone 1kg and Glyceryl Behenate 0.5kg.
Described premixing auxiliary material, preferred, be composed of the following components: microcrystalline Cellulose 102kg, carboxymethyl starch sodium 8kg, polyvidone 2kg and Glyceryl Behenate 1kg.
Described premixing auxiliary material, preferred, be composed of the following components: lactose 110kg, low-substituted hydroxypropyl cellulose 10kg, polyvidone 3.5kg and Glyceryl Behenate 2kg.
Described premixing auxiliary material, preferred, be composed of the following components: mannitol 105kg, polyvinylpolypyrrolidone 2kg, polyvidone 3kg and Glyceryl Behenate 2.5kg.
Described premixing auxiliary material, preferred, be composed of the following components: microcrystalline Cellulose 30kg, lactose 80kg, low-substituted hydroxypropyl cellulose 9kg, polyvidone 4kg and Glyceryl Behenate 2kg.
Because filler type is different, the kind of disintegrating agent is also different, and disintegrate principle there are differences, and based on this, the present invention uses the disintegrating agent of different amounts; The bond properties of polyvidone is good, in water, also can dissolve, and the ratio of its use is compared with filler, less; Equally, Glyceryl Behenate, as lubricant, due to its efficient lubricant effect, also only needs just can reach good lubrication effect on a small quantity; The present invention is the composite auxiliary material that a kind of filled agent, binding agent, disintegrating agent and four kinds of conventional adjuvants of lubricant form.
The preparation technology of described premixing auxiliary material, comprises the following steps:
(1) in container, pass into water, after heated and boiled, insulation is at 70～85 ℃, standby;
(2) filler, disintegrating agent, polyvidone and Glyceryl Behenate are mixed, mix, then while stirring, be fed in container, 70～85 ℃ of insulation high-speed stirred (300～1000rpm) 0.5～3 hour, become solid content and are 10～20% even aqueous slurry;
(3) above-mentioned aqueous slurry spraying is dry, controlling spray-dired temperature is 100～120 ℃; Collect the dried material of spraying, cross 60 mesh sieves, obtain finished product premixing auxiliary material.
Further, after spraying is dry, also can further to the particle appearance of premixing auxiliary material, modify.
Further, adopt fluid bed one step comminution granulation, concrete mode is: the material obtaining after spraying is dry is placed in fluid bed, adopts water as solvent, carries out boiling granulating, is dried, sieves, and obtains finished product.Because the dried material major part of spraying has been the spherical structure of porous, thus in follow-up modification, needn't excessive grooming, it is suitable that the time of pelletize should be controlled.In addition, in industry, fluidized bed airflow powerful (can arrive 0.8MPa during maximum), also larger to the destructiveness of material, therefore, the drying time of this step should not oversize (reach prescription with moisture and be advisable, as 1 hour): the time is oversize, the form of destruction material that can be in a big way.The prilling of fluid bed varies in weight according to material, selects not isometric fluid bed.As the material to about 100kg, can select container is the fluid bed of 450 liters.
Water in described step (1), preferably purified water.Described purified water, the water of the hyoscine making through the way of distillation, ion exchange, hyperfiltration or other suitable methods for drinking water,, containing any additive, is not existing conventional products in prior art.According to < < Chinese Pharmacopoeia > > version in 2010, two appendix XIJ carry out limit test of microbe, show, with the water ratio not boiling, the microorganism total amount of boiling process is obviously less than the technique of not boiling.
Premixing auxiliary material of the present invention is different from the premixing auxiliary material that gone on the market in prior art or other premixing auxiliary material.Premixing auxiliary material of the present invention has comprised filler, disintegrating agent, binding agent and wetting agent, and polyvidone, as binding agent, for taking into account cohesive, does not affect the dissolution characteristic of medicine simultaneously, selects low viscous polyvidone in premixing auxiliary material, as BASF AG produces
k30 or American I SP company produce
k30.Glyceryl Behenate is a kind of adjuvant newly developed, when high concentration, can be used as slow-release material, low concentration finds it is good lubricant by preparing premixing auxiliary material, because Glyceryl Behenate is that (behenic acid is n-docosane acid for the mixing of three kinds of materials, Glyceryl Behenate is single, two, the mixture of three Glyceryl Behenates, account for respectively 18%, 52% and 28%, be for No. CAS 30233-64-8, 91052-55-0, 18641-57-1), therefore, in premixing auxiliary material, changed its original form that exists, not to exist with single microgranule, but be evenly distributed on composite particles, this is different from conventional alkaline magnesium stearate lubricant.Microcrystalline Cellulose is water-fast filler, before and after spraying is dry, the form of Glyceryl Behenate material has a greater degree of improvement to the friction resistant ability of microcrystalline Cellulose (slice power during tabletting), and has compared with Important Relations with the particle diameter of initial microcrystalline Cellulose.And mannitol, lactose are water-soluble filler, the form of Glyceryl Behenate starting material, particle diameter, particle size distribution show by microscope figure the obvious relation of not observed to premixing auxiliary material finished product.
Premixing auxiliary material containing polyvidone and Glyceryl Behenate of the present invention, good fluidity, compressibility is strong, lubricant effect is good, always mixing homogeneity, medicament contg, tablet hardness etc. are changed with the prolongation of doing time, is easy to amplify, indices is better than the adjuvant of physical mixed, reduced the uncontrollable factor of technique, be conducive to large production, this premixing auxiliary material can be used in the direct compression of tablet or the fill of capsule.
In the preparation technology of premixing auxiliary material of the present invention, after filler, disintegrating agent, polyvidone and Glyceryl Behenate mix, then be fed in container, this is to consider the single caking of easily assembling while adding material, and the time few when time is many, the lower step high speed of impact stirs.If four kinds of adjuvants feed intake separately, through test, to find, Glyceryl Behenate at the same temperature, needs the long period just can scatter, and mix rear input, does not observe obvious caking.In addition, while need to stir to feed intake when feeding intake, object is to avoid material in blending process to form bulk and assemble.Mannitol, lactose, polyvidone are soluble in water, do not have the problem of aqueous slurry incomplete mixing, but owing to having added Glyceryl Behenate, in technique, water temperature need to be controlled at 70～85 ℃.The speed of the number feeding intake, the height of water temperature and high-speed stirred, the uniformity after pretty brightness impact is stirred, particularly when preparation contains the premixing auxiliary material of microcrystalline Cellulose.
Inventor be take premixing auxiliary material of the present invention as test group, the adjuvant that the simple physical of take is mixed is matched group, carried out Performance Ratio, from powder fluidity, particle size distribution, carr's index, tensile strength and these aspects of frangible degree, evaluate, evaluation result shows: premixing auxiliary material of the present invention has following characteristics:
(1) powder fluidity is good: be embodied in and be less than 35 ° angle of repose (AngleofRepose, θ), and be less than other matched groups.
(2) meet preparation requirement disintegration: during 45min, stripping is more than 75%, and stripping curve shows, the difference between each sheet is less.
(3) even particle size distribution: particle size distribution is more even, is better than put one of physical mixed; There is good lustrous surface, simultaneously good through tablet friability somascope test physical strength, be difficult for friability.
(4) mix the content uniformity that does not affect material: at material, always sneak out in journey, crude drug (API) only needs and premixing auxiliary material directly mixes, and do not need additional lubricant, and lubricant is uniformly distributed again, therefore saved incorporation time, also do not affected uniformity of dosage units.By comparison, the adjuvant mixing for the simple physical of material, the consumption of Glyceryl Behenate is less, and time more required than crude drug mix homogeneously time that its mix homogeneously needs is long possibly, causes uneven distribution, causes crude drug uniformity decreases simultaneously.
(5) mix the hardness that does not affect tabletting: hardness when incorporation time length does not affect tabletting, the compressibility of material still shows well.And for lubricants such as magnesium stearate, be characterized in that incorporation time is long, and in the outside of material particles, formed thin film, affected release or the stripping of medicine.
(6) can reduce sheet weight: for the tablet of same amount, the consumption that adopts premixing auxiliary material to use is less, and each adjuvant summation during physical mixed is more.May be because spraying dry after, the hole of material increases rapidly, and shows as in appearance spherically, under uniform amt, its specific area is several times or the decades of times under physical mixed, therefore, reaches identical result of extraction, the consumption that adjuvant carrier needs is less.
(7) adopt the adjuvant of " settling at one go " of the present invention can simplify the technological process of production, reduce human cost, shorten workman's labor time, reduce personal error, increase work efficiency and create more social value, these be GMP actively advocate with needs.
(8) reduce research and development difficulty, shorten the research and development time.In common research and development, need to screen filler, disintegrating agent, binding agent and four variable different proportions of lubricant, find out best proportioning, its screening process is time-consuming, effort, costly, and premixing auxiliary material provided by the invention only has a variable, research and development difficulty greatly reduces, therefore, saved the R&D cycle, be conducive to industry and promote.
Accompanying drawing explanation
Fig. 1: be tablet hardness-compression force relation that under 15rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 2: be tablet tensile strength-compression force relation that under 15rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 3: be tablet hardness-compression force relation that under 25rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 4: be tablet tensile strength-compression force relation that under 25rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 5: be tablet hardness-compression force relation that under 35rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 6: be tablet tensile strength-compression force relation that under 35rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 7: be tablet slice power-compression force relation that under 15rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 8: be tablet slice power-compression force relation that under 25rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Fig. 9: be tablet slice power-compression force relation that under 35rpm prepared by embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant at rotating speed.
Figure 10: the dissolution of warevan tablet.
Figure 11: the dissolution of Nifedipine Tablets.
Figure 12: the dissolution of Captopril tablets.
Figure 13: the dissolution of Allopurinol Tablets.
The specific embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1 prepares premixing auxiliary material
In retort, add purified water 900kg, heated and boiled 30min, at 70～85 ℃, insulation, standby.Get respectively microcrystalline Cellulose 95kg, low-substituted hydroxypropyl cellulose 9.6kg, polyvidone 1kg and Glyceryl Behenate 0.7kg, employing side's cone blender first mixes rear three 10 minutes, add again microcrystalline Cellulose to mix 10 minutes, after taking out, while stirring, put in retort, after finishing, high-speed stirred (400rpm) 30 minutes, when stirring, maintain the temperature at 80 ℃, make serosity, adopt spray dryer, under 120 ℃ of conditions of temperature, spraying is dry, atomizing pressure is 1～1.5MPa, slurry flow rate is 1.5～3kg/ minute, obtain finished product 97kg, yield is 91.3%.
Embodiment 2 prepares premixing auxiliary material
In retort, add purified water 580kg, heated and boiled 30min is incubated standby at 70～85 ℃.Get respectively microcrystalline Cellulose 95kg, cross-linking sodium carboxymethyl cellulose 2kg, polyvidone 1kg and Glyceryl Behenate 0.5kg, employing side's cone blender first mixes rear three 5 minutes, add again microcrystalline Cellulose to mix 20 minutes, after taking out, while stirring, put in retort, after finishing, high-speed stirred (300rpm) 40 minutes, when stirring, maintain the temperature at 80 ℃, make serosity, adopt spray dryer, under 115 ℃ of conditions of temperature, spraying is dry, atomizing pressure is 1～1.5MPa, slurry flow rate is 1～2kg/ minute, obtain finished product 91kg, yield is 92.3%.
Embodiment 3 prepares premixing auxiliary material
In retort, add purified water 1100kg, heated and boiled 30min is incubated standby at 70～85 ℃.Get respectively microcrystalline Cellulose 102kg, carboxymethyl starch sodium 8kg, polyvidone 2kg and Glyceryl Behenate 1kg, employing side's cone blender first mixes rear three 10 minutes, add again microcrystalline Cellulose to mix 10 minutes, after taking out, while stirring, put in retort, after finishing, high-speed stirred 60 minutes, when stirring, maintain the temperature at 75 ℃, make serosity, adopt spray dryer, under 110 ℃ of conditions of temperature, spraying is dry, atomizing pressure is 1～1.5MPa, slurry flow rate is 1～3kg/ minute, obtains finished product 105kg, and yield is 92.9%.
Embodiment 4 prepares premixing auxiliary material
In retort, add purified water 650kg, heated and boiled 30min is incubated standby at 70～85 ℃.Get respectively lactose 110kg, low-substituted hydroxypropyl cellulose 10kg, polyvidone 3.5kg and Glyceryl Behenate 2kg, employing side's cone blender first mixes rear three 5 minutes, add again microcrystalline Cellulose to mix 10 minutes, after taking out, while stirring, put in retort, after finishing, high-speed stirred (400rpm) 60 minutes, when stirring, maintain the temperature at 70 ℃, make serosity, adopt spray dryer, under 120 ℃ of conditions of temperature, spraying is dry, atomizing pressure is 1～1.5MPa, slurry flow rate is 1～2kg/ minute, product 107kg in the middle of obtaining, yield is 85.6%.By middle product as in fluid bed, adopt water as solvent, it is 65～75 ℃ that inlet temperature is set, the flow velocity of take carried out boiling granulating as 0.5～1.0kg/ minute, granulate 8 minutes, at 65～75 ℃, be dried to moisture≤2.0%, be dried rear timely collection, and be loaded in double-layer seal bag, obtain finished product 104kg.
In retort, add purified water 950kg, heated and boiled 30min is incubated standby at 70～85 ℃.Get respectively mannitol 105kg, polyvinylpolypyrrolidone 2kg, polyvidone 3kg and Glyceryl Behenate 2.5kg, employing side's cone blender first mixes rear three 5 minutes, add again microcrystalline Cellulose to mix 10 minutes, after taking out, while stirring, put in retort, after finishing, high-speed stirred (400rpm) 60 minutes, when stirring, maintain the temperature at 70 ℃, make serosity, adopt spray dryer, under 105 ℃ of conditions of temperature, spraying is dry, atomizing pressure is 1～1.5MPa, slurry flow rate is 2～3kg/ minute, product 101kg in the middle of obtaining, and yield is 89.8%.By middle product as in fluid bed, adopt water as solvent, it is 65～75 ℃ that inlet temperature is set, the flow velocity of take carried out boiling granulating as 0.5～1.0kg/ minute, granulate 10 minutes, at 65～75 ℃, be dried to moisture≤2.0%, be dried rear timely collection, and be loaded in double-layer seal bag, obtain the about 98kg of finished product.
Embodiment 6 prepares premixing auxiliary material
In retort, add purified water 910kg, heated and boiled 30min is incubated standby at 70～85 ℃.Get respectively microcrystalline Cellulose 30kg, lactose 80kg, low-substituted hydroxypropyl cellulose 9kg, polyvidone 4kg and Glyceryl Behenate 2kg, employing side's cone blender first mixes rear three 5 minutes, add again microcrystalline Cellulose to mix 10 minutes, after taking out, while stirring, put in retort, after finishing, high-speed stirred (400rpm) 30 minutes, when stirring, maintain the temperature at 80 ℃, make serosity, adopt spray dryer, under 110 ℃ of conditions of temperature, spraying is dry, atomizing pressure is 1～1.5MPa, slurry flow rate is 2～3kg/ minute, product 114kg in the middle of obtaining, yield is 91.2%.By middle product as in fluid bed, adopt water as solvent, it is 65～75 ℃ that inlet temperature is set, the flow velocity of take carried out boiling granulating as 0.5～1.0kg/ minute, granulate 5 minutes, at 65～75 ℃, be dried to moisture≤3.0%, be dried rear timely collection, and be loaded in double-layer seal bag, obtain the about 112kg of finished product.
In embodiment 1～6, microcrystalline Cellulose is used the microcrystalline Cellulose PH102 of FMC Corp., and lactose is used 200 order lactose of Shanghai Huamao Pharmaceutical Co, mannitol is used the common mannitol of Nanning pharmaceutical Co. Ltd, and polyvidone is used German BASF AG
k30, cross-linking sodium carboxymethyl cellulose is used German JRS company
carboxymethyl starch sodium is used German JRS company
low-substituted hydroxypropyl cellulose is used the LH-21 of Japan XINYUE, and polyvinylpolypyrrolidone is used the polyplasdoneXL-10 of American I SP company, and Glyceryl Behenate is used French Gattefosse company
888ATO.
The adjuvant of comparative example's 1～6 physical mixed
Comparative example 1～6 supplementary product kind, consumption (as shown in table 1) used is corresponding with embodiment 1～6 respectively, institute's difference is that preparation technology is different: comparative example 1～6th, the physical mixed of adjuvant: first disintegrating agent is mixed to 10 minutes with polyvidone and Glyceryl Behenate, then add microcrystalline Cellulose to mix 20 minutes.
Table 1 comparative example 1～6 material proportion table
Test is the physical property of explanation premixing auxiliary material, premixing auxiliary material prepared by the embodiment 1～6 of take is test group, adjuvant prepared by the comparative example 1～6 of take is matched group, carried out the detection of the aspects such as powder fluidity, particle size distribution, carr's index, tensile strength and frangible degree, at the adjuvant mixing with simple physical aspect some, contrast simultaneously, as follows:
Powder fluidity: the mobility of powder body is larger on the weight differential of the preparations such as granule, capsule, tablet and normal operating impact, for direct compression, more requires to have higher mobility.The mobility of powder body cannot be expressed with single characteristic value, represents conventional angle of repose (AngleofRepose, θ).Refer to free inclined-plane and the formed maximum angular of horizontal plane of powder body accumulation horizon angle of repose.Angle of repose is less, and frictional force is less, and mobility is better, and good fluidity while it is generally acknowledged θ≤30 ° can meet the need for liquidity in production process during θ≤40 °, and data see the following form 2.
Bulk density, tapped density, carr's index: compressibility and the filling capacity of carr's index reflection powder.The powder compressibility that carr's index is large is good, but poor fluidity; Powder fillibility and good fluidity that carr's index is little, but poor compressibility.Generally, when carr's index is between 15%～25% time, the mobility of powder and compressibility all can reach the requirement of rotary tablet machine direct powder compression.Adopt BT-1000 powder body overall characteristic analyzer, measure respectively bulk density and the tapped density of premixing auxiliary material and simple physical mixture, according to formula: (1-bulk density/tapped density) * 100%, calculates carr's index.The results are shown in following table 2.As can be seen from Table 2, the angle of repose of premixing auxiliary material, mobility was better all in 35 °.Bulk density, tapped density and the carr's index of contrast premixing auxiliary material and physical mixed adjuvant, the density of premixing auxiliary material is higher, and carr's index is all within the scope of 15-25%, and this demonstrates premixing auxiliary material is a kind of good vertical compression adjuvant.
Table 2 embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant mobility result
Particle size distribution: adopt particle size analyzer.Particle size distribution is more even, and during tabletting, tablet weight variation is less, and this is particularly important to small dose drug.The particle size distribution comparative result of premixing auxiliary material and physical mixed adjuvant refers to following table 3.As can be seen from Table 3, the particle size distribution of premixing auxiliary material is more even, and while indicating tabletting, tablet weight variation is less, and drug release may be more even.
Table 3 embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant particle size distribution result
| ? | > 140 orders | 140-120 order | 120-100 order | 100-80 order | 80-60 order | < 60 orders |
| Embodiment 1 | 1.40 | 3.80 | 94.40 | 0.40 | 0.00 | 0.00 |
| Comparative example 1 | 5.00 | 56.67 | 22.57 | 9.78 | 4.95 | 1.03 |
| Embodiment 2 | 4.20 | 6.70 | 84.45 | 2.90 | 1.75 | 0.00 |
| Comparative example 2 | 8.80 | 49.50 | 22.10 | 5.90 | 10.70 | 3.00 |
| Embodiment 3 | 1.00 | 8.70 | 84.50 | 4.10 | 1.70 | 0.00 |
| Comparative example 3 | 10.50 | 53.50 | 10.40 | 16.70 | 8.00 | 0.90 |
| Embodiment 4 | 2.60 | 6.50 | 88.00 | 2.80 | 0.10 | 0.00 |
| Comparative example 4 | 2.20 | 31.70 | 25.50 | 31.20 | 6.80 | 2.60 |
| |
1.00 | 4.60 | 5.70 | 87.30 | 1.40 | 0.00 |
| Comparative example 5 | 3.50 | 38.70 | 44.90 | 6.60 | 3.20 | 3.10 |
| Embodiment 6 | 4.20 | 7.40 | 85.70 | 2.10 | 0.60 | 0.00 |
| Comparative example 6 | 1.80 | 67.30 | 12.50 | 7.20 | 7.00 | 4.20 |
Tensile strength: tensile strength is a kind of measurement index of powder compressibility and formability.Concrete assay method is: after tabletting 24h, measure hardness (fc, units/kg/N) and the size (diameter d and thickness h, unit is cm) of tablet, utilize
calculate tensile strength (σ
t, units MPa).After powder is in blocks under identical compression force, the size of tensile strength can embody the formability of powder.Tensile strength is larger, and formability is better.Tabletting on Fette2901 type rotary tablet machine, adopts the circular scrobicula grinding tool that diameter is 8mm to carry out tabletting, and premixing auxiliary material self and corresponding physics adjuvant do not add active component before tabletting.Setting sheet is heavily 200mg, sets tablet machine rotating speed and is respectively 15rpm, 25rpm and 35rpm, and setting tabletting pressure is 5KN, 10KN, 15KN.Measure the hardness after tabletting, measure the thickness of tablet simultaneously, investigate the relation between evaluation hardness-compression force, and the relation between tensile strength-compression force, as shown in Fig. 1～6.
Lubricant effect is evaluated: owing to containing lubricant in this premixing auxiliary material, its lubricity is also to investigate the emphasis of this premixing auxiliary material.Slice power one highest wisdom, below 200N, illustrates that adjuvant is good to the lubricity of medicine.Take simvastatin as model drug, by simvastatin and premixing auxiliary material or physical mixture mix homogeneously, (wherein the weight of simvastatin is 10%, during physical mixed, in ratio corresponding to premixing auxiliary material, add, always be mixed is 10 minutes), selecting of tablet machine model and mould, the setting that rotating speed, pressure, sheet weigh is tested with above-mentioned " tensile strength ".Be recorded in the slice power under different rotating speeds, pressure condition, result is as shown in Fig. 7～9.
Frangible degree: frangible degree can reflect with friability.Friability refer to granule be subject to mechanical stress and process during (rolling, vibration, fluidisation etc.), there is the minimizing of quality aspect in granule or granular debris.Friability is lower, illustrates that granule is more not yielding or is damaged.On the other hand, not being damaged to a certain extent, illustrates that the loss that granule can be subject in later stage operating process is less, is conducive to mix and the operation such as tabletting.Adopt 7.0 editions B methods of European Pharmacopoeia, adopt this device of oscillation device, the glass container that comprises a 105ml, holds granule or the micropill of examine, bears level vibration.Frequency of oscillation and persistent period can constantly change.Frequency of oscillation can be adjusted by graduated disc in the scope of 0-400 beat/min.Persistent period can arrange within the scope of second at 0-9999.By screening, remove fine grained (screen size is 355 μ m or other any suitable sieves) and take about 10.00g granule, put in glass container.Container is arranged on oscillation device.Hard granule or micropill adopt higher-order of oscillation 240s, soft granule or micropill adopt low frequency (as 140 numbers of oscillation/minute) vibration 120s.Screening (355 μ m, or above used same sieve), and take granule or micropill weight.Test 3 duplicate samples, calculate its meansigma methods.Formula is as follows:
T
1loss on drying percentage ratio before=test (meansigma methods of measuring for 2 times);
T
2loss on drying percentage ratio after=test (meansigma methods of measuring for 2 times);
M
1before=test, the quality of granule, take g as unit;
M
2after=test, the quality of granule, take g as unit;
Due to the comparative example of the physical mixed mixture that is non-homogeneous, thus only premixing auxiliary material has been carried out testing (n=3), in Table 4.
The swellability result of table 4 embodiment 1～6 premixing auxiliary material and comparative example's 1～6 physical mixed adjuvant
| ? | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
Embodiment 6 |
| Friability (%) | 0.11 | 0.19 | 0.16 | 0.15 | 0.10 | 0.08 |
Single angle from adjuvant, from the experiment of several aspects such as particle size distribution above, carr's index, hardness-pressure, tensile strength-pressure, frangible degree, in embodiment 1～6, the premixing auxiliary material of preparation is better premixing auxiliary material.But adjuvant finally need to be applied in preparation, therefore the quality of adjuvant finally be take the quality evaluation of preparation, be standard.For investigating the impact of premixing auxiliary material of the present invention on different biological agent categorizing systems (BCS) medicine, select respectively BCSI, BCSII, BCSIII, each medicine of BCSIV class to study different premixing auxiliary materials, measure the dissolution of medicine, as described in embodiment 7～10.
Embodiment 7
Selection be take warfarin sodium as BCSI(highly dissoluble, high osmosis class) model drug, adopt the premixing auxiliary material of same amount and the contrast of physical mixed adjuvant to investigate its release behavior.The circular scrobicula grinding tool that all to use diameter be 6mm, C & C800 rotary tablet machine carries out tabletting, and Hardness Control is at 3～5kp.Dissolution determination method is shown in two the 276th page of < < Chinese Pharmacopoeia > > version in 2010,45 minutes dissolutions of pharmacopeia regulation must not be less than 70%, separately get and within 15,30 minutes, are measured in the same method to obtain release behavior.The consumption of adjuvant and principal agent is in Table 5, and dissolution the results are shown in Figure 10.As can be seen from Figure 10, no matter be 1. premixing auxiliary material or physical mixed adjuvant, different adjuvants affects to the stripping meeting of warfarin sodium, but 45 minutes time, stripping is all higher, has surpassed 70% setting.On the other hand, for BCSI medicine, medicine is subject to the impact of adjuvant smaller.2. premixing auxiliary material is due to process physical modification, and dissolution is all high than unmodified physical mixed material dissolution.3. different adjuvants differed greatly in the time of 15 minutes, in the time of 30 minutes, obviously dwindled, and in the time of 45 minutes, difference is less, explanation is along with the prolongation of time, and medicine progressively diffuses out from adjuvant, for adjuvant soluble in water, as the adjuvant that contains lactose and mannitol, stripping is faster.
The prescription of table 5 warevan tablet
| Specification: 5mg/ sheet | Prescription two (premixing auxiliary material is dry mixed) | Prescription two (physical mixed adjuvant, is dry mixed) |
| Supplementary material source | 1000 consumptions (g) | 1000 consumptions (g) |
| |
5 | 5 |
| The premixing auxiliary material of embodiment 1 gained | 95 | — |
| Comparative example 1 mixed accessories | — | 95 |
| The premixing auxiliary material of embodiment 2 gained | 95 | — |
| Comparative example 2 mixed accessories | — | 95 |
| The premixing auxiliary material of embodiment 3 gained | 95 | — |
| Comparative example 3 mixed accessories | — | 95 |
| The premixing auxiliary material of embodiment 4 gained | 95 | — |
| Comparative example 4 mixed accessories | — | 95 |
| The premixing auxiliary material of |
95 | — |
| Comparative example 5 mixed accessories | — | 95 |
| The premixing auxiliary material of embodiment 6 gained | 95 | — |
| Comparative example 6 mixed accessories | — | 95 |
Embodiment 8
In the present embodiment, select to take nifedipine as BCSII(low-solubility, high osmosis class) model drug, adopt the premixing auxiliary material of same amount and the contrast of physical mixed adjuvant to investigate its release behavior.The circular scrobicula grinding tool that all to use diameter be 8mm, C & C800 rotary tablet machine carries out tabletting, and Hardness Control is at 5～8kp.Dissolution determination method is shown in two the 944th page of < < Chinese Pharmacopoeia > > version in 2010,60 minutes dissolutions of pharmacopeia regulation must not be less than 75%, separately get and within 15,30,45 minutes, are measured in the same method to obtain release behavior.The consumption of adjuvant and principal agent is in Table 6, and dissolution the results are shown in Figure 11.As can be seen from Figure 11, the dissolution of tablet prepared by premixing auxiliary material is all higher than the tablet of physical mixed on each time, and in addition, the difference of adjuvant can obviously affect the release of medicine, even the premixing auxiliary material of embodiment 1～6, its release behavior also has certain difference.
The prescription of table 6 Nifedipine Tablets
| Specification: 10mg/ sheet | Prescription two (premixing auxiliary material is dry mixed) | Prescription two (physical mixed adjuvant, is dry mixed) |
| Supplementary material source | 1000 consumptions (g) | 1000 consumptions (g) |
| |
10 | 10 |
| The premixing auxiliary material of embodiment 1 gained | 185 | — |
| Comparative example 1 mixed accessories | — | 185 |
| The premixing auxiliary material of embodiment 2 gained | 185 | — |
| Comparative example 2 mixed accessories | — | 185 |
| The premixing auxiliary material of embodiment 3 gained | 185 | — |
| Comparative example 3 mixed accessories | — | 185 |
| The premixing auxiliary material of embodiment 4 gained | 185 | — |
| Comparative example 4 mixed accessories | — | 185 |
| The premixing auxiliary material of |
185 | — |
| Comparative example 5 mixed accessories | — | 185 |
| The premixing auxiliary material of embodiment 6 gained | 185 | — |
| Comparative example 6 mixed accessories | — | 185 |
Embodiment 9
In the present embodiment, select to take captopril as BCSIII(highly dissoluble, hypotonicity class) model drug, adopt the premixing auxiliary material of same amount and the contrast of physical mixed adjuvant to investigate its release behavior.The circular scrobicula grinding tool that all to use diameter be 5.5mm, C & C800 rotary tablet machine carries out tabletting, and Hardness Control is at 3～5kp.Dissolution determination method is shown in two the 131st page of < < Chinese Pharmacopoeia > > version in 2010,20 minutes dissolutions of pharmacopeia regulation must not be less than 80%, separately get and within 5,10,15 minutes, are measured in the same method to obtain release behavior.The consumption of adjuvant and principal agent is in Table 7, and dissolution the results are shown in Figure 12.As can be seen from Figure 12, different adjuvants produces certain impact to preparation, but the dissolution of the tablet that in the time of 20 minutes prepared by premixing auxiliary material is all higher than limit, and tablet prepared by the adjuvant of physical mixed has, reached limit, what have does not have, and illustrates that premixing auxiliary material is obviously better than physical mixed adjuvant.
The prescription of table 7 Captopril tablets
| Specification: 12.5mg/ sheet | Prescription two (premixing auxiliary material is dry mixed) | Prescription two (physical mixed adjuvant, is dry mixed) |
| Supplementary material source | 1000 consumptions (g) | 1000 consumptions (g) |
| Captopril | 12.5 | 12.5 |
| The premixing auxiliary material of embodiment 1 gained | 60 | — |
| Comparative example 1 mixed accessories | — | 60 |
| The premixing auxiliary material of embodiment 2 gained | 60 | — |
| Comparative example 2 mixed accessories | — | 60 |
| The premixing auxiliary material of embodiment 3 gained | 60 | — |
| Comparative example 3 mixed accessories | — | 60 |
| The premixing auxiliary material of embodiment 4 gained | 60 | — |
| Comparative example 4 mixed accessories | — | 60 |
| The premixing auxiliary material of |
60 | — |
| Comparative example 5 mixed accessories | — | 60 |
| The premixing auxiliary material of embodiment 6 gained | 60 | — |
| Comparative example 6 mixed accessories | — | 60 |
In the present embodiment, select to take allopurinol as BCSIV(low-solubility, hypotonicity class) model drug, adopt the premixing auxiliary material of same amount and the contrast of physical mixed adjuvant to investigate its release behavior.The circular scrobicula grinding tool that all to use diameter be 9mm, C & C800 rotary tablet machine carries out tabletting, and Hardness Control is at 6～9kp.Dissolution determination method is shown in two the 352nd page of < < Chinese Pharmacopoeia > > version in 2010,45 minutes dissolutions of pharmacopeia regulation must not be less than 70%, separately get and within 15,30 minutes, are measured in the same method to obtain release behavior.The consumption of adjuvant and principal agent is in Table 8, and dissolution the results are shown in Figure 13.As can be seen from Figure 13 the tablet that, prepared by different adjuvants is very large to the release difference of medicine.For realizing at the appointed time drug dissolution, reach the limitation, should screen prescription, adjust kind and the consumption of premixing auxiliary material.It can also be seen that, the premixing auxiliary material that embodiment 6 obtains, after being prepared into tablet, dissolution is the highest, illustrates that this premixing auxiliary material is conducive to the stripping of medicine most.
The prescription of table 8 Allopurinol Tablets
| Specification: 0.1g/ sheet | Prescription two (premixing auxiliary material is dry mixed) | Prescription two (physical mixed adjuvant, is dry mixed) |
| Supplementary material source | 1000 consumptions (g) | 1000 consumptions (g) |
| |
100 | 100 |
| The premixing auxiliary material of embodiment 1 gained | 145 | — |
| Comparative example 1 mixed accessories | — | 145 |
| The premixing auxiliary material of embodiment 2 gained | 145 | — |
| Comparative example 2 mixed accessories | — | 145 |
| The premixing auxiliary material of embodiment 3 gained | 145 | — |
| Comparative example 3 mixed accessories | — | 145 |
| The premixing auxiliary material of embodiment 4 gained | 145 | — |
| Comparative example 4 mixed accessories | — | 145 |
| The premixing auxiliary material of |
145 | — |
| Comparative example 5 mixed accessories | — | 145 |
| The premixing auxiliary material of embodiment 6 gained | 145 | — |
| Comparative example 6 mixed accessories | — | 145 |
Therefore, as can be seen from the above results, premixing auxiliary material of the present invention is prepared into tablet at particle size distribution, mobility and lubricant effect and the medicine different with four classes and investigates the adjuvant that the many aspects such as its dissolution are all better than its physical mixed.The combination of filler, disintegrating agent, polyvidone and Glyceryl Behenate that this explanation originally provides produces a desired effect, can meet preparation production requirement, this implying premixing auxiliary material provided by the invention saving the preparation production time, raise labour efficiency, simplify production technology, improve the aspects such as GMP operation layout and play an important role.
Claims (6)
1. a premixing auxiliary material, it is characterized in that: by polyvidone, Glyceryl Behenate, and pharmaceutic adjuvant filler, disintegrating agent form, wherein, the weight ratio of filler, disintegrating agent, polyvidone and Glyceryl Behenate is: (80～98.5): (10～0.5): (5～0.5): (5～0.5).
2. a kind of premixing auxiliary material according to claim 1, is characterized in that: the weight ratio of described filler, disintegrating agent, polyvidone and Glyceryl Behenate is: (85～98): (10～0.5): (3～1): (2～0.5).
3. a kind of premixing auxiliary material according to claim 1 and 2, is characterized in that: described filler is selected from any in microcrystalline Cellulose, mannitol, lactose, or the mixture of any two or more compositions.
4. a kind of premixing auxiliary material according to claim 1 and 2, it is characterized in that: described disintegrating agent is selected from any in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, or the mixture of any two or more compositions.
5. the preparation technology of a kind of premixing auxiliary material described in any one in claim 1～4, is characterized in that: comprise the following steps:
(1) in container, pass into water, after heated and boiled, insulation is at 70～85 ℃, standby;
(2) filler, disintegrating agent, polyvidone and Glyceryl Behenate are mixed, mix, be then fed in container, 70～85 ℃ of insulation high-speed stirred 0.5～3 hour, become solid content and are 10～20% even aqueous slurry;
(3) above-mentioned aqueous slurry spraying is dry, controlling spray-dired temperature is 100～120 ℃; Collect the dried material of spraying, cross 60 mesh sieves, obtain premixing auxiliary material.
6. the preparation technology of a kind of premixing auxiliary material according to claim 5, is characterized in that: in described step (3), after spraying is dry, the material obtaining after spraying is dry is placed in fluid bed, adopt water as solvent, carry out boiling granulating, be dried, sieve, obtain finished product.
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| CN107569692A (en) * | 2017-09-01 | 2018-01-12 | 山东聊城阿华制药股份有限公司 | A kind of microcrystalline cellulose carmethose pre-mixing agent preparation method |
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| CN114306619A (en) * | 2022-01-29 | 2022-04-12 | 杭州沐源生物医药科技有限公司 | High-stability famciclovir composition and preparation method thereof |
| CN116270515A (en) * | 2023-02-09 | 2023-06-23 | 北京诚济制药股份有限公司 | Preparation method for improving quality of beraprost sodium tablet product |
| CN116270515B (en) * | 2023-02-09 | 2023-08-18 | 北京诚济制药股份有限公司 | Preparation method for improving quality of beraprost sodium tablet product |
| CN116459347A (en) * | 2023-06-07 | 2023-07-21 | 江苏西典药用辅料有限公司 | Mannitol and microcrystalline cellulose-based composite auxiliary material and preparation method thereof |
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