CN105168156A - Scutellaria baicalensis general flavone dispersible tablets and manufacturing method thereof - Google Patents

Scutellaria baicalensis general flavone dispersible tablets and manufacturing method thereof Download PDF

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CN105168156A
CN105168156A CN201510281988.8A CN201510281988A CN105168156A CN 105168156 A CN105168156 A CN 105168156A CN 201510281988 A CN201510281988 A CN 201510281988A CN 105168156 A CN105168156 A CN 105168156A
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radix scutellariae
total flavones
dispersible tablet
scutellariae total
gross weight
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CN105168156B (en
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张佳佳
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Zhejiang University ZJU
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Zhejiang Medical College
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Abstract

The present invention provides a manufacturing method of Scutellaria baicalensis general flavone dispersible tablets. The method comprises the steps of: A) stirring, mixing and granulating a Scutellaria baicalensis extract and accessory materials by a high-speed stirring molding machine, wherein the Scutellaria baicalensis general flavones in the Scutellaria baicalensis extract is no less than 45%, and the accessory material include a disintegrants containing CMS-Na and PVPP, a filler containing microcrystalline cellulose and TY, and lauryl sodium sulfate and NP; and B) drying the prepared granules, sieving through a screen of 30 mesh and finishing to obtain particles no more than 30 mesh, adding PVPP, silica powder and disintegrant, pressing to obtain Scutellaria baicalensis general flavone dispersible tablets, wherein the disintegrant comprises CMS-Na and PVPP.

Description

A kind of Radix Scutellariae total flavones dispersible tablet and manufacture method thereof
Technical field
The present invention relates to a kind of Radix Scutellariae total flavones tablet and manufacture method thereof, particularly relate to a kind of Radix Scutellariae total flavones dispersible tablet and manufacture method thereof.
Background technology
Radix Scutellariae [Scutellariabaicalensis] is the famous Chinese medicine of China, records the earliest in Shennong's Herbal, is classified as grass roots medicine top grade.The traditional Chinese medical science is thought, Radix Scutellariae has heat clearing and damp drying, eliminating fire and detoxication, hemostasis, antiabortive function, for dysentery, and cough due to lung-heat, calentura excessive thirst, jaundice, conjunctival congestion and swelling pain, accumulated heat haematemesis, frequent fetal movement, the diseases such as carbuncle furuncle.The effective ingredient of Radix Scutellariae is flavonoid, extracts at present and identify that the flavones ingredient of structure has tens kinds from Radix Scutellariae.Modern pharmacological research shows, skullcapflavone has antibacterial, blood pressure lowering, calmness, diuresis, function of gallbladder promoting, antiinflammatory, antiallergic action isoreactivity.Existing single preparation of baikal skullcap root dosage form has ordinary tablet, injection, nasal drop etc.
Dispersible tablet is the novel form occurred the eighties, refers to that meeting water disintegrate can form the non-packet garment piece of uniform Viscous suspension liquid rapidly.It has taking convenience, and absorb fast, the feature that bioavailability is high and untoward reaction is little, causes the concern of people day by day.Dispersible tablets of Chinese medicine so far there are no bibliographical information, there is no launch.This novel form of dispersible tablet is applied to the exploitation of Chinese medicine two kind new medicine by this research first, and expands disease treatment scope.Due to Radix Scutellariae effective site, as root is insoluble in water, making dispersible tablet can shorten disintegration time, can form uniform suspension, be conducive to the stripping of medicine after disintegrate, can be effective rapidly.Dispersible tablet not only can directly be swallowed, and also can drop in water and take after dispersion, especially be suitable for the patient of dysphagia.
One, the research overview of dispersible tablet
Tablet is one of current most widely used oral dosage form, it is accurate that it has dosage, steady quality, takes and preserves conveniently, the advantages such as mechanization production, the dissolution of usual tablet and bioavailability comparatively pill are good, but tablet also has many shortcomings, need in tablet to add some excipient, and pass through compression forming, dissolution comparatively powder and capsule slowly, affects its bioavailability sometimes; Some Tablet and Capsula agent often need take multi-disc (grain) more greatly or once due to volume, and to old man, child and the patient swallowing solid difficulty bring trouble.In this case, oral solution, suspensoid and Emulsion etc. are comparatively superior, but liquid preparation has again the shortcoming such as medicine stability difference and storing inconvenience.Over nearly 20 years, abroad develop and meet the non-packet garment piece that water can form rapidly uniform Viscous suspension liquid, be i.e. dispersible tablet (dispersibletablets).
1. the Recent Advances of dispersible tablet
It is reported, the external dispersible tablet gone on the market has aspirin dispersible tablet, aspirin phenacetin caffeine dispersible tablet, Sulfamethoxazole Compound dispersible tablet, piroxicam dispersible tablet, ranitidine dispersible tablet, paracetamol compound dispersible tablet, diclofenac dispersible tablet, mefenamic acid dispersible tablet, amoxicillin dispersible tablet, potentiation amoxicillin dispersible tablet, Benserazide dispersible tablet etc. more than 10 are planted.British Pharmacopoeia takes in aspirin dispersible tablet and compound sulfamethoxazole dispersible tablet in 1980 first.In addition, what go on the market successively also has narcotine, acyclovir, kind such as tens, amoxicillin etc.Chinese Pharmacopoeia version in 2000 has also taken in this one dosage type low temperature of dispersible tablet, two annex have worked out quality standard general rule with reference to British Pharmacopoeia 1993 editions: dispersible tablet checks by inspection technique disintegration, unless otherwise specified, in (20 ± 1) DEG C water, 3min should all disintegrates; Dispersing uniformity checks: get dispersible tablet 2, put jolting in 100ml water, should disperse completely and by No. 2 sieves; Dispersible tablet presses the inspection of dissolution test method, should conform with the regulations.National Drug Administration's approved new drug has clarithromycin, Azithromycin dispersible tablet etc.The unit of current domestic development dispersible tablet is a lot, declares and forms climax, as: roxithromycin dispersing tablet has 23 to declare, and clarithromycin has 27 to declare, and Azithromycin dispersible tablet reaches 58 to be declared.2. the feature of dispersible tablet
" British Pharmacopoeia " dispersible tablet formulation general rule specifies: dispersible tablet refers to meets the non-packet garment piece that water can form rapidly uniform Viscous suspension liquid.Dispersible tablet is 3min planted agent's disintegrate in the water of 19-21 DEG C, dispersible tablet is put into 100ml water, and after being stirred to complete disintegrate, granule should all by the screen cloth of 710 μm.
Dispersible tablet is mainly adapted to: 1. insoluble drug and have the medicine carbamazepine of bioavailability concerns water insoluble, and common formulations is tablet, and slowly and not exclusively, dissolution is difficult to reach pharmacopoeial requirements oral absorption.
2. the medicine that dosage is large: as acetaminophen, oxaprozine is large due to dosage, once often need take multi-disc, brings inconvenience to especially patient that is old, young and dysphagia.Dispersible tablet meets water disintegrate can form homogenous suspension rapidly, combines the advantage of tablet and liquid preparation, and avoids its shortcoming.Dispersible tablet is not suitable for the medicine that toxic and side effects is comparatively large, safety coefficient is lower and soluble in water, and therefore the exploitation of this kind of dosage form should be selectable, and not every ordinary tablet all should make dispersible tablet into.
Dispersible tablet compares with effervescent tablet: water put into by dispersible tablet and effervescent tablet all can disintegrate within 3min, unlike, form homogenous suspension after dispersible tablet disintegrate, effervescent tablet forms solution; Do not need effervescent (as carbonate and solid organic acid) and water soluble adjuvant in the prescription of dispersible tablet, preparation technology is identical with general non-packet garment piece; Do not need the gentle relative humidity in control room; Take after can disperseing in water or swallow, chewing clothes.It can thus be appreciated that dispersible tablet has more advantage than effervescent tablet.
Dispersible tablet and ordinary tablet, the comparing of capsule: (1) dispersible tablet can to disperse and by the screen cloth of 710 μm, therefore absorb fast, bioavailability is high, suitable with oral suspensions in 3 minutes in (20 ± 1) DEG C water in disintegrate.Compared with ordinary tablet, capsule, the advantage of dispersible tablet be 1. disintegrate and stripping rapid.The dissolution t of aspirin dispersible tablet 50=1.161min, t d=2.109min, the dissolution t of amoxicillin dispersible tablet 50=1.62min, t d=2.46min, all considerably beyond the general tablet of this medicine.2. bioavailability is high, suitable with oral suspensions.Two chlorine aromatic acid dispersible tablet studies its relative bioavailability with 12 healthy volunteers together with enteric coatel tablets.Find that the blood medicine peak time of dispersible tablet shifts to an earlier date 1.5-4.25h than enteric coatel tablets.And dispersible tablet upon administration 2-2.5h there is second peak value.Dispersible tablet starts to absorb soon, is applicable to acute pain patient.Amoxicillin dispersible tablet (500mg) is swallowed to 12 healthy volunteers, in water after dispersion oral with take suspensoid and capsule (equal 500mg) measures relative bioavailability.Result shows, dispersible tablet two kinds of oral ways and suspensoid are bioequivalent, and maximum blood concentration average than capsule is high by 33%, and area under curve (AUC) is high by 23%.
In table 1.
The bioavailability of table 1. amoxicillin different dosage form
Document is had to prepare ibuprofen dispersible tablet and the pharmacokinetics compared with marketed tablet in rabbit body and bioavailability, the C of result ibuprofen dispersible tablet and contrast medicine ibuprofen ordinary tablet maxbe respectively (9.79 ± 2.25) and (4.54 ± 1.50) μ g/ml; T maxbe respectively (0.27 ± 0.07) and (2.03 ± 0.53) h; t 1/2be respectively (6.65 ± 2.14) and (9.17 ± 4.38) h; AUC is respectively (94.11 ± 28.38) and (65.20 ± 18.38) μ ghml -1.The relative bioavailability of ibuprofen dispersible tablet and contrast medicine ibuprofen ordinary tablet is 164.11%.The bioavailability of ibuprofen dispersible tablet is significantly better than ordinary tablet.
(2) volume of conventional tablet, capsule is comparatively large, or once often need use multi-disc (grain), particularly gives old, young and swallows the patient that solid has difficulties and bring trouble.Dispersible tablet has disintegration rate can put into the rear oral advantage of water dispersion soon.Also can add sweeting agent and correctives.
3. the prescription of dispersible tablet and technique
The prescription composition of dispersible tablet, still forms full-bodied swelling adjuvant containing disintegrating agent and chance water except medicine.Control the key factor of dispersible tablet quality, one is select suitable adjuvant, and two is the granularities controlling medicine and adjuvant.(1) Formulation of discrete piece
1. diluent: microcrystalline Cellulose, mannitol and starch etc. can be adopted.
2. disintegrating agent: extensive use high-quality disintegrating agent in dispersible tablet.Identical health is summed up and is thought, the disintegrating agent of high-quality generally refers to that swellbility is greater than the adjuvant of 5ml/g.As carboxymethyl starch sodium (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone (PVPP), cross-linking sodium carboxymethyl cellulose (CMC-Na) etc.Generally do not select the starch that swellbility is less, microcrystalline Cellulose (MCC) and In Natural Silicate magnalium.Jia Yan etc. are in the prescription screening of Famotidine Dispersible Tablet, once detailed research was done to the consumption of carboxymethyl starch sodium, result shows: 1% ~ 2% on the impact of disintegrate not obvious (1.8-1.6min), 3% ~ 7% obviously accelerates disintegrate (0.8-0.7min), and 8% ~ 10% is delayed disintegrate (1.1-1.7min) on the contrary.Dispersible tablet can use a kind of or a kind of upper disintegrating agent.What use a kind of disintegrating agent has acetaminophen dispersible tablet, ibuprofen dispersible tablet, oxaprozine dispersible tablet, ketoprofen distribution sheet, acetaminophen dispersible tablet, compound recipe flu dispersible tablet etc.What use two or more has Famotidine Dispersible Tablet, nimesulide dispersible tablet, carbamazepine dispersible tablet etc.Disintegrating agent adds sometimes, sometimes Nei Jia and additional share.Additional disintegrating agent makes disintegration of tablet become coarse granule, plays and acts on first; Inside add, make the disintegrate of coarse granule secondary be fine grained.The disintegrating agent use amount of dispersible tablet is large, such as, enough with the consumption of 2% ~ 5% when CMS-Na, L-HPC are used alone in general tablet, and in dispersible tablet during several disintegrating agent use in conjunction often one just exceed this consumption.
3. swelling adjuvant: the swelling adjuvant of dispersible tablet can adopt guar gum, XANTHAN GUM, alginate, glucosan, amylum pregelatinisatum, polysaccharide, hydrophilic cellulose derivant is (as carboxymethylcellulose calcium, hydroxypropyl cellulose, hydroxypropyl emthylcellulose).Microcrystalline Cellulose is excellent filler and disintegrating agent, main as suspending agent in dispersible tablet, has disintegrate and suspending dual function concurrently.Amylum pregelatinisatum has good compressibility and mobility, has the effect promoting drug-eluting.
4. binding agent: the binding agent of dispersible tablet adopts hydrophilic adhesive mostly, as hypromellose (HPMC) and polyvidone (PVP), wherein applying is aqueous solution or the dilute alcohol solution of PVP more widely.Minority adopts starch slurry.To hydrophobic drug, make binding agent with PVP aqueous solution, be not only easy to evenly moistening, and hydrophobic drug particle surface can be made to become hydrophilic, be conducive to medicine disintegration and stripping.
5. surfactant: the employing of surfactant, significantly can promote the disintegrate of tablet and the stripping of medicine.Wherein that comparatively conventional is sodium lauryl sulphate (SLS).Cimetidine dispersible tablet is when adding Surfactant SDS, and dissolution rate is obviously accelerated.In table 2.
Table 2. sago for the SLS that to wake up in dispersible tablet on the percentile impact of drug-eluting
6. fluidizer: extensively adopt vapor-phase silicon dioxide and micropowder silica gel as fluidizer in dispersible tablet.Micropowder silica gel has good mobility, has larger absorption power to medicine, and its hydrophilic ability is strong, can accelerate the disintegrate of tablet, be conducive to the stripping of medicine when consumption is more than 1%.
7. lubricant: large multiplex hydrophilic lubricant in dispersible tablet, as Pulvis Talci or Pulvis Talci and magnesium stearate, castor oil hydrogenated share, or uses hydrophilic lubricant sodium stearyl fumarate, or uses soluble oil PEG-6000.
(2) preparation technology of place's sheet
For most of insoluble drug, the main fast process of its process in leaching drug absorption often, thus also directly decides the bioavailability of medicine.The key improving solid dosage forms Chinese medicine dissolution is surface area and its dissolubility of raising of increasing medicine.But along with the increase of specific surface area, the surface free energy of particle also increases thereupon, after acquiring a certain degree, free energy can lower automatically, and small-particle can reassemble, and hinders aggregation of particles on the contrary, and increases the wettability of particle surface, thus improves the stripping of medicine.
The method of granulating of dispersible tablet: the preparation technology of dispersible tablet is identical with general tablet.Therefore method of granulating is also identical.Conventional method of granulating has fluid-bed marumerization, High Shear Mixer Granulator and extruding to granulate.The granule almost spherical that fluid-bed marumerization is made, granularity is little and even, and granule has pore, and thus mobility and compressibility are all better, and drug-eluting might as well.Though extruding is granulated also can prepare dispersible tablet, granular mass is generally poor, affects disintegrate and the stripping of tablet.
Grain diameter requires: drug dissolution is relevant with grain diameter size, particle diameter is less, drug-eluting is faster, the wet grain of dispersible tablet requires at 1mm (18 order) below, dry granule granulate will at 0.6mm (30 order) below, even require at 0.305mm (about 50 order) below, this granule more than general tablet wants thin.For adapting to the requirement of high speed tabletting, the mobility of dispersible tablet granule will be got well, and generally all adding gas phase micropowder silica gel is fluidizer.
The advantages such as in sum, it is fast that dispersible tablet has drug-eluting speed, and the high and untoward reaction of bioavailability is little, employing conventional tablet production equipment can be produced, and is a kind of novel troche had a extensive future.In recent years, the pharmaceutic adjuvant that China puts into production has the adjuvant that the multiple disintegrating properties such as carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, amylum pregelatinisatum (pregelatinized Starch), sucrose fatty acid ester are good, also has I, II, III, No. IV other adjuvant such as acrylic resin and micropowder silica gel also to go on the market.We should discuss prior art, utilize state-owned adjuvant, develop new dispersible tablet, fundamentally solve the quality problems of old product.
Two, Radix Scutellariae research overview
Radix Scutellariae is the dry root of labiate Radix Scutellariae (ScutellariabaicalensisGeori).For conventional Chinese medicine, there are clearing away heat-fire, removing toxic substances, hemostasis, the effect such as antiabortive.For diseases such as damp-heat dysentery, cough due to lung-heat, calentura excessive thirst, jaundice, conjunctival congestion and swelling pain, accumulated heat haematemesis, frequent fetal movement, carbuncle furuncle.
Chemical composition: containing multiple flavone derivative, wherein mainly contains baicalin, wogonoside, oroxylin A glucuronide, baicalin, wogonin.Also containing neobaicalein I, II, oroxylin A, about 30 kinds of flavone compounds such as chrysin.In addition, still containing cupreol, benzoic acid, Radix Scutellariae fecula.
Component analysis: nearly ten years much research has been carried out to content determination of Baicalin method in Radix Scutellariae and compound preparation thereof.That wherein comparatively commonly uses has ultraviolet spectrophotometry, thin layer chromatography scanning and high performance liquid chromatography." Chinese Pharmacopoeia " (95 editions) have recorded content determination of Baicalin method, be adopt ultraviolet method in λ=278 ± 1nm place directly mensuration.Huang Laojin has made summary in Radix Scutellariae and compound preparation thereof to content determination of Baicalin method in Radix Scutellariae and compound preparation thereof.
Pharmacological research: pharmacologically confirmed that baicalin has the effects such as antibacterial, heat clearing away, blood pressure lowering, calmness, diuresis, function of gallbladder promoting, antiinflammatory antiallergic action, removing toxic substances.Baicalin is specificity 12-lipoxygenase inhibitor.Many to the pharmacological research of baicalin.The effective ingredient of Radix Scutellariae and the extraction of main component, research at home and technique attain maturation.Even if exist at patent medicine, utilize effective site, as preparation also its example not general of root or effective ingredient.Single Radix Scutellariae and compound preparation of baikal skullcap root all have antipyretic and antidote functions, doublely control acute cell and acute viral disease.Main dosage form is injection, and minority is tablet, capsule.Single preparation of baikal skullcap root has baicalin sheet, baicalin for injection liquid, baicalin injection, baicalin aluminium glue capsule etc.Compound preparation has SHUANGHUANGLIAN ZHUSHEYE, Fufang Huangqin Tablets by HPLC, Pollen Typhae injection, compound Radix Scutellariae injection, Yin Zhi Huang injection etc.
Summary of the invention
Main purpose of the present invention is the Radix Scutellariae total flavones tablet providing the rapid disintegrate of a kind of energy, stripping, absorption, onset, can swallow, chew clothes, containing sucking, also can add water and being dispersed into suspension, is applicable to old young patient and takes.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, wherein this Radix Scutellariae total flavones dispersible tablet is insoluble in water for Radix Scutellariae extract, but clinical treatment needs again to adopt the feature of quick-effective preparation to develop, this Radix Scutellariae total flavones dispersible tablet can make the rapid disintegrate stripping of medicine absorb, onset.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, wherein this Radix Scutellariae total flavones dispersible tablet is large for common Chinese tablet extractum volume, viscosity is strong, needed for tabletting, adjuvant is many, and the shortcoming that dose is large develops, and wherein this Radix Scutellariae total flavones dispersible tablet adopts Radix Scutellariae effective site, if root is principal agent raw material, adjuvant only accounts for 55%, patient's dose is greatly reduced, also reduces cost.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, wherein this Radix Scutellariae total flavones dispersible tablet can in 20 ± 1 DEG C of water in 3 minutes disintegrate formed homogenous suspension.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, wherein the Adding Way of the disintegrating agent of this Radix Scutellariae total flavones dispersible tablet is the disintegrating agent addition that interior addition and outer addition combine, thus make the tablet of this Radix Scutellariae total flavones dispersible tablet disintegrate can become coarse granule rapidly, and coarse granule is made again to be dispersed into rapidly fine grained formation homogenous suspension.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, and wherein the granularity of the Radix Scutellariae extract of this Radix Scutellariae total flavones dispersible tablet is not less than 100 orders, has good suspension ability to make this Radix Scutellariae total flavones dispersible tablet after disintegrate.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, and wherein the disintegrating agent of this Radix Scutellariae total flavones dispersible tablet and binding agent can ensure that the existing qualified hardness of tablet again can disintegrate in 3min.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, and wherein the disintegrating agent of this Radix Scutellariae total flavones dispersible tablet comprises PVPP and CMS-Na.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, and the Surfactant SDS wherein in this Radix Scutellariae total flavones dispersible tablet, can promote disintegrate and the stripping of tablet significantly.In addition, the concentration of Surfactant SDS is 0.54%, and it can significantly help Radix Scutellariae total flavones to dissolve.
Main purpose of the present invention is to provide a kind of Radix Scutellariae total flavones dispersible tablet, wherein the granulation of this Radix Scutellariae total flavones dispersible tablet is stirred by homogenizer and is granulated, the raw material making this Radix Scutellariae total flavones dispersible tablet carries out mixing, mediates, granulates in a turret vessel, granulate with traditional extruding and compare, there is province's operation, the feature such as easy to operate, quick.Fluidized bed granulation mixing, can be granulated, and drying completes in an equipment, and it is comparatively even that this legal system obtains grain graininess, and complete, good fluidity, has simplified operation.
The present inventor also further research and with the outward appearance of flavone dispersible tablet, hardness, disintegration, dispersed homogeneous degree for index, filter out the kind of prescription adjuvant, heating differential analysis method shows, selected adjuvant and medicine do not interact; With dissolution in vitro T 50for index, orthogonal experiment is adopted to be optimized prescription ratio of adjuvant; Methodological study is carried out to the content of determined by ultraviolet spectrophotometry Radix Scutellariae total flavones dispersible tablet Radix Scutellariae total flavones, Radix Scutellariae total flavones dispersible tablet In Vitro Dissolution test method and condition have been investigated; Dispersible tablet three kinds of different method of granulating are compared.
Experimental data shows herein, and the disintegrating agent of Radix Scutellariae total flavones dispersible tablet is carboxymethyl starch sodium and polyvinylpolypyrrolidone, and diluent is TY, and binding agent is NP (pyrrolidone), and determines the optimum proportioning of adjuvant; Determine the method for Radix Scutellariae total flavones content in determined by ultraviolet spectrophotometry Radix Scutellariae total flavones dispersible tablet, filter out the dissolution medium that 0.54% sodium lauryl sulphate is Radix Scutellariae total flavones dispersible tablet, establish dispersible tablet dissolution determination method and the method by computer Program extraction stripping parameter; Determine the process conditions adopting High Shear Mixer Granulator legal system for Radix Scutellariae total flavones dispersible tablet.Pilot scale setting-out shows, its preparation process meets large production requirement, and obtained Radix Scutellariae total flavones dispersible tablet disintegration time is lower than 3min, and after disintegrate, granule suspendible is even, and by 710 μm of screen clothes, reaches the requirement of dispersible tablet.
In addition, present invention also offers Radix Scutellariae total flavones dispersible tablet method of quality control, adopt HPLC method to measure the content of Radix Scutellariae B component in Radix Scutellariae total flavones dispersible tablet, and moisture, hardness, tablet weight variation, disintegration, dispersed homogeneous degree, dissolution and microorganism are controlled.Result shows, the response rate that the invention provides the Radix Scutellariae B component of method of quality control is 99.12%, and precision is high, show.Each inspection item all meets the requirements.The quality control standard of this dispersible tablet, can react the quality of said preparation, method is easy, practical comprehensively.
The present invention has also carried out preliminarily stabilised Journal of Sex Research: under three batch samples (two In Aluminium Foil Packing) being put respectively room temperature and 40 DEG C, relative humidity 75% condition, 0 month, January, February, March regularly checks, result shows that this preparation is stable, and it is 2 years that effect duration can fix tentatively.
By research, this invention also solves difficult point and key problem in technology prepared by dispersible tablets of Chinese medicine, substantially complete the research work of Chinese medicine two kind new medicine preparation process aspect.
Another object of the present invention there is provided a kind of employing Radix Scutellariae effective site, and if root is raw material, the Radix Scutellariae total flavones dispersible tablet that adjuvant use amount is few, can reduce drug manufacture cost and reduce Patient drug's use amount.
Another advantage of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet of the disintegrating agent containing high swelling property and provides its suitable amounts, to ensure that dispersible tablet Quick uniform disperses.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet adding appropriate surfactant, and to improve mobility of particle, the wettability of tablet, promotes the disintegrate of tablet and the stripping of medicine.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet with high-quality binding agent, and provides the preferable amount of binding agent.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet with high-quality filler, makes granule have higher flow ability, has thus both had height compressibility, and also can not produce larger elastic restoring force and cause loose pieces.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet manufacture method, and wherein the Adding Way of disintegrating agent selects inside and outside addition.Additionally make the rapid disintegrate of tablet become coarse granule, inside add and make coarse granule again be dispersed into rapidly fine grained to form homogenous suspension.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet manufacture method, and wherein Radix Scutellariae adopts 100 order fine powders, and make its stripping fast, after disintegrate, suspension ability is good.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet manufacture method, wherein adds Surfactant SDS, can promote disintegrate and the stripping of tablet significantly.Surfactant can reduce tablet surface tension force, increases the wettability of tablet, makes moisture borrow the capillarity of tablet, and rapid permeability, to label, accelerates disintegration rate, is conducive to increasing stripping.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet manufacture method, and wherein the method operation is simple, easy to operate, quick, Radix Scutellariae total flavones dispersible tablet hardness large, good looking appearance, complete, and meet the requirements disintegration, stripping is rapid.
Another object of the present invention there is provided a kind of Radix Scutellariae total flavones dispersible tablet manufacture method, wherein selects 0.54% sodium lauryl sulphate to be dissolution medium, and the dissolubility of Radix Scutellariae total flavones is increased, and drug-eluting is complete.
According to the present invention, aforementioned and other object can be achieved by a kind of Radix Scutellariae total flavones dispersible tablet, wherein Radix Scutellariae total flavones dispersible tablet comprises Radix Scutellariae total flavones extract and adjuvant, wherein this adjuvant comprises the disintegrating agent being not less than this Radix Scutellariae total flavones dispersible tablet gross weight 8%, be not less than the filler of this Radix Scutellariae total flavones dispersible tablet gross weight 42.6%, be not less than the sodium lauryl sulphate of this Radix Scutellariae total flavones dispersible tablet gross weight 0.5%, be not less than the NP (pyrrolidone) of this Radix Scutellariae total flavones dispersible tablet gross weight 5%, be not less than the micropowder silica gel of this Radix Scutellariae total flavones dispersible tablet gross weight 1.3%, residual components is extractive of general flavone, wherein in this extractive of general flavone, the composition of Radix Scutellariae total flavones is not less than 45%, wherein this disintegrating agent comprises CMS-Na and PVPP, this filler comprises microcrystalline Cellulose and TY.
On the other hand, present invention also offers a kind of manufacture method of Radix Scutellariae dispersant, comprise the steps:
Steps A: mixed by Radix Scutellariae total flavones, filler and disintegrating agent one, obtains mixture one;
Step B: described mixture one is mixed with binding agent and surfactant, obtains mixture two;
Step C: drying is carried out to mixture two;
Step D: the mixture two of drying is carried out mixing aftershaping with disintegrating agent two and fluidizer, obtains Radix Scutellariae total
Flavone dispersible tablet.
Accompanying drawing explanation
Figure 1A ~ 1J is the differential thermal analysis curve of each principal agent according to Radix Scutellariae total flavones dispersible tablet of the present invention and adjuvant.
Fig. 2 is the uv absorption spectra according to Radix Scutellariae total flavones of the present invention.
Fig. 3 is Radix Scutellariae total flavones standard curve, shows the linear relationship between the concentration of Radix Scutellariae total flavones solution in ultraviolet spectrophotometry and trap.
Fig. 4 is the uv absorption spectra of the mixed accessories according to Radix Scutellariae total flavones dispersible tablet of the present invention.
Fig. 5 is the uv absorption spectra according to the mixed accessories of Radix Scutellariae total flavones dispersible tablet of the present invention except sodium lauryl sulphate.
Fig. 6 is the uv absorption spectra of the aqueous solution according to Radix Scutellariae total flavones of the present invention.
Fig. 7 is the uv absorption spectra according to PH6.8 phosphate buffer of the present invention.
Fig. 8 is according to the uv absorption spectra containing 0.54% lauryl sodium sulfate aqueous solution of the present invention.
Fig. 9 shows in the dissolution medium screening process according to Radix Scutellariae total flavones dispersible tablet of the present invention, the cumulative defaultlogic of different dissolution medium.
Figure 10 is the uv absorption spectra of 0.54% lauryl sodium sulfate aqueous solution of blank auxiliary according to Radix Scutellariae total flavones of the present invention.
Figure 11 is not containing the uv absorption spectra of 0.54% lauryl sodium sulfate aqueous solution of the blank auxiliary of sodium lauryl sulphate according to of the present invention.
Figure 12 is the particle size distribution figure according to extruding granulation gained granule of the present invention.
Figure 13 is the particle size distribution figure according to High Shear Mixer Granulator method gained granule of the present invention.
Figure 14 is the particle size distribution figure according to fluidized bed granulation method gained granule of the present invention.
Figure 15 shows the cumulative defaultlogic of three kinds of different method of granulating according to Radix Scutellariae total flavones dispersible tablet of the present invention.
Figure 16 shows according to the impact of micropowder silica gel consumption in astragalus dispersible tablets manufacture process of the present invention for dry granule angle of repose.
Figure 17 shows the moisture equilibrium at dry side curve according to the dry granule in Radix Scutellariae total flavones dispersible tablet manufacture process of the present invention.
Figure 18 is the flow chart of the manufacturing process according to Radix Scutellariae total flavones dispersible tablet of the present invention.
Figure 19 is the high-efficient liquid phase chromatogram according to negative control solution of the present invention.
Figure 20 is the high-efficient liquid phase chromatogram according to reference substance solution of the present invention.
Figure 21 is the high-efficient liquid phase chromatogram according to sample solution of the present invention.
Detailed description of the invention
Below describe and realize the present invention for disclosing the present invention to enable those skilled in the art.Preferred embodiment in below describing only as an example, it may occur to persons skilled in the art that other apparent modification.The ultimate principle of the present invention defined in the following description can be applied to other embodiments, deformation program, improvement project, equivalent and not deviate from the other technologies scheme of the spirit and scope of the present invention.
One. the research of Radix Scutellariae total flavones dispersible tablet formulation technique
(1) experiment material, reagent and instrument
1, experiment material: Radix Scutellariae total flavones (river Chinese medicine provided, and content is 65% ± 5%)
(pharmaceutical grade, Zhejiang Huzhou looks forward to chemical pharmaceutcal corporation, Ltd to TY.Lot number: 010405); Microcrystalline Cellulose (MCC, pharmaceutical grade, Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong, lot number 990110); Lactose (pharmaceutical grade.Harbin Pharmaceutical Factory, lot number: 960815); cL (pharmaceutical grade, BASF Corp. of Germany's product);
Carboxymethyl starch sodium (CMS-Na, imported from Holland subpackage); Low-substituted hydroxypropyl cellulose (L-HPC, pharmaceutical grade, Zhejiang Huzhou chemical industry affiliated company, lot number 991029); Sodium lauryl sulphate (SLS, chemical reagent wholesale department, Tianjin is sold, lot number 981201); Tween-80 (pharmaceutical grade, Shanghai Volkswagen pharmaceutcal corporation, Ltd, lot number 010524); Micropowder silica gel (pharmaceutical grade, Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong, lot number: 980924); Hydroxypropyl emthylcellulose (HPMC, pharmaceutical grade, Zhejiang Huzhou chemical industry affiliated company, lot number 981215); NP (pyrrolidone) (pharmaceutical grade, Zhejiang eyot chemical industry affiliated company, 980718).
2, reagent: agents useful for same is analytical pure.
3, key instrument: ZRS-4 intelligence digestion instrument (Radio Factory of Tianjin Univ.); ZB-1C Intelligent disintegration tester (Radio Factory of Tianjin Univ.); FT-2000 tablet friability detector (Tianjin silicon new science and technology company limited); PYD-1 matrix agent hardness-testing device (Tianjin bass Te Ke company); FL-5 type boiling granulating device (Huafa Pharmaceutical Mating Development Co., Shanghai); HLY-10 type mixer-granulator (Chinese-foreign joint Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai); The heavy single punch tablet machine (Far East, Shanghai pharmaceutical machine factory) of ZDY-8; 21 rush rotary tablet machine (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai); Prunus mume (sieb.) sieb.et zucc. Teller moisture test apparatus (Mettler-Toledo Instrument (Shanghai) Co., Ltd.).
(2) dispersible tablet prescription composition
Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium, polyvinylpolypyrrolidone, NP (pyrrolidone), sodium lauryl sulphate, micropowder silica gel
(3) preparation process research
1, dosage form selection
(1) character of prescription Chinese medicine: Radix Scutellariae total flavones is the effective site extracted in Radix Scutellariae, as root, in extract, Radix Scutellariae total flavones content is 60% ± 5%.This product is insoluble in water, is soluble in organic solvent.
(2) dosage form selection: due to the effective site extracted in Radix Scutellariae, as root is insoluble in water, clinical needs makes quick-effective preparation, if make ordinary tablet, then drug-eluting is slow, is difficult to reach requirement, make the stripping that dispersible tablet then can significantly improve medicine, reach curative effect rapidly.Dispersible tablet has good stability, is easy to carry, transport, and storage, the advantages such as taking convenience, not only can directly swallow, and also can chew clothes, containing sucking or dropping into rapid disintegrate in water, in fruit juice, take after forming uniform suspension.Its adjuvant is identical with general non-packet garment piece with preparation technology, and not needing increases equipment investment and production cycle, and thus this product selects tablet formulation.
2, the screening of dispersible tablet supplementary product kind
(1) Radix Scutellariae total flavones dispersible tablet Formulation
According to literature survey, determine that the basic prescription of Radix Scutellariae total flavones dispersible tablet is: medicine 45%, microcrystalline cellulose 46.2%, sodium lauryl sulphate 0.5%, binding agent NP (pyrrolidone) concentration 3%, micropowder silica gel 1.3%.On this basis, filler is filtered out from the conventional adjuvant of dispersible tablet, disintegrating agent and binding agent, mix medicine with filler, disintegrating agent, adds binding agent soft material, containing the sodium lauryl sulphate of recipe quantity 0.5% in binding agent, 30 mesh sieves are granulated, 70 DEG C of dryings, 30 mesh sieve granulate, adding 1.3% micropowder silica gel is fluidizer, by regulation sheet weight sheet on single punch tablet machine.
(2) dispersible tablet adjuvant screening quality evaluation index
Outward appearance: complete bright and clean, uniform color, without loose pieces, sliver.
Hardness: measure with tablet hardness tester, replication 10 times, averages.
Disintegration: by Chinese Pharmacopoeia version regulation in 2000, measure disintegration in the water of 19-21 DEG C.
Dispersed homogeneous degree: by British Pharmacopoeia 93 editions regulation, gets dispersible tablet 2 and puts into 100ml water, disperse after being stirred to complete disintegrate, be poured on the screen cloth of 710 μm, all should pass through screen cloth.
(3) screening of filler
Take CMS-Na as disintegrating agent, sodium lauryl sulphate is lubricant, and micropowder silica gel is fluidizer, and NP (pyrrolidone) is binding agent, and the filler different with table 1 makes dispersible tablet.The results are shown in Table 3.
The screening of table 3. filler
Result shows: starch, lactose, separately as filler, occur that phenomenon is split on top.Filler good looking appearance made by Icing Sugar, but disintegration time exceeds standard, therefore all undesirable.Make separately filler with microcrystalline Cellulose and NP (pyrrolidone) and then reach requirement.Wherein microcrystalline Cellulose is expensive, therefore considers to adopt mixed filler.By comparing, determine to make filler with TY and microcrystalline Cellulose, obtained slice, thin piece disintegrate is fast, and suspendible is even, and easily granulate, fine powder is less.
(4) screening of disintegrating agent
Filler (microcrystalline Cellulose: TY=1:1), disintegrating agent is added in medicine, with 3%NP (pyrrolidone) aqueous solution for binding agent, 0.5% dodecyl is lubricant, and 1.3% micropowder silicon is fluidizer, makes dispersible tablet with different disintegrating agents.Result shows: alone PVPP effect is best, be secondly L-HPC and CMS-Na, but PVPP is expensive, and the tablet of L-HPL compacting has hardening after placing, the tendency that disintegration time extends, and therefore considers to adopt mixing disintegrating agent.Make disintegrating agent through test with CMS-Na, PVPP mixing, reach good effect.In table 4.
The screening of table 4. disintegrating agent
(5) screening of binding agent
Filler microcrystalline Cellulose, TY is added in medicine, with 0.5% sodium lauryl sulphate for lubricant, 1.3% micropowder silica gel is fluidizer, disintegrating agent is CMS-Na, PVPP, respectively with 2%HPMC, 3%NP (pyrrolidone) aqueous solution, 3%NP (pyrrolidone) dilute alcohol solution are that binding agent is granulated, and are pressed into dispersible tablet.Result shows: 3%NP (pyrrolidone) aqueous solution is that the disintegration of tablet that binding agent is made is fast, and uniform color is complete attractive in appearance; The granule fines that 3%NP (pyrrolidone) Diluted Alcohol liquid obtains is more, and has the phenomenon of pushing up and splitting; The tablet disintegration times that 2%HPMC obtains is longer.Therefore determine that binding agent is 3%NP (pyrrolidone) aqueous solution.In table 5.
The screening of table 5. binding agent
(6) surfactant is on the impact of disintegration of tablet
Surfactant can increase the wettability of tablet, makes moisture borrow capillarity rapid permeability to play disintegration to the sheet heart.Because this prescription drug is insoluble in water, be not easily the moistening of water institute, therefore add proper amount of surfactant.By principal agent, microcrystalline Cellulose, TY, 3%NP (pyrrolidone), 1.3% micropowder silica gel, CMS-Na and PVPP granulation, tabletting.Result shows, after adding Tween-80 or sodium lauryl sulphate, disintegration time all can shorten, but granule fines increases.Sodium lauryl sulphate is with lubrication, and the tablet of compacting is more attractive in appearance, therefore selects sodium lauryl sulphate.In table 6.
Table 6. surfactant is on the impact of disintegration of tablet
(7) disintegrating agent Adding Way is on the impact of tablet
The Adding Way of disintegrating agent also has impact to disintegrate effect.Test select CMS-Na, PVPP all in add, add in CMS-Na, PVPP is additional contrasts, add in result CMS-Na, the additional hardness of PVPP is large, and disintegration time is shorter, and thus select in CMS-Na and add, PVPP is additional.In table 7.
Table 7. disintegrating agent Adding Way is on the impact of tablet
(8) principal agent and adjuvant repercussion study: the adjuvant (as filler) that consumption is large is by principal agent: adjuvant=1:5 mixes, few (as disintegrating agent, the fluidizer) of consumption is by principal agent: adjuvant=20:1 mixing, carries out heating differential analysis.Result shows that selected adjuvant and principal agent do not interact.See Figure 1A ~ 1J (wherein Figure 1A is principal agent, and Figure 1B ~ 1J is adjuvant)
(9) primary election prescription is determined: through above-mentioned test, the prescription obtaining Preliminary screening is: Radix Scutellariae total flavones, microcrystalline Cellulose, TY, CMS-Na, PVPP, 0.5% sodium lauryl sulphate, 1.3% micropowder silica gel, 3%NP (pyrrolidone) aqueous solution.
3. the optimization of ratio of adjuvant
Because dissolution directly can reflect the release characteristics of tablet Chinese traditional medicine, therefore on the basis of above-mentioned result of the test, with dissolution T 50for evaluation index, by Three factors-levels orthogonal test, the consumption proportion of adjuvant in primary election prescription is optimized.
The selection of factor level, in table 8.
Table 8. factor level table
(2) preparation method of Radix Scutellariae total flavones dispersible tablet
Radix Scutellariae total flavones powder and each adjuvant are all crossed 100 mesh sieves, takes by orthogonal table 7 prescription.Drug powder and microcrystalline Cellulose, TY, CMS-Na and sodium lauryl sulphate are mixed, add about 16mlNP (pyrrolidone) aqueous solution to granulate, 70 DEG C of dryings, after 30 mesh sieve granulate, add PVPP, micropowder silica gel is mixed, and is pressed into for test piece, for the Hardness Control of test piece about 3.5 kgfs.
(3) Orthogonal Experiment and Design
Because considering disintegrating agent and binding agent, may reciprocal action be had between disintegrating agent and filler, therefore selecting L 18(3 7) arranging test, each test all repeats 3 times, and result of the test and variance analysis are in table 9, table 10.
Table 9. orthogonal experiments
Table 10. analysis of variance table
F 0.01(2,39)＝5.18；F 0.01(4,39)＝3.83
(4) reciprocal action of factor A and B, A and C.In table 11, table 12.
The reciprocal action of table 11. factor A and B
Result shows: optimum collocation is A 2b 3.
The reciprocal action of table 12. factor A and C
Result shows: optimum collocation is A 2c 3.
Conclusion: variance analysis shows, disintegrating agent, filler, binding agent are to dissolution T 50all have appreciable impact, its primary and secondary order is: binding agent > filler > disintegrating agent.Reciprocal action table shows that optimum collocation is for A 2b 3c 3.Namely disintegrating agent is total amount 8% (CMS-Na:PVPP); Binder concn is 5%; Microcrystalline Cellulose consumption is 24%.Determine that the prescription of Radix Scutellariae total flavones dispersible tablet consists of thus: Radix Scutellariae total flavones 45%, disintegrating agent (CMS-Na, PVPP) 8%, filler (microcrystalline Cellulose, TY) 42.6%, sodium lauryl sulphate 0.5%, NP (pyrrolidone) 5%, micropowder silica gel 1.3%.
(4) Radix Scutellariae total flavones dispersible tablet In Vitro Dissolution test
In orthogonal test, index used is dissolution T 50, therefore before doing orthogonal test, methodology examination has been carried out to the In Vitro Dissolution test of Radix Scutellariae total flavones dispersible tablet.
Because index used in orthogonal test is T 50there are 18 prescriptions, each prescription 3 repeated experiments, are equivalent to common palpus and survey 18 × 3=54 T 50, T 50eachly to be obtained by 6 points, therefore must measure 54 × 6=324 data altogether, if by high performance liquid chromatography, instrument condition is had any problem, therefore consideration employing ultraviolet spectrophotometry.
1, the methodological study of determined by ultraviolet spectrophotometry Radix Scutellariae total flavones content
(1) instrument and reagent:
1. instrument: UV-1206 ultraviolet-visible spectrophotometer (Japanese Shimadzu), METTERAE240
100000/analytical balance (Switzerland) KQ3200 ultrasonic cleaner (Kunshan Ultrasonic Instruments Co., Ltd.)
The preparation of test sample: get Radix Scutellariae total flavones dispersible tablet 20 porphyrizes, precision takes about 0.01g in 50ml to 10ml volumetric flask, and the ethanol adding 95% is settled to scale, measures trap in 276nm wavelength place, calculates content.
2. reagent: agents useful for same is analytical pure.
(2) method and result
1. the determination of determined wavelength
Get Radix Scutellariae total flavones 95% alcoholic solution in the scanning of 200 ~ 400nm wavelength place, show that Radix Scutellariae total flavones has maximum absorption band at 276nm wavelength place.Therefore determined wavelength is decided to be 276nm.See Fig. 2.
2. the examination of linear relationship
The above-mentioned reference substance solution 0.10,0.25,0.40 of accurate absorption, 0.55,0.70,0.85ml is in 10ml volumetric flask, be settled to scale with 95% ethanol, being made into concentration is 1.32,3.3,5.28,7.26,9.24,11.22, the alcoholic solution of 13.2 μ g/ml, makes rectilinear regression with trap A to concentration C, obtains regression equation: A=0.08011C+0.009298 (r=0.9999).
Radix Scutellariae total flavones has good linear relationship, in table 13 and Fig. 3 in 1.32 ~ 13.2 μ g/ml concentration ranges.
The trap of the reference substance solution of table 13. variable concentrations
3. the determination of supersound extraction time
Use sample determination method, setting extraction time is 15 minutes, and 30 minutes, 45 minutes, 1 hour, result of the test showed, 30min has extracted completely, and after extracting, residue is white.In table 14.
Table 14. different supersound extraction time result of the test
4. repeatability test
Precision takes 5 parts, sample (every part of about 0.01g), is placed in 50ml volumetric flask, respectively adds 95% ethanol 40ml supersound extraction 30min, lets cool rear ethanol and be settled to scale, filters, gets 1ml and be diluted in 10ml volumetric flask, measures content in table 15.
The assay result of Radix Scutellariae total flavones in the same batch sample of table 15.
5. recovery test: precision takes Radix Scutellariae total flavones and mixing blank auxiliary, then presses said determination method and measures trap, calculate content and the response rate.The results are shown in Table 16.
Table 16. Radix Scutellariae total flavones recovery test result
Add up: X=103.38, RSD%=1.34%.
6. blank interference test
Precision takes the mixed accessories 0.0055g by prescription proportioning, volumetric flask is placed in 40ml95% ethanol, supersound extraction half an hour, let cool rear use 95% and quantitatively cause scale, get 1ml to 10ml volumetric flask, with 95% ethanol dilution to scale, in 200-400nm length scanning, find slightly to absorb at 276nm place, but impact is little, can ignore, see Fig. 4.Separately get the blank auxiliary of scarce sodium lauryl sulphate, operate by above method, in 200-400nm length scanning, find to absorb in 276nm place nothing, see Fig. 5.Interference component thus in provable mixed accessories is sodium lauryl sulphate.
7. sample determination: sample thief, by the process of need testing solution preparation method, uses determined by ultraviolet spectrophotometry trap, the content in calculation sample.
2, the screening of dissolution medium
(1) dissolution medium: Radix Scutellariae total flavones is insoluble in water, for the medicine that some water solublity are poor, sometimes proper amount of surfactant can be added in dissolution medium, the most frequently used is sodium lauryl sulphate, here we select water recently distilled, PH6.8 phosphate buffer, 0.54% lauryl sodium sulfate aqueous solution is that dissolution medium screens.
(2) determination of determined wavelength:
Use the aqueous solution of Radix Scutellariae total flavones respectively, PH6.8 phosphate buffer, containing 0.54% lauryl sodium sulfate aqueous solution, in 200-400nm length scanning, determine aqueous solution, PH6.8 phosphate buffer, the determined wavelength of 0.54% lauryl sodium sulfate aqueous solution is respectively 271.5nm, and 267.5 and 276.5nm.See Fig. 6,7,8.
(3) determination of leaching condition: select paddle method, rotating speed 100r/min, temperature (37 ± 0.5) DEG C.
(4) drafting of standard curve: take respectively be dried to constant weight Radix Scutellariae total flavones 0.001g in 3 100ml volumetric flasks, add above-mentioned 3 kinds of dissolution mediums respectively, blank is made with corresponding dissolution medium, trap is measured at respective determined wavelength, with concentration C, trap A is returned, obtain equation
A distilled water=0.06956C+0.001357 (r=0.9998)
A pH6.8 phosphate buffer=0.094726C-0.00014 (r=0.9999)
A 0.54% lauryl sodium sulfate aqueous solution=0.092432C+0.005429 (r=0.9999)
Result shows: in 3 kinds of media, Radix Scutellariae total flavones in 1-8 μ g/ml concentration range all in good linear relationship.
(5) cumulative defaultlogic (%) measures
Dissolution medium 1000ml, ultrasonic degas 15 minutes, carries out 2 at Radix Scutellariae total flavones dispersible tablet dissolution test respectively, 5,10,20,30,45min samples 5ml (filling into isothermal equivalent medium), through 0.8 μm of membrane filtration, precision measures 0.25ml in 5ml volumetric flask, quantitatively be diluted to 5ml by respective media, using respective media as blank, survey absorbance at corresponding determined wavelength place, calculate cumulative defaultlogic (%), the results are shown in Table 17 and Fig. 9.
The cumulative defaultlogic (n=3, x ± s) of table 17. three kinds of dissolution mediums
Note: 1. aqueous solution; The phosphate buffer of 2.PH6.8; 3.0.54% lauryl sodium sulfate aqueous solution
By comparing, with 0.54% lauryl sodium sulfate aqueous solution for dissolution medium.
3, the mensuration of Dissolution of Tablet
(1) instrument and medicine
UV-1206 type ultraviolet spectrophotometer (Japanese Shimadzu); ZRS-4 intelligence digestion instrument (Radio Factory of Tianjin Univ.);
Radix Scutellariae total flavones (river Chinese medicine provided); Radix Scutellariae total flavones dispersible tablet (self-control).
(2) method and result
1. the drafting of standard curve
It is appropriate that precision takes the Radix Scutellariae total flavones being dried to constant weight, puts in 100ml measuring bottle, add 0.54% sodium dodecyl sulfate solution and be diluted to scale.Be blank by 0.54% lauryl sodium sulfate aqueous solution, measure its trap A respectively at 276.5nm wavelength, with A, linear regression is carried out to concentration C, obtain regression equation: A=0.092432+0.005429 (r=0.9999).Result shows that Radix Scutellariae total flavones has good linear relationship within the scope of 1.1 ~ 7.7 μ g/ml.
2. dissolution recovery test
Take Radix Scutellariae total flavones by prescription proportioning precision and blank mixed accessories carries out response rate experiment, recording average recovery rate is 97.36%.RSD＝1.59％。In table 18.
Table 18. dissolution response rate result
Average recovery rate: X=97.36%RSD%=1.59
3. blank interference test: 0.54% lauryl sodium sulfate aqueous solution of getting the blank auxiliary of scarce Radix Scutellariae total flavones, in 200 ~ 400nm length scanning, finds slightly to absorb at 276.5nm ripple and strong point, but can ignore.Separately get 0.54% lauryl sodium sulfate aqueous solution of the blank auxiliary not containing sodium lauryl sulphate in 200 ~ 400nm length scanning, find in 276.5nm ripple and strong point without absorption, it can thus be appreciated that the interference factor in blank auxiliary is sodium lauryl sulphate, but can ignore, see Figure 10,11.
4. assay: get Radix Scutellariae total flavones dispersible tablet powder and be about 0.01g and put 50ml volumetric flask, add 95% ethanol 40ml supersound extraction 30min, let cool rear use 95% ethanol and be settled to scale, filter, in accurate absorption 1ml to 10ml volumetric flask, with 95% ethanol dilution to scale, measure trap with ultraviolet spectrophotometry at 276nm wavelength place, calculate the content of Radix Scutellariae total flavones.
5. the mensuration of dissolution: according to the dissolution (n=6) of Chinese Pharmacopoeia version annex dissolution method mensuration Radix Scutellariae total flavones dispersible tablet in 2000, adopt slurry processes, medium is 0.54% lauryl sodium sulfate aqueous solution, rotating speed 100r/min, and temperature is 37 ± 0.5 DEG C.Respectively at 2,5,10,20,30,45min samples 5ml, supplements the isopyknic dissolution medium of isothermal.Filter with 0.8 μm of microporous filter membrane during sampling, get filtrate 0.25ml in 5ml volumetric flask, be settled to scale with dissolution medium, survey trap in 276.5nm wavelength place.
The process of 6. stripping data:
According to Weibull (Weibull) distribution function F (t)=e -(t-α) m/t0, after Mathematical treatment, obtain lnln (1/ (1-F (t))=mln (t-a)-lnt 0, list of references, goes out T with VisualBasic6.0 program calculation 50, the parameters such as Td, m.Its program code is shown in annex 1,2.
(5) research of moulding process
1, the selection of method of granulating
Granulation is the key operation of tablet manufacturing, and granular mass is the important guarantee of tablet quality.In order to find the process route of applicable suitability for industrialized production, granulate to wetting, the granule that fast Speed mixer and fluidized bed granulation three kinds of method of granulating obtain and tablet quality compare.
(1) Radix Scutellariae total flavones dispersible tablet quality evaluation index
Disintegration time: by Chinese Pharmacopoeia 2000 editions regulation, measure disintegration in the water of 19-21 DEG C.
Dispersed homogeneous degree: according to British Pharmacopoeia 93 years version regulations, two panels Radix Scutellariae total flavones dispersible tablet test sample is put into 100ml water, is stirred to and disperses completely, should by the screen cloth of 710 μ.
Dissolution: measure according to dissolution determination method.
Tablet hardness: measure with tablet hardness tester, replication 10 times, gets its meansigma methods.
Tablet weight variation: by the regulation of Chinese Pharmacopoeia version in 2000 second annex, measures 20 calculating mean values.
Tablet appearance: the unilateral smoothness of perusal dispersible tablet, occurs with or without situations such as piebaldism, loose pieces, slivers.
(2) the prescription composition of Radix Scutellariae total flavones dispersible tablet
Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium, polyvinylpolypyrrolidone, sodium lauryl sulphate, micropowder silica gel, 5%NT aqueous solution.
(3) different method of granulating tabletting
1. granulation is extruded: by recipe quantity by Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium fully mix, add 5%NP (pyrrolidone) aqueous solution being dissolved with sodium lauryl sulphate and make soft material, 30 mesh sieves are granulated, 70 DEG C of dryings, dry granule 30 mesh sieve granulate, add PVPP and micropowder silica gel, are pressed into the dispersible tablet of every sheet containing total flavones 160mg.
2. High Shear Mixer Granulator: Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium are put in HLY-10 type mix and blend granulator by recipe quantity; first mix; then 5%NP (pyrrolidone) aqueous solution added containing sodium lauryl sulphate is that binding agent is granulated; 70 DEG C of dryings; dry granule 30 mesh sieve granulate; add micropowder silica gel, PVPP is pressed into the dispersible tablet of every sheet pastille 160mg.
3. fluidized bed granulation: by 2 times of recipe quantity by Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium is put in FL-5 type boiling granulating device, being that binding agent is granulated containing 5%NP (pyrrolidone) aqueous solution of sodium lauryl sulphate, 70 DEG C of dryings, dry granule 30 mesh sieve granulate, add micropowder silica gel, and PVPP is pressed into the dispersible tablet of every sheet pastille 160mg.
(4) semi-finished granules quality comparation
1. angle of repose: angle of repose is one of main method representing interparticle force.The quality of the large I reflection mobility of particle of angle of repose.The mensuration of angle of repose adopts fixed funnel method: top certain distance funnel being fixed on horizontal positioned diagram paper, funnel end opening is H apart from the height of diagram paper, carefully granule is poured in funnel, until the nib contacts of the cone formed under funnel is to the end opening of funnel, diameter at the bottom of cone is 2R, then tg α=H/R, α angle is angle of repose.The angle of repose of three kinds of made granules of different method of granulating is in table 19.Result shows, fluidized bed granulation gained mobility of particle is best, is secondly High Shear Mixer Granulator.Extruding granulation gained mobility of particle is poor.
The angle of repose of table 19 three kinds of made granules of different method of granulating
2. the particle size distribution of three kinds of made granules of different method of granulating
Different method of granulating has obvious impact to particle size distribution, if fine powder particulate is too much, easily produces sliver during tabletting, loose pieces, corner hair lack and the phenomenon such as sticking, therefore should control the granularity of granule.Result of the test shows: the fine powder amount (<100 order) that extruding is granulated reaches 49.38%, and High Shear Mixer Granulator fine powder amount accounts for 15.98%, and the fine powder amount of fluidized bed granulation accounts for 46.46%.The granule fines that High Shear Mixer Granulator obtains is more moderate, is conducive to tabletting.And extruding is granulated and fluidized bed granulation fine powder amount is higher.In table 20,21,22 and Figure 12,13,14.
Table 20. extrudes granulation particle size distribution
Table 21. High Shear Mixer Granulator particle size distribution
Table 22. fluidized bed granulation particle size distribution
(5) different method of granulating is on the impact of Radix Scutellariae total flavones dispersible tablet quality
The quality of granule obtained by different method of granulating on Radix Scutellariae total flavones dispersible tablet has obvious impact, and the tablet hardness that High Shear Mixer Granulator obtains is large, and good looking appearance is complete, and meets the requirements disintegration, and stripping is rapid.The tablet mobility that extruding granulation obtains is poor, and the tablet hardness that fluidized bed granulation obtains does not reach requirement, and has top to split phenomenon.In table 21.
The different method of granulating of table 23. is to Radix Scutellariae total flavones dispersible tablet quality influence
The Comparative Study on Dissolution of (6) three kinds of different method of granulating tablets
The granular mass difference that different method of granulating is obtained, we adopt uniform pressure tabletting, then carry out dissolution and compare.
1. the mensuration of the cumulative defaultlogic of three kinds of different method of granulating
The mensuration of cumulative defaultlogic adopts paddle method: the lauryl sodium sulfate aqueous solution 1000ml getting 0.54% is dissolution medium, 2 are carried out respectively at dissolution test, 5,10,20,30,45min samples 5ml (filling into isothermal equivalent medium immediately), through 0.8 μm of membrane filtration, precision measures 0.25ml in 5ml volumetric flask, is quantitatively diluted to 5ml by the lauryl sodium sulfate aqueous solution of 0.54%, and the lauryl sodium sulfate aqueous solution using 0.54% is as blank, measure absorbance at 276.5nm wavelength place, calculate cumulative defaultlogic (%).. the cumulative defaultlogic of the tablet that result three kinds of different method of granulating obtain without obvious difference, in table 24 and Figure 15.
The cumulative defaultlogic of table 24. three kinds of different method of granulating
2. three kinds of different method of granulating made Radix Scutellariae total flavones dispersible tablet dissolution T 50single factor analysis
With dissolution T 50for index, the dispersible tablet obtained to three kinds of different method of granulating carries out one factor analysis of variance, and result shows that three kinds of method of granulating are without obvious difference, in table 25.
The T of the made dispersible tablet of the different method of granulating of table 25. 50
Table 26. analysis of variance table
By the comparison of above three kinds of method of granulating, determine to adopt High Shear Mixer Granulator method, and granulating process parameter is investigated.
2, the research of High Shear Mixer Granulator technological parameter
Affect High Shear Mixer Granulator because have: the rotating speed of stirring paddle, granulating cutter, stir and Granulation time.Because the granule needed for dispersible tablet is less, therefore we select paddle to open low speed, and granulating cutter is opened at a high speed.
(1) determination of incorporation time: the mixing between solid can not reach evenly distributed completely, can only reach the uniformity of macroscopic view, therefore usually use the method for statistical analysis.Here we adopt standard deviation sigma or variances sigma 2, be the straightforward procedure comparatively commonly used.
σ＝[1/(n-1)∑(x i-x) 2] 1/2
σ 2＝1/(n-1)∑(x i-x) 2
N represents frequency in sampling, x irepresent point rate of a certain component the I time sampling, x represents the average mark rate of a certain component in sample, with x=1/n ∑ x ireplace the theory point rate of a certain component.At σ, σ 2computational process in, by sampling number of times, sample position, adds the impact of point rate etc., has random error.
Result of calculation: σ or σ 2be worth less, more close to meansigma methods; When these values are 0, this mixture reaches and mixes completely.
Test method: in different time three different parts samplings from container, sampling amount is about 0.01g, measures content, calculates σ value.Result shows σ, σ after 3 minutes 2be worth less, therefore incorporation time is decided to be 3 minutes.In table 27.
σ, σ of the different incorporation time of table 27. 2value
(2) determination of Granulation time: ocular estimate, is as the criterion with obtained uniform particles.
Test method: take principal agent and adjuvant blanking by prescription; vessel is closed up and carries out rapid stirring and mix 3 minutes; then paddle is opened low speed; granulating cutter is opened at a high speed; again 5%NP (pyrrolidone) aqueous solution is added from form, observe from form, shut down when epigranular; pour out wet granular, dry in 70 DEG C of baking ovens.
3, the determination of fluidizer consumption
In order to improve the mobility of granule, appropriate fluidizer can being added, its consumption, determining angle of repose by measuring.The general consumption that fluidizer is made in micropowder silica gel is 0.15%-3%, and the angle of repose of micropowder silica gel different amounts is in table 28 and Figure 16.
Table 28. micropowder silica gel different amounts is on the impact of fluidizer effect
As shown in Figure 16, after the consumption of micropowder silica gel reaches 1%, the mobility of granule is better, then it is less on impact angle of repose to increase consumption.Can accelerate the disintegrate of tablet when the consumption of micropowder silica gel is more than 1%, be conducive to the absorption of medicine, therefore we select fluidizer consumption to be 1.3%.
4, the hygroscopicity of granule is investigated
The hygroscopicity of granule has important impact to tabletting, therefore determines the balance Moisture absorption rate of dry granule.
The assay method of balance Moisture absorption rate: precision takes dry granule and is about 1.0g, totally 12 parts are placed in 12 uncovered weighed weight and the weighing botle of numbering respectively, are paved into the thickness of about 2mm.Then weighing botle is put into the exsiccator filling the sulphuric acid of certain relative humidity or the saturated solution of salt, exsiccator is put in 25 DEG C of constant incubators to preserve and namely reach poised state in 7 days, take out the rapid precise weighing of weighing botle, calculated equilibrium hydroscopicity (%), the results are shown in Table 29, table 30.
Particle weight × 100% before balance Moisture absorption rate (%)=(after moisture absorption before particle weight-moisture absorption particle weight)/moisture absorption
The relative humidity of saturated solution 25 DEG C time of table 29. variable concentrations sulphuric acid or different salt
The balance Moisture absorption rate of dry granule under the different relative humidity of table 30.
With balance Moisture absorption rate for vertical coordinate, take relative humidity as abscissa, draw moisture equilibrium at dry side curve, the results are shown in Figure 17.
Result shows: dry granule hygroscopicity is not strong, and when relative humidity is less than 60%, the change of its hygroscopic capacity is not obvious, and when being greater than 60%, its hygroscopic capacity obviously increases, and therefore the relative humidity in workshop should control below 60%.
5, tablet hardness is on the impact of Radix Scutellariae total flavones dispersible tablet disintegration time
Find in test that disintegration time and the hardness of Radix Scutellariae total flavones dispersible tablet have obvious relation.When hardness is larger, the outward appearance of tablet is better, but disintegration time is also longer; When hardness hour, easily there is the phenomenon such as loose pieces, sliver again.Investigated the disintegration with a collection of granule institute's compressed tablets under different pressures condition, find out suitable briquetting pressure, result shows for this reason, and Hardness Control disintegration time between 4-5 kgf is proper, in table 31.
Table 31. hardness is on the impact of tablet disintegration times
6, preparation technology: by above-mentioned research; determine Radix Scutellariae total flavones dispersible tablet preparation technology: Radix Scutellariae total flavones powder and adjuvant cross 100 mesh sieves respectively; add filler and Nei Jia disintegrating agent; in High Speed Stirring Machine container, mix 3min, add 5%NP (pyrrolidone) the aqueous solution 160ml containing Surfactant, granulation, 70 DEG C of dryings; 30 mesh sieve granulate; add additional disintegrating agent and fluidizer mix homogeneously, tabletting, to obtain final product.
7, the process conditions of formed product
Tablet machine: ZDY 8heavy single punch tablet machine
Flap-type: round
Punch die:
Granule water content: 2 ~ 5%
Sheet weight: 0.35g checks once every fixing time
Institute's medication powder and adjuvant all cross 100 mesh sieves, and unilateral color and luster is relatively more even, binder concn 5%.Consumption is 160ml, made uniform particles, and fine powder is less, and baking temperature is 70 DEG C.
8, the selection of packaging material
Tested from the moisture equilibrium at dry side of granule, when relative humidity is greater than 60%, its hygroscopic capacity obviously increases, and therefore, the production environment relative humidity of tablet should control below 60%.The tablet suppressed being positioned over relative humidity is place after one month in the weighing apparatus wet environment of 75%, and find the situation that tablet has deliquescing, hardness diminishes, therefore tablet must have packaging, adopts two In Aluminium Foil Packing.
(6) pilot scale
Carry out pilot scale three batches by the prescription determined and technique, often criticize and feed intake 10,000.
1, prescription composition
Radix Scutellariae total flavones 45%, disintegrating agent (CMS-Na, PVPP) 8%, filler (microcrystalline Cellulose, TY) 42.6%, sodium lauryl sulphate 0.5%, NP (pyrrolidone) 5%, micropowder silica gel 1.3%.
2, preparation method: get Radix Scutellariae total flavones fine powder, microcrystalline Cellulose, TY, CMS-Na in High Speed Stirring Machine container; after mixing 3min; 5%NP (pyrrolidone) aqueous solution poured in form containing SLS is granulated; till uniform particles; by wet grain drying, granulate, adds PVPP, micropowder silica gel; rush in rotary tablet machine in 21 after mixing and be pressed into the circular piece of every sheet containing Radix Scutellariae total flavones 160mg, sheet is 0.35g heavily about.
3, scale up test result
Carry out semi-finished granules to three batches of pilot scale Radix Scutellariae total flavones dispersible tablets and dispersible tablet checks, result shows: mobility of particle is good, and fine powder amount is moderate.The outward appearance of tablet, disintegration time, dispersed homogeneous degree, hardness, dissolution, content and tablet weight variation are all qualified, in table 32,33.
Table 32, semi-finished granules quality measurements
Table 33. dispersible tablet quality measurements
Table 34. lab scale and pilot scale dispersible tablet stripping parameter T 50, T drelatively
Table 35. dispersible tablet T 50, T dvariance analysis
Result shows: the dissolution there was no significant difference of pilot scale and lab scale.
One, prescription
Radix Scutellariae total flavonoid aglycone: 160g; Microcrystalline Cellulose: 84g; Pregelatinized Starch: 62.48g;
Carboxymethyl starch sodium: 21g; Polyvinylpolypyrrolidone: 7g; Sodium lauryl sulphate: 1.75g;
Polyoxyethylene sorbitan monoleate: 1.22g; Pulvis Talci: 4.55g; 30 POVIDONE K 30 BP/USP 3:8g; Distilled water: appropriate.
Make 1000 altogether
Two, method for making
Took the Radix Scutellariae total flavonoid aglycone of 100 mesh sieves, and added microcrystalline Cellulose and pregelatinized Starch, carboxymethyl starch sodium is in mixer-granulator, and stirring paddle keeps off mixing 1 to 3 minute soon, then opens to slow gear; Granulating cutter is opened to fast gear and is stirred 3 to 4 minutes from the 5% PVP K30 liquid that charge door adds containing surfactant, and adding distil water stirs 3 to 4 minutes.Take out wet granular in 70 DEG C of dryings, dry granule is with after 30 mesh sieve granulate, and add polyvinylpolypyrrolidone and Pulvis Talci and to sieve mix homogeneously, tab is heavily 0,35g, and tabletting, to obtain final product.
Three, technological process
Technological process as shown in figure 18.
Four, preparations shaping Journal of Sex Research
Test material, reagent and instrument
Test material:
Radix Scutellariae total flavonoid aglycone (in river, pharmaceutical technology center is from carrying);
Pregelatinized Starch pharmaceutical grade, looks forward to chemical pharmaceutcal corporation, Ltd lot number purchased from Zhejiang Huzhou: 20010405;
Microcrystalline Cellulose pharmaceutical grade, purchased from Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong's lot number: 19990110;
Carboxymethyl starch sodium pharmaceutical grade, purchased from upper sea-freight grand Chemical Co., Ltd. lot number: 20010115;
Sodium lauryl sulphate pharmaceutical grade, lot number is sold in chemical reagent wholesale department, Tianjin: 20000504;
Two, the preliminary study of quality standard
(1) material and instrument
1, sample: Radix Scutellariae total flavones dispersible tablet (self-control, lot number: 010618,010620,010625)
2, reference substance: Radix Scutellariae B component (river Chinese medicine provided)
3, key instrument: Waters600E system (comprising Waters600Contrdler, Waters600Pump, Qaters486 detector), WATERSPC800 work station, Switzerland 1/10000 balance (METTLERAE240)
4, reagent: methanol used, ethanol, phosphoric acid are analytical pure, acetonitrile is chromatographically pure.
(2) research of quality standard
1, character: in three batches, test agent is yellowish-brown, feeble QI, mildly bitter flavor, therefore the character of this product is decided to be yellowish-brown tablet, feeble QI, mildly bitter flavor.
2, differentiate: (summary)
3, check
(1) inspection of moisture content: measure according to first method (oven drying method) in " (Pharmacopoeia of People's Republic of China) 2000 editions, annex Ⅸ H ", water content must not more than 7.0%.Get this product powder about 4g, accurately weighed, according to this method operation, measure dry rear example weight, calculate water content in test sample.Water content, all between 3 ~ 5%, meets the requirements.The check result of three batch samples is in table 36.
Table 36. three batch sample moisture determination result
(2) disintegration: testing under inspection technique (" Chinese Pharmacopoeia " version in 2000 annex) item by disintegration, take water as disintegrate medium, control temperature 20 ± 1 DEG C.Should complete disintegrate in 3min.Three batch sample measurement results are in table 37.
The disintegration time measurement result of table 37 three batch sample
(3) dispersed homogeneous degree: get this product two panels, puts in 100ml water, is stirred to complete disintegrate dispersion, inclines on 24 eye mesh screens, all should pass through screen cloth.The dispersed homogeneous degree of three batch samples all meets the requirements as a result.
(4) dispersible tablet dissolution: adopt paddle method (see " Chinese Pharmacopoeia " version in 2000 annex): the lauryl sodium sulfate aqueous solution 1000ml getting 0.54% is dissolution medium, ultrasonic degas 15 points of name clocks, 2 are carried out respectively at dissolution test, 5, 10, 20, 30, 45min samples 5ml (filling into isothermal equivalent medium immediately), through 0.8 μm of membrane filtration, precision measures 0.25ml in 5ml volumetric flask, quantitatively 5ml is diluted to by the lauryl sodium sulfate aqueous solution of 0.54%, lauryl sodium sulfate aqueous solution using 0.54% is as blank, absorbance is measured at 276.5nm wavelength place, calculate dissolution T 50the results are shown in Table 38.
The dissolution T of table 38, three batch samples 50measurement result
(5) tablet weight variation: test according under tablet weight variation inspection technique (" Chinese Pharmacopoeia " 2000 editions one annex I D) item, three batch sample measurement results are in table 39.
The tablet weight variation measurement result of table 39. three batch sample
Visible all regulation ± 5% within, conform with the regulations.
(6) health examination: according to microbial limit test (" Chinese Pharmacopoeia " version in 2000, one, annex Ⅹ III C) in inspection technique item under test, pathogenic bacterium, the demodicid mite that lives must not detect, bacterial population must not more than 100/gram, fungi count must not more than 100/gram, and three batch sample check results are in table 40.
Table 40. three batch sample health examination result
4, assay
(1) instrument and reagent
Instrument: Waters600E system (comprising Waters600Contrdler, Waters600Pump, Qaters486 detector), WATERSPC800 work station, Switzerland 1/10000 balance (METTLERAE240)
Reagent: methanol used, ethanol, phosphoric acid are analytical pure, acetonitrile is chromatographically pure.
Reference substance: Radix Scutellariae B component (river Chinese medicine provided)
Sample: Radix Scutellariae total flavones dispersible tablet (self-control: lot number: 010618,010620,010625)
(2) method and result:
1. chromatographic condition
A, chromatographic condition: NOVA-PAKC 18(3.9mm × 150mm) chromatographic column, column temperature 20 DEG C, flow velocity 1.0ml/min.Mobile phase: acetonitrile-water (35:65), adjusts pH value to be 4 with phosphoric acid.Sensitivity 0.1AUFS.Sample size 20 η l.
The determination of b, determined wavelength: get Radix Scutellariae B methanol solution, in 200-400nm spectral scan, its maximum absorption wavelength is 277nm.
2. the preparation of contrast solution: precision takes Radix Scutellariae B component 0.98mg, is placed in 100ml volumetric flask, adds methanol dilution to scale, shakes up, obtain reference substance solution.
3. the preparation of need testing solution: get Radix Scutellariae total flavones dispersible tablet 20, put porphyrize in mortar, precision takes about 0.1g, is placed in 250ml round-bottomed flask, adds 95% ethanol 30ml reflux, extract, 3 hours, filter, use 5ml95% washing with alcohol residue 3 times respectively, merging filtrate, standardize solution is in 50ml volumetric flask, shake up, to obtain final product.
4. the preparation of negative control solution: the sample getting scarce Radix Scutellariae total flavones, makes negative control solution by " preparation of need testing solution " method.
The HPLC figure of negative control solution, reference substance solution, sample solution is shown in Figure 19,20,21.
5. the investigation of linear relationship: accurate absorption reference substance solution 0.1,0.3,1,3,10, ml, in 10ml volumetric flask, is settled to scale with 95% ethanol, is made into 0.098,0.294, the alcoholic solution of 0.98,2.94,9.8 μ g/ml, measures peak area by above-mentioned chromatographic condition.With sample introduction concentration C (μ g/ml), rectilinear regression is done to integrating peak areas value A, obtain regression equation: A=364597C+10731.84 (r=0.9995).Result shows, Radix Scutellariae B component has good linear relationship in 0.098 ~ 9.8 μ g/ml concentration range.In table 41.
Table 41. reference substance peak area measurement result
6. Precision Experiment: the accurate Radix Scutellariae B component reference substance solution 20 μ l that draws repeats sample introduction 5 times, and relative standard deviation is 1.87%, and precision is high.The results are shown in Table 42.
The continuous 5 secondary peak area estimation results of table 42. same sample
7. replica test: precision takes 6 parts, same lot number (001068) sample, every part of about 0.1g, by the operation of " preparation of need testing solution " item, sample introduction 20 μ l, peak area is converted into content, and its relative standard deviation is 1.85%, favorable reproducibility.The results are shown in Table 43.
Table 43. same lot number 6 increment product assay result
8. stability experiment: get need testing solution sample introduction 20 μ l, every 2h sample introduction once, sample introduction 5 times altogether, RSD%=1.28%, shows that test liquid is stable in 10h.In table 44.
Table 44. stability test result
9. response rate experiment: adopt application of sample to reclaim algoscopy.Result average recovery rate 99.04%, relative standard deviation 0.92%, meets the requirements, in table 45.
Table 45. Radix Scutellariae B component average recovery result
10. sample tests: by above-mentioned content assaying method, has carried out assay to test agent in 3 batches.It the results are shown in Table 46.
The assay of test agent in table 46, pilot scale three batches
(3) quality standard
Radix Scutellariae total flavones dispersible tablet
HuangqinFensanPian
[prescription composition] Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium, polyvinylpolypyrrolidone, sodium lauryl sulphate, micropowder silica gel, 5%NP (pyrrolidone) aqueous solution
Radix Scutellariae total flavones, microcrystalline Cellulose, TY, carboxymethyl starch sodium are placed in the container of High Speed Stirring Machine by [method for making]; first mix homogeneously; add 5%NP (pyrrolidone) the aqueous solution 160ml containing SLS by form again, granulate, till uniform particles.Take out wet granular, 70 DEG C of dryings, 30 mesh sieve granulate, add additional disintegrating agent and fluidizer, tabletting, pack and get final product.
[character] this product is yellowish-brown tablet, feeble QI, mildly bitter flavor.
[inspection]
(1) inspection of moisture content: measure according to first method (oven drying method) in " (Pharmacopoeia of People's Republic of China) 2000 editions, annex Ⅸ H ", water content must not more than 7.0%.Get this product powder about 4g, accurately weighed, according to this method operation, measure dry rear example weight, calculate water content in test sample.Water content control is between 3 ~ 5%.
(2) disintegration: testing under inspection technique (" Chinese Pharmacopoeia " version in 2000 annex) item by disintegration, take water as disintegrate medium, control temperature 20 ± 1 DEG C.Should complete disintegrate in 3min.Three batch sample measurement results are in table 34.
(3) dispersed homogeneous degree: get this product two panels, puts in 100ml water, is stirred to complete disintegrate dispersion, inclines on 24 eye mesh screens, all should pass through screen cloth.
(4) dispersible tablet dissolution: adopt paddle method (see " Chinese Pharmacopoeia " version in 2000 annex): the lauryl sodium sulfate aqueous solution 1000ml getting 0.54% is dissolution medium, ultrasonic degas 15 points of name clocks, 2 are carried out respectively at dissolution test, 5, 10, 20, 30, 45min samples 5ml (filling into isothermal equivalent medium immediately), through 0.8 μm of membrane filtration, precision measures 0.25ml in 5ml volumetric flask, quantitatively 5ml is diluted to by the lauryl sodium sulfate aqueous solution of 0.54%, lauryl sodium sulfate aqueous solution using 0.54% is as blank, absorbance is measured at 276.5nm wavelength place, calculate dissolution results T 50.
(5) tablet weight variation: test according under tablet weight variation inspection technique (" Chinese Pharmacopoeia " 2000 editions one annex I D) item, tablet weight variation should control within 5%.
(6) health examination: according to microbial limit test (" Chinese Pharmacopoeia " version in 2000, one, annex Ⅹ III C) in inspection technique item under test, pathogenic bacterium, the demodicid mite that lives must not detect, bacterial population must not more than 1000/gram, and fungi count must not more than 100/gram.
[assay]
1, chromatographic condition
NOVA-PAKC 18(3.9mm × 150mm) chromatographic column, column temperature 20 DEG C, flow velocity 1.0ml/min.Mobile phase: acetonitrile-water (35:65), adjusts pH value to be 4 with phosphoric acid.Sensitivity 0.1AUFS.Sample size 20 μ l.Determined wavelength 277nm.
2, the preparation of contrast solution
Precision takes Radix Scutellariae B component 0.98mg, is placed in 100ml volumetric flask, adds methanol dilution to scale, shakes up, obtain reference substance solution.
3, the preparation of need testing solution
Get Radix Scutellariae total flavones dispersible tablet 20, put porphyrize in mortar, precision takes about 0.1g, is placed in 250ml round-bottomed flask, add 95% ethanol 30ml reflux, extract, 3 hours, filter, use 5ml95% washing with alcohol residue 3 times respectively, merging filtrate, standardize solution, in 50ml volumetric flask, shakes up, and to obtain final product.
4, sample tests
Accurate absorption need testing solution 20 μ l, inject high performance liquid chromatograph, record chromatogram, by external standard method with calculated by peak area, to obtain final product.
[usage and consumption] is oral, 3 times on the one, one time 1, warm water takes.
[specification] every sheet is containing Radix Scutellariae total flavones 0.16g.
Three, Radix Scutellariae total flavones dispersible tablet primary stability experiment
Three batches of Radix Scutellariae total flavones dispersible tablets (010618,010620,010625) prepared by the prescription determined according to the present invention, technique carry out primary stability test.Concrete test method and result as follows:
Room temperature reserved sample observing method
Medicine: lot number 010618,010620,010625, river Chinese medicine provided.
Experimental procedure: under three batch samples (two In Aluminium Foil Packing) are put normal room temperature, at 0 month, 1 month, 2 months, within 3 months, indices was made regular check at interval, the results are shown in Table 47, table 48, table 49.
Table 47. room temperature reserved sample observing report sample lot number: 010618
Table 48. room temperature reserved sample observing report sample lot number: 010620
Table 49. room temperature reserved sample observing report sample lot number: 010625
Conclusion: according to the room temperature reserved sample observing result to three batch samples, shows that Radix Scutellariae total flavones dispersible tablet was stable in three months.
Low temperature Acceleration study
Medicine: lot number 010618,010620,010625, river Chinese medicine provided.
Experimental procedure: this product (two In Aluminium Foil Packing) put under the condition of constant temperature (37-40 DEG C), relative humidity 75% and preserve 3 months, monthly (0,1,2, March) timing sampling, inspection indices, the results are shown in Table 50, table 51.
Table 50. low temperature accelerated test report sample lot number: 010618
Table 51. low temperature accelerated test report sample lot number: 010620
Result shows, this product is stablized 3 months low temperature accelerated tests, and therefore its effect duration can be fixed tentatively is 2 years, but its effect duration should be determined according to after the final result of continuation room temperature reserved sample observing again.
One skilled in the art will understand that the embodiments of the invention shown in foregoing description and accompanying drawing only limit the present invention as an example and not.Object of the present invention is complete and effectively realize.Function of the present invention and structural principle are shown in an embodiment and are illustrated, do not deviating under described principle, embodiments of the present invention can have any distortion or amendment.

Claims (20)

1. a Radix Scutellariae total flavones dispersible tablet, it is characterized in that, comprise Radix Scutellariae total flavones extract and adjuvant, wherein this adjuvant comprises the disintegrating agent being not less than this Radix Scutellariae total flavones dispersible tablet gross weight 8%, be not less than the filler of this Radix Scutellariae total flavones dispersible tablet gross weight 42.6%, be not less than the pyrrolidone of this Radix Scutellariae total flavones dispersible tablet gross weight 5%, residual components is extractive of general flavone, wherein in this extractive of general flavone, the composition of Radix Scutellariae total flavones is not less than 45%, wherein this disintegrating agent comprises carboxymethyl starch sodium and crospolyvinylpyrrolidone, this filler comprises microcrystalline Cellulose and TY.
2. Radix Scutellariae total flavones dispersible tablet as claimed in claim 1, it is characterized in that, this adjuvant also comprises lubricant and fluidizer further.
3. Radix Scutellariae total flavones dispersible tablet as claimed in claim 2, it is characterized in that, this lubricant is hydrophilic lubricant, this fluidizer is micropowder silica gel, wherein this hydrophilic lubricant accounts for 0.3% ~ 0.9% of this Radix Scutellariae total flavones dispersible tablet gross weight, and this differential silica gel accounts for 1% ~ 1.3% of this Radix Scutellariae total flavones dispersible tablet gross weight.
4. Radix Scutellariae total flavones dispersible tablet as claimed in claim 3, it is characterized in that, this hydrophilic lubricant accounts for 0.5% of this Radix Scutellariae total flavones dispersible tablet gross weight.
5. the Radix Scutellariae total flavones dispersible tablet as described in claim 1,2,3 or 4, it is characterized in that, wherein this Radix Scutellariae total flavones extract and this adjuvant are first made into granularity and are less than 30 object granules, and then this granularity are less than after 30 object granules mix with disintegrating agent, are pressed into dispersible tablet.
6. Radix Scutellariae total flavones dispersible tablet as claimed in claim 1, is characterized in that, comprises the sodium lauryl sulphate that is not less than this Radix Scutellariae total flavones dispersible tablet gross weight 0.5% and the micropowder silica gel higher than this Radix Scutellariae total flavones dispersible tablet gross weight 1.3% further.
7. a Radix Scutellariae total flavones dispersible tablet, it is characterized in that, comprise Radix Scutellariae total flavones and adjuvant, wherein this adjuvant comprises the disintegrating agent being not less than this Radix Scutellariae total flavones dispersible tablet gross weight 8%, be not less than the filler of this Radix Scutellariae total flavones dispersible tablet gross weight 42.6%, be not less than the pyrrolidone of this Radix Scutellariae total flavones dispersible tablet gross weight 5%, residual components is total flavones, and wherein this disintegrating agent comprises carboxymethyl starch sodium and crospolyvinylpyrrolidone, and this filler comprises microcrystalline Cellulose and TY.
8. Radix Scutellariae total flavones dispersible tablet as claimed in claim 7, it is characterized in that, this adjuvant also comprises lubricant and fluidizer further.
9. Radix Scutellariae total flavones dispersible tablet as claimed in claim 8, it is characterized in that, this lubricant is hydrophilic lubricant, this fluidizer is micropowder silica gel, wherein this hydrophilic lubricant accounts for 0.3% ~ 0.9% of this Radix Scutellariae total flavones dispersible tablet gross weight, and this differential silica gel accounts for 1% ~ 1.3% of this Radix Scutellariae total flavones dispersible tablet gross weight.
10. Radix Scutellariae total flavones dispersible tablet as claimed in claim 9, it is characterized in that, this hydrophilic lubricant accounts for 0.5% of this Radix Scutellariae total flavones dispersible tablet gross weight.
11. Radix Scutellariae total flavones dispersible tablets as described in claim 7,8,9 or 10, it is characterized in that, wherein this Radix Scutellariae total flavones and this adjuvant are first made into granularity and are less than 30 object granules, and then this granularity are less than after 30 object granules mix with disintegrating agent, are pressed into dispersible tablet.
12. Radix Scutellariae total flavones dispersible tablets as claimed in claim 7, is characterized in that, comprise the sodium lauryl sulphate that is not less than this Radix Scutellariae total flavones dispersible tablet gross weight 0.5% and the micropowder silica gel higher than this Radix Scutellariae total flavones dispersible tablet gross weight 1.3% further.
The manufacture method of 13. 1 kinds of Radix Scutellariae total flavones dispersible tablets, is characterized in that, comprises the following steps:
A) by high-speed stirring mixing machine, Radix Scutellariae extract and adjuvant are carried out being uniformly mixed granulation, Radix Scutellariae total flavones wherein in this Radix Scutellariae extract is not less than 45%, this adjuvant comprises disintegrating agent, filler, sodium lauryl sulphate, pyrrolidone, wherein this disintegrating agent comprises carboxymethyl starch sodium and crospolyvinylpyrrolidone, and this filler comprises microcrystalline Cellulose and TY; With
B) particle drying will be obtained, and through 30 mesh sieve granulate, obtain being not more than 30 order granules, add crospolyvinylpyrrolidone, micropowder silica gel and disintegrating agent to be mixed, compacting, obtain Radix Scutellariae total flavones dispersible tablet, wherein this disintegrating agent comprises carboxymethyl starch sodium and crospolyvinylpyrrolidone.
14. Radix Scutellariae dispersible tablet manufacture methods as claimed in claim 13, it is characterized in that, the granularity of Radix Scutellariae total flavones extract and adjuvant is all less than 100 orders.
15. Radix Scutellariae dispersible tablet manufacture methods as claimed in claim 13, it is characterized in that, this adjuvant also comprises lubricant and fluidizer further, wherein this lubricant is hydrophilic lubricant, this fluidizer is micropowder silica gel, wherein this hydrophilic lubricant accounts for 0.3% ~ 0.9% of this Radix Scutellariae total flavones dispersible tablet gross weight, and this differential silica gel accounts for 1% ~ 1.3% of this Radix Scutellariae total flavones dispersible tablet gross weight.
16. Radix Scutellariae dispersible tablet manufacture methods as claimed in claim 14, it is characterized in that, this adjuvant also comprises lubricant and fluidizer further, wherein this lubricant is hydrophilic lubricant, this fluidizer is micropowder silica gel, wherein this hydrophilic lubricant accounts for 0.3% ~ 0.9% of this Radix Scutellariae total flavones dispersible tablet gross weight, and this differential silica gel accounts for 1% ~ 1.3% of this Radix Scutellariae total flavones dispersible tablet gross weight.
The manufacture method of 17. 1 kinds of Radix Scutellariae total flavones dispersible tablets, is characterized in that, comprises the following steps:
A) by high-speed stirring mixing machine, Radix Scutellariae total flavones and adjuvant are carried out being uniformly mixed granulation, this adjuvant comprises disintegrating agent, filler, sodium lauryl sulphate, pyrrolidone, wherein this disintegrating agent comprises carboxymethyl starch sodium and crospolyvinylpyrrolidone, and this filler comprises microcrystalline Cellulose and TY; With
B) particle drying will be obtained, and through 30 mesh sieve granulate, obtain being not more than 30 order granules, add crospolyvinylpyrrolidone, micropowder silica gel and disintegrating agent to be mixed, compacting, obtain Radix Scutellariae total flavones dispersible tablet, wherein this disintegrating agent comprises carboxymethyl starch sodium and crospolyvinylpyrrolidone.
18. Radix Scutellariae dispersible tablet manufacture methods as claimed in claim 17, it is characterized in that, the granularity of Radix Scutellariae total flavones and adjuvant is all less than 100 orders.
19. Radix Scutellariae dispersible tablet manufacture methods as claimed in claim 17, it is characterized in that, this adjuvant also comprises lubricant and fluidizer further, wherein this lubricant is hydrophilic lubricant, this fluidizer is micropowder silica gel, wherein this hydrophilic lubricant accounts for 0.3% ~ 0.9% of this Radix Scutellariae total flavones dispersible tablet gross weight, and this differential silica gel accounts for 1% ~ 1.3% of this Radix Scutellariae total flavones dispersible tablet gross weight.
20. Radix Scutellariae dispersible tablet manufacture methods as claimed in claim 18, it is characterized in that, this adjuvant also comprises lubricant and fluidizer further, wherein this lubricant is hydrophilic lubricant, this fluidizer is micropowder silica gel, wherein this hydrophilic lubricant accounts for 0.3% ~ 0.9% of this Radix Scutellariae total flavones dispersible tablet gross weight, and this differential silica gel accounts for 1% ~ 1.3% of this Radix Scutellariae total flavones dispersible tablet gross weight.
CN201510281988.8A 2015-05-28 2015-05-28 A kind of Scullcap total-flavonoid dispersible tablet and its manufacturing method Expired - Fee Related CN105168156B (en)

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