CN105168156B - A kind of Scullcap total-flavonoid dispersible tablet and its manufacturing method - Google Patents

Abstract

The present invention provides a kind of manufacturing method of Scullcap total-flavonoid dispersible tablet, it is comprising steps of A) pass through high-speed stirring mixing machine, Baical Skullcap root P.E and auxiliary material are stirred mixing granulation, wherein the Scullcap total-flavonoid in the Baical Skullcap root P.E is not less than 45%, the auxiliary material includes disintegrating agent, filler, lauryl sodium sulfate, NP, wherein the disintegrating agent includes CMS-Na and PVPP, which includes microcrystalline cellulose and TY；With step B) by obtained particle drying, and through 30 mesh sieve whole grains, obtain that PVPP, superfine silica gel powder and disintegrating agent is added and is mixed, suppresses, obtains Scullcap total-flavonoid dispersible tablet, wherein the disintegrating agent includes CMS-Na and PVPP no more than 30 mesh particles.

Description

A kind of Scullcap total-flavonoid dispersible tablet and its manufacturing method

Technical field

The present invention relates to a kind of Scullcap total-flavonoid tablet and its manufacturing method more particularly to a kind of Scullcap total-flavonoid dispersible tablets And its manufacturing method.

Background technique

Radix scutellariae [Scutellaria baicalensis] is the famous traditional Chinese medicine in China, is recorded earliest in " legendary god of farming's book on Chinese herbal medicine Through ", it is classified as grass roots medicine top grade.Chinese medicine thinks that radix scutellariae has heat-clearing and damp-drying drug, and purging fire for removing toxin is stopped blooding, and the function of miscarriage prevention is used for dysentery, Cough with lung heat, pyreticosis and polydipsia, jaundice, red eye, swell pain, accumulated heat haematemesis, threatened abortion, the diseases such as carbuncle swells boil.The effective component of radix scutellariae For flavonoids, is extracted from radix scutellariae at present and identify that the flavones ingredient of structure existing ten is several.Modern pharmacological studies have shown that yellow A kind of reed mentioned in ancient books flavones has antibacterial, decompression, calmness, diuresis, cholagogue, anti-inflammatory, antiallergic action isoreactivity.Existing single preparation of baikal skullcap root agent Type has ordinary tablet, injection, nasal drop etc..

Dispersible tablet is the novel form occurred the eighties, refers to that chance water energy is disintegrated rapidly and forms the non-of uniform Viscous suspension liquid Coating tablet.It has convenient to take, absorbs fast, bioavilability height and the small feature of adverse reaction increasingly cause the pass of people Note.Dispersible tablets of traditional Chinese medicine so far there are no document report, there is no launch.By dispersible tablet, this novel form is applied to for the first time for this research The exploitation of two kind new medicine of Chinese medicine, and expand disease treatment range.Since radix scutellariae active component, such as root are insoluble in water, it is made Dispersible tablet can shorten disintegration time, can form uniform suspension after disintegration, be conducive to the dissolution of drug, can be effective rapidly.Point Discrete piece not only can be swallowed directly, can also put into water after dispersing and take, be suitable for the patient of dysphagia especially.

One, the research overview of dispersible tablet

Tablet is one of current most widely used oral dosage form, it has dosage accurate, and quality is stablized, take with The advantages that storage is convenient, mechanization production, the dissolution rate and bioavilability of usual tablet are good compared with pill, but tablet also has much Disadvantage needs in tablet that several excipient are added, and by compression forming, dissolution rate is slow compared with powder and capsule, influences it sometimes Bioavilability；Certain tablets and capsules are given old man, child and are gulped down since volume is larger or once need to often take multi-disc (grain) The patient of pharynx solid difficulty brings trouble.In this case, oral solution, suspension and emulsion etc. are more superior, but Liquid preparation has the shortcomings that medicine stability difference and storing are inconvenient again.In the past 20 years, foreign countries develop chance water and can quickly form The non-packet garment piece of uniform Viscous suspension liquid, i.e. dispersible tablet (dispersible tablets).

1. the Recent Advances of dispersible tablet

It is reported that the external dispersible tablet listed has aspirin dispersible tablet, compound aspirin dispersible tablet, compound sulfonamide First oxazole dispersible tablet, piroxicam dispersible tablet, ranitidine dispersible tablet, paracetamol compound dispersible tablet, Diclofenac dispersible tablet, Mefenamic acid dispersible tablet, amoxycillin dispersible tablet, synergy amoxycillin dispersible tablet, Benserazide dispersible tablet etc. 10 More than.Aspirin dispersible tablet and Co-trimoxazole dispersible tablet are taken in for the first time within British Pharmacopoeia 1980.In addition, successively The also narcotine of listing, acyclovir, more than ten of Amoxicillin etc. kind.Chinese Pharmacopoeia version in 2000 has also taken in dispersible tablet This one dosage type low temperature, two annex have worked out quality standard general rule referring to British Pharmacopoeia 1993 editions: dispersible tablet is by disintegration time limit test It checks, unless otherwise specified, in (20 ± 1) DEG C water, 3min should be all disintegrated；Dispersing uniformity inspection: taking dispersible tablet 2, It sets in 100ml water and shakes, should be completely dispersed and by No. 2 sieves；Dispersible tablet presses the inspection of dissolution test method, should meet regulation.State Drug Administration of family approved new drug has clarithromycin, Azithromycin dispersible tablet etc..Domestic development is dispersed at present There are many unit of piece, declare and forming climax, such as: roxithromycin dispersing tablet has 23 to declare, and clarithromycin has 27 Family declares, and Azithromycin dispersible tablet is declared up to 58.

2. the characteristics of dispersible tablet

" British Pharmacopoeia " dispersible tablet formulation general rule regulation: dispersible tablet refers to that uniform Viscous suspension liquid can be quickly formed by meeting water Non-packet garment piece.Dispersible tablet should be disintegrated in 3min in 19-21 DEG C of water, and dispersible tablet is put into 100ml water, be stirred to complete Particle should all pass through 710 μm of sieve after disintegration.

Dispersible tablet is mainly adapted to: 1. insoluble drug and having the drug carbamazepine of bioavailability concerns not dissolve in Water, common formulations are tablet, and oral absorption is slow and incomplete, and dissolution rate is extremely difficult to pharmacopoeial requirements.

2. the big drug of dosage: such as paracetamol, oxaprozine once need to often take multi-disc since dosage is big, Especially inconvenience is brought to the patient of old, children and dysphagia.Dispersible tablet, which meets water, to be disintegrated to form homogenous suspension rapidly, comprehensive The advantages of tablet and liquid preparation, and avoid its disadvantage.Dispersible tablet be not suitable for that toxic side effect is larger, safety coefficient is lower and Drug soluble easily in water, therefore the exploitation of this kind of dosage form should be selectively, not every ordinary tablet is all preferably changed to dispersion Piece.

Dispersible tablet is compared with effervescent tablet: dispersible tablet can be disintegrated within 3min into the water with effervescent tablet, different It is that homogenous suspension is formed after dispersible tablet disintegration, effervescent tablet forms solution；Effervescent agent (such as carbon is not needed in the prescription of dispersible tablet Hydrochlorate and solid organic acid) and water soluble adjuvant, preparation process it is identical with general non-packet garment piece；It is mildly relatively wet to be not required to control room Degree；It takes or swallows after can dispersing in water, chew clothes.It follows that dispersible tablet have the advantages that than effervescent tablet it is more.

Dispersible tablet is compared with ordinary tablet, capsule: (1) dispersible tablet can be disintegrated in 3 minutes point in (20 ± 1) DEG C water It dissipates and can be by 710 μm of sieve, therefore absorbs fast, bioavilability height, it is suitable with oral suspensions.With ordinary tablet, capsule Agent is compared, and the advantage of dispersible tablet is 1. to be disintegrated and dissolve out rapidly.The dissolution rate t of aspirin dispersible tablet₅₀=1.161min, t_d =2.109min, the dissolution rate t of amoxicillin dispersible tablet₅₀=1.62min, t_d=2.46min, considerably beyond the general of the medicine Tablet.2. bioavilability is high, suitable with oral suspensions.Double chlorine aromatic acid dispersible tablets are together with enteric coatel tablets with 12 healthy will Hope person studies its relative bioavailability.It was found that the blood medicine peak time of dispersible tablet shifts to an earlier date 1.5-4.25h than enteric coatel tablets.And disperse There is second peak value to piece in 2-2.5h upon administration.Dispersible tablet starts to absorb fastly, is suitable for acute pain patient.Amoxicillin point Discrete piece (500mg) is oral after swallowing to 12 healthy volunteers, dispersing in water and takes suspension and capsule (equal 500mg) survey Determine relative bioavailability.The result shows that two kinds of oral ways of dispersible tablet and suspension are bioequivalences, it is average than capsule Maximum blood concentration is high by 33%, and area under the curve (AUC) is high by 23%.It is shown in Table 1.

The bioavilability of 1. amoxycillin different dosage forms of table

There is document to prepare brufen dispersible tablet and compared with marketed tablet in the intracorporal pharmacokinetics of rabbit and biology benefit Expenditure, as a result brufen dispersible tablet and control drug brufen ordinary tablet C_maxRespectively (9.79 ± 2.25) and (4.54 ± 1.50)μg/ml；T_maxRespectively (0.27 ± 0.07) and (2.03 ± 0.53) h；t_1/2Respectively (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.Brufen dispersible tablet and control The relative bioavailability of drug brufen ordinary tablet is 164.11%.The bioavilability of brufen dispersible tablet is significantly better than general Logical piece.

(2) conventional tablet, the volume of capsule are larger, or once need to often use multi-disc (grain), especially give old, children and swallow The Case treatment that solid has difficulties brings trouble.Dispersible tablet takes orally excellent after there is disintegration rate can disperse into the water fastly Point.Sweetener and corrigent can also be added.

3. the prescription and technique of dispersible tablet

The composition of dispersible tablet still forms highly viscous swelling auxiliary material containing disintegrating agent and chance water in addition to drug.Control Disperse the key factor of tablet quality, first is that suitable auxiliary material is selected, second is that the granularity of control drug and auxiliary material.

(1) Formulation of discrete piece

1. diluent: microcrystalline cellulose, mannitol and starch etc. can be used.

2. disintegrating agent: high-quality disintegrating agent being widely applied in dispersible tablet.Identical health summary thinks that good disintegrating agent is usually Refer to that swellbility is greater than the auxiliary material of 5ml/g.Such as sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), crosslinking Polyvinylpyrrolidone (PVPP), croscarmellose sodium (CMC-Na) etc..Generally the lesser starch of swellbility is not selected, Microcrystalline cellulose (MCC) and In Natural Silicate magnalium.Jia Yan etc. once formed sediment to carboxymethyl in the prescription screening of Famotidine Dispersible Tablet The dosage of powder sodium made detailed research, the results showed that and the influence of 1%~2% pair of disintegration is unobvious (1.8-1.6min), and 3% ~7% obviously accelerates disintegration (0.8-0.7min), and 8%~10% delays disintegration (1.1-1.7min) instead.Dispersible tablet can Use a kind of or a kind of upper disintegrating agent.Using a kind of disintegrating agent have paracetamol dispersible tablet, brufen dispersible tablet, Oxaprozine dispersible tablet, ketoprofen distribution piece, paracetamol dispersible tablet, compound flu dispersible tablet etc..Use two or more Have Famotidine Dispersible Tablet, nimesulide dispersible tablet, carbamazepine dispersible tablet etc..Disintegrating agent sometimes in plus, sometimes Nei Jia with It is additional to share.Additional disintegrating agent makes disintegration of tablet at coarse granule, serves for the first time；And it is interior plus then make coarse granule it is secondary disintegration be thin Particle.The disintegrating agent usage amount of dispersible tablet is big, for example, with 2%~5% when CMS-Na, L-HPC are used alone in general tablet Dosage reached, and often a kind of when several disintegrating agent use in conjunction in dispersible tablet is just more than this dosage.

3. being swollen auxiliary material: the swelling auxiliary material of dispersible tablet can be used guar gum, XANTHAN GUM, alginates, glucan, compressibility and form sediment Powder, polysaccharide, hydrophilic cellulose derivative (such as calcium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose). Microcrystalline cellulose is excellent filler and disintegrating agent, and suspending agent is mainly used as in dispersible tablet, disintegration is had both and suspending is dual Effect.Amylum pregelatinisatum has good compressibility and mobility, has the effect of promoting drug-eluting.

4. adhesive: the adhesive of dispersible tablet mostly uses greatly hydrophilic adhesive, such as hydroxypropyl methylcellulose (HPMC) and poly- It ties up ketone (PVP), wherein applying wide aqueous solution or dilute alcohol solution for PVP.Minority uses starch slurry.To hydrophobicity medicine Object makees adhesive with PVP aqueous solution, is not only easy to uniformly moisten, and hydrophobic drug particle surface can be made to become hydrophily, have Conducive to medicine disintegration and dissolution.

5. surfactant: the use of surfactant can significantly promote the disintegration of tablet and the dissolution of drug.Wherein compared with The most commonly used is lauryl sodium sulfate (SLS).Cimetidine dispersible tablet is the case where adding Surfactant SDS Under, dissolution rate is obviously accelerated.It is shown in Table 2.

2. sago of table replaces influence of the SLS to drug-eluting percentage in dispersible tablet of waking up

6. glidant: vapor-phase silica i.e. superfine silica gel powder being widely used in dispersible tablet as glidant.Superfine silica gel powder With good mobility, there is biggish absorption power to drug, hydrophilic ability is strong, and dosage can accelerate tablet at 1% or more Disintegration, be conducive to the dissolution of drug.

7. lubricant: hydrophilic lubricant multi-purpose greatly in dispersible tablet, such as talcum powder or talcum powder and magnesium stearate, hydrogenation castor Sesame oil shares, or with hydrophilic lubricant sodium stearyl fumarate, or with soluble oil PEG-6000.

(2) preparation process of piece at

For most of insoluble drugs, process in leaching is often the main fast process of drug absorption, thus also directly certainly Determine the bioavilability of drug.The key for improving drug dissolution in solid dosage forms is to increase surface area and the raising of drug Its solubility.But with the increase of specific surface area, the surface free energy of particle is also increased with it, and reaches a certain level rear free energy It can lower automatically, small particles can reassemble, and the aggregation of particle be hindered instead, and increase the wettability of particle surface, to mention The dissolution of high drug.

The method of granulating of dispersible tablet: the preparation process of dispersible tablet is identical as general tablet.Therefore method of granulating is also identical.Often Method of granulating has fluid-bed marumerization, High Shear Mixer Granulator and squeezes granulation.Particle made of fluid-bed marumerization Almost spherical, granularity is small and uniform, and particle has stomata, thus mobility and compressibility are preferable, and drug-eluting might as well.It squeezes Though compacting grain can also prepare dispersible tablet, granular mass is generally poor, influences the disintegration and dissolution of tablet.

Grain diameter requirement: drug dissolution is related with grain diameter size, and partial size is smaller, and drug-eluting is faster, dispersion The wet grain of piece is required in 1mm (18 mesh) hereinafter, dry particl whole grain will be in 0.6mm (30 mesh) hereinafter, even requiring in 0.305mm (about 50 mesh) is hereinafter, this is thin more than the particle of general tablet.For the requirement for adapting to high speed tabletting, the mobility of dispersible tablet particle It is better, generally aerating phase superfine silica gel powder is glidant.

In conclusion dispersible tablet has many advantages, such as that drug-eluting speed is fast, bioavilability height and adverse reaction are small, use Conventional tablet production equipment can produce, and be a kind of novel troche having a extensive future.In recent years, what China put into production is medicinal auxiliary Material has sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, amylum pregelatinisatum (pregelatinized starch), sucrose fatty ester etc. a variety of The good auxiliary material of disintegrating property, there are also other auxiliary materials such as I, II, III, No. IV acrylic resin and superfine silica gel powder also to have listed.I Should discuss the prior art, using state-owned auxiliary material, develop new dispersible tablet, fundamentally solve old product quality problems.

Two, radix scutellariae research overview

Radix scutellariae is the dry root of Lamiaceae plant radix scutellariae (Scutellaria baicalensis Geori).In common Medicine has the effects of clearing heat-fire, removing toxic substances, hemostasis, miscarriage prevention.It is swollen for damp-heat dysentery, cough with lung heat, pyreticosis and polydipsia, jaundice, hot eyes Bitterly, the diseases such as accumulated heat haematemesis, threatened abortion, carbuncle swells boil.

Chemical component: contain a variety of flavone derivatives, wherein mainly having scutelloside, wogonoside, qroxylin A glucose Aldehydic acid glycosides, baicalein, wogonin.Also containing about 30 kinds of flavonoids such as neobaicalein I, II, qroxylin A, chrysins Object.In addition, still contain cupreol, and benzoic acid, radix scutellariae fecula.

Constituent analysis: many has been carried out to content determination of Baicalin method in radix scutellariae and its compound preparation nearly ten years and has been ground Study carefully.It is wherein more common to have ultraviolet spectrophotometry, thin layer chromatography scanning and high performance liquid chromatography." Chinese Pharmacopoeia " (95 editions) receipts Content determination of Baicalin method has been carried, has been the directly measurement at the ± 1nm of λ=278 using ultraviolet method.Huang Laojin is to radix scutellariae and its again Content determination of Baicalin method in radix scutellariae and its compound preparation is summarized in square preparation.

Pharmacological research: pharmacologically it has been confirmed that scutelloside has antibacterial, heat-clearing, decompression, calmness, diuresis, cholagogue, anti-inflammatory resistance The effects of state reaction, removing toxic substances.Baicalein is specific 12- lipoxygenase inhibitor.It is relatively more to the pharmacological research of baicalein.It is yellow Maturation has been attained in the extraction of the effective component and main component of a kind of reed mentioned in ancient books, research and technique at home.Even if existing in patent medicine, using effective Position, such as the preparation of root or effective component also its not general example.Single radix scutellariae and compound preparation of baikal skullcap root all have clearing heat and detoxicating work With simultaneous to control acute cell and acute viral disease.Main dosage form is injection, and minority is tablet, capsule.Single radix scutellariae Preparation has scutelloside piece, baicalin for injection liquid, baicalein injection, baicalein aluminium glue capsule etc..Compound preparation has 'Shuang Hualian ' injection Liquid, Fufang Huangqin Tablets by HPLC, cattail pollen injection, compound radix scutellariae injection, Yin Zhi Huang injection etc..

Summary of the invention

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid pieces that can be disintegrated rapidly, dissolve out, absorb, work Agent can swallow, and chew clothes, containing sucking, can also add water dispersion at suspension, old young patient is suitble to take.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablets, wherein the Scullcap total-flavonoid dispersible tablet needle Water is insoluble in Baical Skullcap root P.E, but clinical treatment need to be used again and be developed the characteristics of quick-effective preparation, the Scullcap total-flavonoid point Discrete piece can make drug be disintegrated dissolution absorption rapidly, work.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablets, wherein the Scullcap total-flavonoid dispersible tablet needle Big to common traditional Chinese medicine tablet medicinal extract volume, viscosity is strong, and auxiliary material needed for tabletting is more, and the big disadvantage of dose develops, and wherein should Scullcap total-flavonoid dispersible tablet uses radix scutellariae active component, and if root is main ingredient raw material, auxiliary material only accounts for 55%, keeps patient's dose big It is big to reduce, also reduce cost.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablets, and wherein the Scullcap total-flavonoid dispersible tablet can Disintegration forms homogenous suspension in 3 minutes in 20 ± 1 DEG C of water.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablet, the wherein Scullcap total-flavonoid dispersible tablet The Adding Way of disintegrating agent is the disintegrating agent addition that interior addition and outer addition combine, so that the Scullcap total-flavonoid dispersible tablet Tablet can be disintegrated into coarse granule rapidly, and make coarse granule be dispersed into rapidly again fine grained formed homogenous suspension.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablet, the wherein Scullcap total-flavonoid dispersible tablet The granularity of Baical Skullcap root P.E is not less than 100 mesh, so that the Scullcap total-flavonoid dispersible tablet has good suspension ability after disintegration.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablet, the wherein Scullcap total-flavonoid dispersible tablet Disintegrating agent can guarantee that the hardness of the existing qualification of tablet can be disintegrated in 3min again with adhesive.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablet, the wherein Scullcap total-flavonoid dispersible tablet Disintegrating agent includes PVPP and CMS-Na.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablets, wherein in the Scullcap total-flavonoid dispersible tablet Surfactant SDS, promote the disintegration and dissolution of tablet with can dramatically.In addition, surfactant sodium dodecyl The concentration of base sodium sulphate is 0.54%, significantly Scullcap total-flavonoid can be helped to dissolve.

The main purpose of the present invention is to provide a kind of Scullcap total-flavonoid dispersible tablet, the wherein Scullcap total-flavonoid dispersible tablet Granulation by high-speed mixer stirring granulation, the raw material for being made the Scullcap total-flavonoid dispersible tablet mixed in a turret vessel, It mediates, pelletize and compared with traditional extruding granulation, have the characteristics that province's process, easy to operate, quick.Fluidized bed granulation energy handle Mixing, granulation, drying are completed in an equipment, which obtains that grain graininess is more uniform, and completely, good fluidity has simplified work Sequence.

The present inventor also further research and with the appearance of flavones dispersible tablet, hardness, disintegration time limited, be uniformly dispersed Degree is index, filters out the type of prescription auxiliary material, heating differential analysis method shows that selected auxiliary material does not interact with drug；With Dissolution in vitro T₅₀For index, prescription auxiliary material proportion is optimized using orthogonal experiment；Ultraviolet spectrophotometry is surveyed The content for determining Scullcap total-flavonoid dispersible tablet Scullcap total-flavonoid has carried out methodological study, to Scullcap total-flavonoid dispersible tablet In Vitro Dissolution Test method and condition are investigated；Three kinds of dispersible tablet different method of granulating are compared.

This paper experimental data show Scullcap total-flavonoid dispersible tablet disintegrating agent be sodium carboxymethyl starch and crospovidone, Diluent is TY (l-tyrosine), and adhesive is NP (pyrrolones), and the optimum proportioning of auxiliary material has been determined；Determine ultraviolet spectrometry light The method that degree method measures Scullcap total-flavonoid content in Scullcap total-flavonoid dispersible tablet filters out 0.54% lauryl sodium sulfate as Huang The dissolution medium of a kind of reed mentioned in ancient books total flavones dispersible tablet establishes dispersible tablet dissolution determination method and dissolves out parameter with computer Program extraction Method；The process conditions that Scullcap total-flavonoid dispersible tablet is prepared using High Shear Mixer Granulator method have been determined.Pilot scale setting-out shows it Preparation process meets mass production requirement, and obtained Scullcap total-flavonoid dispersible tablet disintegration time is lower than 3min, and particle is mixed after disintegration It is outstanding uniform, and the requirement of dispersible tablet can have been reached by 710 μm of sieves.

In addition, the present invention also provides Scullcap total-flavonoid dispersible tablet method of quality control, it is total using HPLC method measurement radix scutellariae The content of radix scutellariae B component in flavones dispersible tablet, and to moisture, hardness, tablet weight variation, disintegration time limited, dispersed homogeneous degree, dissolution rate And microorganism is controlled.The result shows that the rate of recovery that the present invention provides the radix scutellariae B component of method of quality control is 99.12%, Precision is high, shows.Each inspection item meets the requirements.The quality control standard of the dispersible tablet can react this comprehensively The quality of preparation, method is easy, practical.

The present invention has also carried out preliminarily stabilised Journal of Sex Research: by three batches of samples (double aluminum foil packaging) set respectively room temperature and 40 DEG C, Under the conditions of relative humidity 75%, periodically checked 0 month, January, 2 months, March, the results showed that this preparation be it is stable, effectively It is 2 years that phase, which can fix tentatively,.

By research, this invention also solves the difficult points and key problem in technology of dispersible tablets of traditional Chinese medicine preparation, are substantially finished Research work in terms of two kind new medicine preparation process of medicine.

Radix scutellariae active component is used it is a further object of the present invention to provide a kind of, if root is raw material, auxiliary material usage amount Few Scullcap total-flavonoid dispersible tablet can reduce drug production cost and reduce Patient drug's usage amount.

There is provided a kind of Scullcap total-flavonoid dispersible tablets of disintegrating agent containing high swelling property for another advantage of the present invention simultaneously Its suitable amounts is provided, to guarantee that dispersible tablet Quick uniform disperses.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoid dispersible tablet for adding suitable surfactant, with Mobility of particle is improved, the wetability of tablet promotes the disintegration of tablet and the dissolution of drug.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoid dispersible tablets with high-quality adhesive, and provide The preferable amount of adhesive.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoid dispersible tablets with high-quality filler, have particle There is higher flow ability, thus both there is height compressibility, biggish elastic restoring force will not be generated and cause loose pieces.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoids to disperse piece making method, the wherein addition of disintegrating agent Addition inside and outside method selection.It is additional that tablet is made to be disintegrated into coarse granule rapidly, it is interior plus coarse granule is made to be dispersed into fine grained rapidly again Form homogenous suspension.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoids to disperse piece making method, and wherein radix scutellariae uses 100 Mesh fine powder keeps its dissolution fast, and suspension ability is good after disintegration.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoids to disperse piece making method, wherein surface-active is added Agent lauryl sodium sulfate promotes the disintegration and dissolution of tablet in which can dramatically.Surfactant can reduce tablet surface tension, increase The wetability for adding tablet makes moisture borrow the capillarity of tablet, penetrates into label rapidly, accelerates disintegration rate, is conducive to increase Solubilization goes out.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoids to disperse piece making method, wherein the letter of this method process It is single, easy to operate, quick, Scullcap total-flavonoid dispersion sheet hardness it is big, good appearance, completely, and disintegration time limited meets the requirements, Dissolution is rapid.

It is a further object of the present invention to provide a kind of Scullcap total-flavonoids to disperse piece making method, wherein selecting 0.54% ten Sodium dialkyl sulfate is dissolution medium, increases the solubility of Scullcap total-flavonoid, drug-eluting is complete.

According to the present invention, aforementioned and its other purposes can be achieved by a kind of Scullcap total-flavonoid dispersible tablet, wherein Scullcap total-flavonoid dispersible tablet includes radix scutellariae total flavone extract and auxiliary material, and wherein the auxiliary material includes not less than the Scullcap total-flavonoid point The disintegrating agent of discrete piece gross weight 8%, not less than the filler of the Scullcap total-flavonoid dispersible tablet gross weight 42.6%, not less than the radix scutellariae it is total The lauryl sodium sulfate of flavones dispersible tablet gross weight 0.5%, not less than the NP (pyrroles of the Scullcap total-flavonoid dispersible tablet gross weight 5% Ketone), not less than the superfine silica gel powder of the Scullcap total-flavonoid dispersible tablet gross weight 1.3%, residual components are extractive of general flavone, wherein In the extractive of general flavone, the ingredient of Scullcap total-flavonoid is not less than 45%, and wherein the disintegrating agent includes CMS-Na and PVPP, this is filled out Filling agent includes microcrystalline cellulose and TY (l-tyrosine).

On the other hand, the present invention also provides a kind of manufacturing method of radix scutellariae dispersing agent, include the following steps:

Step A: Scullcap total-flavonoid, filler and disintegrating agent one are mixed, mixture one is obtained；

Step B: the mixture one is mixed with adhesive and surfactant, obtains mixture two；

Step C: mixture two is dried；

Step D: forming after dry mixture two is mixed with disintegrating agent two and glidant, obtains Scullcap total-flavonoid point Discrete piece.

Detailed description of the invention

Figure 1A~1J is each main ingredient of Scullcap total-flavonoid dispersible tablet according to the present invention and the differential thermal analysis curve of auxiliary material.

Fig. 2 is the uv absorption spectra of Scullcap total-flavonoid according to the present invention.

Fig. 3 is Scullcap total-flavonoid standard curve, show in ultraviolet spectrophotometry the concentration of Scullcap total-flavonoid solution with Linear relationship between trap.

Fig. 4 is the uv absorption spectra of the mixed accessories of Scullcap total-flavonoid dispersible tablet according to the present invention.

Fig. 5 is the ultraviolet suction of mixed accessories of the Scullcap total-flavonoid dispersible tablet in addition to lauryl sodium sulfate according to the present invention Receive spectrogram.

Fig. 6 is the uv absorption spectra of the aqueous solution of Scullcap total-flavonoid according to the present invention.

Fig. 7 is the uv absorption spectra of PH6.8 phosphate buffer according to the present invention.

Fig. 8 is the uv absorption spectra containing 0.54% lauryl sodium sulfate aqueous solution according to the present invention.

Fig. 9 is shown in the dissolution medium screening process of Scullcap total-flavonoid dispersible tablet according to the present invention, and difference dissolution is situated between The cumulative defaultlogic of matter.

Figure 10 is 0.54% lauryl sodium sulfate aqueous solution of the blank auxiliary of Scullcap total-flavonoid according to the present invention Uv absorption spectra.

Figure 11 is 0.54% lauryl sodium sulfate of the blank auxiliary without lauryl sodium sulfate according to the present invention The uv absorption spectra of aqueous solution.

Figure 12 is the particle size distribution figure for squeezing particle obtained by granulation according to the present invention.

Figure 13 is the particle size distribution figure of High Shear Mixer Granulator method gained particle according to the present invention.

Figure 14 is the particle size distribution figure of fluidized bed granulation method gained particle according to the present invention.

Figure 15 shows the accumulation dissolution hundred of three kinds of different method of granulating of Scullcap total-flavonoid dispersible tablet according to the present invention Divide rate.

Figure 16 shows superfine silica gel powder dosage in astragalus dispersible tablets manufacturing process according to the present invention and stops for dry particl The influence at angle.

Figure 17 shows the moisture equilibrium at dry side of the dry particl in Scullcap total-flavonoid dispersible tablet manufacturing process according to the present invention songs Line.

Figure 18 is the flow chart of the manufacturing process of Scullcap total-flavonoid dispersible tablet according to the present invention.

Figure 19 is the high-efficient liquid phase chromatogram of negative control solution according to the present invention.

Figure 20 is the high-efficient liquid phase chromatogram of reference substance solution according to the present invention.

Figure 21 is the high-efficient liquid phase chromatogram of sample solution according to the present invention.

Specific embodiment

It is described below for disclosing the present invention so that those skilled in the art can be realized the present invention.It is excellent in being described below Embodiment is selected to be only used as illustrating, it may occur to persons skilled in the art that other obvious modifications.It defines in the following description Basic principle of the invention can be applied to other embodiments, deformation scheme, improvement project, equivalent program and do not carry on the back Other technologies scheme from the spirit and scope of the present invention.

The research of one, Scullcap total-flavonoid dispersible tablet formulation technique

(1) experimental material, reagent and instrument

1, experimental material: Scullcap total-flavonoid (river Chinese medicine is provided, and content is 65% ± 5%)

(pharmaceutical grade, Zhejiang Huzhou look forward to chemical pharmaceutcal corporation, Ltd to TY (l-tyrosine).Lot number: 010405)；Crystallite is fine Tie up plain (MCC, pharmaceutical grade, Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong, lot number 990110)；Lactose (pharmaceutical grade.Harbin pharmacy Factory, lot number: 960815)；CL (pharmaceutical grade, BASF Corp. of Germany's product)；

Sodium carboxymethyl starch (CMS-Na, imported from Holland packing)；Low-substituted hydroxypropyl cellulose (L-HPC, pharmaceutical grade, Zhejiang Rivers and lakes state chemical industry affiliated company, lot number 991029)；Lauryl sodium sulfate (sell, lot number by SLS, Tianjin chemical reagent wholesale department 981201)；Tween-80 (pharmaceutical grade, Shanghai Volkswagen pharmaceutcal corporation, Ltd, lot number 010524)；Superfine silica gel powder (pharmaceutical grade, Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong, lot number: 980924)；Hydroxypropyl methyl cellulose (HPMC, pharmaceutical grade, Zhejiang Huzhou Work affiliated company, lot number 981215)；NP (pyrrolones) (pharmaceutical grade, Zhejiang eyot chemical industry affiliated company, 980718).

2, reagent: agents useful for same is that analysis is pure.

3, key instrument: ZRS-4 intelligence digestion instrument (Radio Factory of Tianjin Univ.)；ZB-1C intelligent disintegration tester (University Of Tianjin Radio factory)；FT-2000 tablet friability detector (Tianjin silicon new science and technology Co., Ltd)；PYD-1 matrix agent hardness test Instrument (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)；(Shanghai is remote for ZDY-8 heavy type single-punch tablet press Dong Zhiyaojixiechang)；21 rush rotary tablet machine (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai)；Plum Teller moisture teller (Mettler-Toledo Instrument (Shanghai) Co., Ltd.).

(2) dispersible tablet composition

Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), sodium carboxymethyl starch, crospovidone, NP (pyrroles Ketone), lauryl sodium sulfate, superfine silica gel powder

(3) preparation process is studied

1, dosage form selection

(1) in prescription drug property: Scullcap total-flavonoid is the active component that extracts in radix scutellariae, such as root, in extract Scullcap total-flavonoid content is 60% ± 5%.This product is insoluble in water, is soluble in organic solvent.

(2) dosage form selection: since active component extracted in radix scutellariae, such as root are insoluble in water, clinic needs that speed is made Preparation is imitated, if ordinary tablet is made, drug-eluting is slow, it is difficult to reach requirement, dispersible tablet, which is made, can then significantly improve drug Dissolution, is rapidly reached curative effect.The advantages that dispersible tablet has stability good, easy to carry, transports, storage, convenient to take, not only may be used Directly to swallow, clothes can also be chewed, containing sucking or putting into water, be disintegrated rapidly in fruit juice, are taken after forming uniform suspension.Its Auxiliary material and preparation process are identical as general non-packet garment piece, are not required to increase equipment investment and production cycle, thus this product selection dispersion Tablet form.

2, the screening of dispersible tablet supplementary product kind

(1) Scullcap total-flavonoid dispersible tablet Formulation

According to literature survey, the basic prescription of Scullcap total-flavonoid dispersible tablet is determined are as follows: drug 45%, microcrystalline cellulose 46.2%, lauryl sodium sulfate 0.5%, adhesive NP (pyrrolones) concentration 3%, superfine silica gel powder 1.3%.On this basis, Filler, disintegrating agent and adhesive are filtered out from the common auxiliary material of dispersible tablet, drug is mixed with filler, disintegrating agent, is added Adhesive softwood, the lauryl sodium sulfate containing recipe quantity 0.5% in adhesive, the granulation of 30 meshes, 70 DEG C of dryings, 30 meshes Whole grain, adding 1.3% superfine silica gel powder is glidant, by regulation slice weight tabletting on single-punch tablet press.

(2) dispersible tablet auxiliary material screens quality evaluation index

Appearance: complete bright and clean, uniform color, without loose pieces, sliver.

Hardness: it with the measurement of tablet hardness tester, replication 10 times, is averaged.

Disintegration time limited: by Chinese Pharmacopoeia version regulation in 2000, disintegration time limited is measured in 19-21 DEG C of water.

Dispersed homogeneous degree: providing by British Pharmacopoeia 93 editions, take dispersible tablet 2 to be put into 100ml water, stirring to complete disintegration After disperse, be poured on 710 μm of sieve, should all pass through sieve.

(3) screening of filler

Using CMS-Na as disintegrating agent, lauryl sodium sulfate is lubricant, and superfine silica gel powder is glidant, and NP (pyrrolones) is Dispersible tablet is made with the different filler of table 1 in adhesive.It the results are shown in Table 3.

The screening of 3. filler of table

The result shows that: there is capping phenomenon separately as filler in starch, lactose.Icing Sugar makees filler good appearance, but Disintegration time is exceeded, therefore undesirable.With microcrystalline cellulose and NP (pyrrolones), individually making filler then reaches requirement. Wherein microcrystalline cellulose is expensive, therefore is considered as mixed filler.By comparing, determine with TY (l-tyrosine) with it is micro- Crystalline cellulose makees filler, and piece disintegration obtained is fast, is suspended uniformly, is easy granulation, fine powder is less.

(4) screening of disintegrating agent

Filler (microcrystalline cellulose: TY (l-tyrosine)=1:1), disintegrating agent is added, in drug with 3%NP (pyrroles Ketone) aqueous solution be adhesive, 0.5% dodecyl be lubricant, 1.3% micro mist silicon be glidant, with different disintegrating agent systems At dispersible tablet.The result shows that: it is applied alone PVPP effect best, is secondly L-HPC and CMS-Na, but PVPP is expensive, and L- The tablet of HPL compacting is hardened after placing, the extended tendency of disintegration time, therefore is considered as mixing disintegrating agent.Tested with Disintegrating agent is made in CMS-Na, PVPP mixing, has reached good effect.It is shown in Table 4.

The screening of 4. disintegrating agent of table

(5) screening of adhesive

Filler microcrystalline cellulose, TY (l-tyrosine) are added in drug, is lubrication with 0.5% lauryl sodium sulfate Agent, 1.3% superfine silica gel powder are glidant, and disintegrating agent CMS-Na, PVPP, respectively with 2%HPMC, 3%NP (pyrrolones) is water-soluble Liquid, 3%NP (pyrrolones) dilute alcohol solution are adhesive granulation, are pressed into dispersible tablet.The result shows that: 3%NP (pyrrolones) is water-soluble Liquid is that disintegration of tablet made of adhesive is fast, uniform color, complete beautiful；Particle made from 3%NP (pyrrolones) Diluted Alcohol liquid Fine powder is more, and has the phenomenon that capping；Tablet disintegration times made from 2%HPMC are longer.It is thus determined that adhesive is 3%NP (pyrrolones) aqueous solution.It is shown in Table 5.

The screening of 5. adhesive of table

(6) influence of the surfactant to disintegration of tablet

Surfactant can increase the wetability of tablet, makes moisture that capillarity be borrowed to penetrate into the piece heart rapidly and plays disintegration work With.It since this prescription drug is insoluble in water, is not easy to be soaked by water, therefore proper amount of surfactant is added.By main ingredient, microcrystalline cellulose Element, TY (l-tyrosine), 3%NP (pyrrolones), 1.3% superfine silica gel powder, CMS-Na and PVPP granulation, tabletting.The result shows that adding After entering Tween-80 or lauryl sodium sulfate, disintegration time be can be shortened, but granule fines increase.Dodecyl sulphate For sodium with lubricating action, the tablet of compacting is more attractive, therefore selects lauryl sodium sulfate.It is shown in Table 6.

Influence of 6. surfactant of table to disintegration of tablet

(7) influence of the disintegrating agent Adding Way to tablet

The Adding Way of disintegrating agent also has an impact to disintegration effect.Test selects CMS-Na, PVPP are all interior to add, CMS-Na It is interior plus, PVPP is additional contrasts, as a result in CMS-Na plus, the additional hardness of PVPP is big, and disintegration time is shorter, thus selects CMS- Plus, PVPP is additional in Na.It is shown in Table 7.

Influence of the 7. disintegrating agent Adding Way of table to tablet

(8) main ingredient is with auxiliary material repercussion study: the big auxiliary material of dosage (such as filler) is by main ingredient: auxiliary material=1:5 is mixed, Dosage few (such as disintegrating agent, glidant) presses main ingredient: auxiliary material=20:1 mixing carries out heating differential analysis.The result shows that selected auxiliary material It does not interact with main ingredient.See Figure 1A~1J (wherein Figure 1A is main ingredient, and Figure 1B~1J is auxiliary material)

(9) it determines primary election prescription: passing through above-mentioned test, obtain the prescription of preliminary screening are as follows: Scullcap total-flavonoid, microcrystalline cellulose Element, TY (l-tyrosine), CMS-Na, PVPP, 0.5% lauryl sodium sulfate, 1.3% superfine silica gel powder, 3%NP (pyrrolones) water Solution.

3. the optimization of ratio of adjuvant

Since dissolution rate can directly reflect the release characteristics of tablet Chinese traditional medicine, on the basis of above-mentioned test result On, with dissolution rate T₅₀For evaluation index, carried out with consumption proportion of the Three factors-levels orthogonal test to auxiliary material in primary election prescription Optimization.

The selection of factor level, is shown in Table 8.

8. factor level table of table

(2) preparation method of Scullcap total-flavonoid dispersible tablet

Scullcap total-flavonoid powder and each auxiliary material are sieved with 100 mesh sieve, weighed by 7 prescription of orthogonal arrage.By drug powder with it is micro- Crystalline cellulose, TY (l-tyrosine), CMS-Na and lauryl sodium sulfate mix, and add about 16mlNP (pyrrolones) aqueous solution system After 30 mesh sieves, PVPP is added in grain, 70 DEG C of dryings, and superfine silica gel powder is mixed, and is pressed into for test piece, is controlled for the hardness of test piece At 3.5 Kgfs or so.

(3) Orthogonal Experiment and Design

Because considering disintegrating agent and adhesive, there may be reciprocation between disintegrating agent and filler, therefore select L₁₈ (3⁷) test is arranged, test is repeated 3 times every time, and test result and variance analysis are shown in Table 9, table 10.

9. orthogonal experiments of table

10. analysis of variance table of table

F_0.01(2,39)=5.18；F_0.01(4,39)=3.83

(4) reciprocation of factor A and B, A and C.It is shown in Table 11, table 12.

The reciprocation of table 11. factor A and B

The result shows that: optimal collocation is A₂B₃。

The reciprocation of table 12. factor A and C

The result shows that: optimal collocation is A₂C₃。

Conclusion: variance analysis shows disintegrating agent, filler, adhesive to dissolution rate T₅₀It has a significant impact, primary and secondary is suitable Sequence are as follows: adhesive > filler > disintegrating agent.Reciprocation table shows that optimal collocation is A₂B₃C₃.I.e. disintegrating agent is total amount 8% (CMS-Na:PVPP)；Binder concn is 5%；Microcrystalline cellulose dosage is 24%.Thereby determine that Scullcap total-flavonoid dispersible tablet Composition are as follows: Scullcap total-flavonoid 45%, disintegrating agent (CMS-Na, PVPP) 8%, filler (microcrystalline cellulose, TY (L- junket ammonia Acid)) 42.6%, lauryl sodium sulfate 0.5%, NP (pyrrolones) 5%, superfine silica gel powder 1.3%.

(4) Scullcap total-flavonoid dispersible tablet In Vitro Dissolution is tested

Index used is dissolution rate T in orthogonal test₅₀, therefore before doing orthogonal test, to Scullcap total-flavonoid dispersible tablet In Vitro Dissolution test has carried out methodology examination.

Since index used in orthogonal test is T₅₀There are 18 prescriptions, each prescription 3 repeated experiments are equivalent to total palpus and survey 18 × 3=54 T₅₀, T₅₀It is each found out by 6 points, therefore 54 × 6=324 data must be measured altogether, if using high-efficient liquid phase color Spectrometry, instrument condition are had any problem, therefore are considered as ultraviolet spectrophotometry.

1, the methodological study of determined by ultraviolet spectrophotometry Scullcap total-flavonoid content

(1) instrument and reagent:

1. instrument: UV-1206 ultraviolet-visible spectrophotometer (Japanese Shimadzu), METTER AE240

Ten a ten thousandth assay balance (Switzerland) KQ3200 ultrasonic cleaners (Kunshan Ultrasonic Instruments Co., Ltd.)

The preparation of test sample: take Scullcap total-flavonoid dispersible tablet 20 it is finely ground, precision weigh about 0.01g in 50ml to 10ml hold In measuring bottle, 95% ethyl alcohol is added to be settled to scale, trap is measured at 276nm wavelength, calculates content.

2. reagent: agents useful for same is that analysis is pure.

(2) method and result

1. the determination of Detection wavelength

It takes 95% ethanol solution of Scullcap total-flavonoid to scan at 200~400nm wavelength, shows Scullcap total-flavonoid in 276nm There is maximum absorption band at wavelength.Therefore will test wavelength is set to 276nm.See Fig. 2.

2. the examination of linear relationship

Precision draws above-mentioned reference substance solution 0.10,0.25,0.40,0.55,0.70,0.85ml in 10ml volumetric flask, uses 95% ethyl alcohol is settled to scale, and it is molten to be made into the ethyl alcohol that concentration is 1.32,3.3,5.28,7.26,9.24,11.22,13.2 μ g/ml Liquid makees linear regression to concentration C with trap A, obtains regression equation: A=0.08011C+0.009298 (r=0.9999).

Scullcap total-flavonoid has good linear relationship in 1.32~13.2 μ g/ml concentration ranges, is shown in Table 13 and Fig. 3.

The trap of the reference substance solution of 13. various concentration of table

3. the determination of ultrasonic extraction time

With sample measuring method, extraction time is set as 15 minutes, 30 minutes, 45 minutes, 1 hour, test result showed 30min has been extracted completely, and residue is white after extraction.It is shown in Table 14.

The different ultrasonic extraction time test results of table 14.

4. reappearance test

Precision weighs 5 parts of sample (every part of about 0.01g), is placed in 50ml volumetric flask, and respectively plus 95% ethyl alcohol 40ml ultrasound mentions 30min is taken, is settled to scale with ethyl alcohol after letting cool, filters, 1ml is taken to be diluted in 10ml volumetric flask, measurement content is shown in Table 15.

The assay result of Scullcap total-flavonoid in 15. same batches of samples of table

5. recovery test: precision weighs Scullcap total-flavonoid and mixing blank auxiliary, then measures by said determination method Trap calculates content and the rate of recovery.It the results are shown in Table 16.

16. Scullcap total-flavonoid recovery test result of table

It counts: X=103.38, RSD%=1.34%.

6. blank interference test

Precision weighs the mixed accessories 0.0055g matched by prescription, is placed in volumetric flask, ultrasonic extraction with 40ml95% ethyl alcohol Half an hour quantitatively causes scale with 95% after letting cool, and takes 1ml to 10ml volumetric flask, scale is diluted to 95% ethyl alcohol, in 200- 400nm length scanning, discovery slightly absorb at 276nm, but influence less, to can be neglected, see Fig. 4.Separately take scarce dodecane The blank auxiliary of base sodium sulphate, operates by the above process, and in 200-400nm length scanning, discovery, without absorption, is shown at 276nm Fig. 5.Thus the interference component in provable mixed accessories is lauryl sodium sulfate.

7. sample measures: sample is taken, by the processing of test solution the preparation method, with determined by ultraviolet spectrophotometry trap, Calculate the content in sample.

2, the screening of dissolution medium

(1) dissolution medium: Scullcap total-flavonoid is insoluble in water, and the drug poor for some water solubilitys can dissolve out sometimes Proper amount of surfactant is added in medium, the most commonly used is lauryl sodium sulfate, we select water recently distilled herein, PH6.8 phosphate buffer, 0.54% lauryl sodium sulfate aqueous solution are that dissolution medium is screened.

(2) determination of Detection wavelength:

The aqueous solution of Scullcap total-flavonoid is used respectively, and PH6.8 phosphate buffer is water-soluble containing 0.54% lauryl sodium sulfate Liquid determines aqueous solution, PH6.8 phosphate buffer, 0.54% lauryl sodium sulfate aqueous solution in 200-400nm length scanning Detection wavelength be respectively 271.5nm, 267.5 and 276.5nm.See Fig. 6,7,8.

(3) paddle method, revolving speed 100r/min, temperature (37 ± 0.5) DEG C the determination of leaching condition: are selected.

(4) drafting of standard curve: the dry Scullcap total-flavonoid 0.001g to constant weight is weighed respectively in 3 100ml capacity In bottle, above-mentioned 3 kinds of dissolution mediums are separately added into, blank control is made with corresponding dissolution medium, measured and absorb in respective Detection wavelength Degree returns trap A with concentration C, obtains 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)

The result shows that: in 3 kinds of media, Scullcap total-flavonoid is in good linear relationship in 1-8 μ g/ml concentration range.

(5) cumulative defaultlogic (%) measures

Dissolution medium 1000ml ultrasonic degassing 15 minutes, carries out 2,5 in Scullcap total-flavonoid dispersible tablet dissolution test respectively, 10,20,30,45min samplings 5ml (filling into isothermal equivalent medium), through 0.8 μm of membrane filtration, precision measures 0.25ml and holds in 5ml Measuring bottle is quantitatively diluted to 5ml with respective media, and using respective media as blank control, absorbance is surveyed at corresponding Detection wavelength, It calculates cumulative defaultlogic (%), the results are shown in Table 17 and Fig. 9.

The cumulative defaultlogic (n=3, x ± s) of 17. 3 kinds of dissolution mediums of table

Note: 1. aqueous solutions；The phosphate buffer of 2.PH6.8；3.0.54% lauryl sodium sulfate aqueous solution

By comparing, using 0.54% lauryl sodium sulfate aqueous solution as dissolution medium.

3, the measurement of Dissolution of Tablet

(1) instrument and drug

UV-1206 type ultraviolet specrophotometer (Japanese Shimadzu)；ZRS-4 intelligence digestion instrument (Radio Factory of Tianjin Univ.)；

Scullcap total-flavonoid (river Chinese medicine is provided)；Scullcap total-flavonoid dispersible tablet (self-control).

(2) method and result

1. the drafting of standard curve

The Scullcap total-flavonoid that precision weighs drying to constant weight is appropriate, sets in 100ml measuring bottle, adds 0.54% dodecyl sulphate Sodium solution is diluted to scale.It is blank with 0.54% lauryl sodium sulfate aqueous solution, measures its suction respectively in 276.5nm wavelength Receipts degree A carries out linear regression to concentration C with A, obtains regression equation: A=0.092432+0.005429 (r=0.9999).As a result Show that Scullcap total-flavonoid has good linear relationship within the scope of 1.1~7.7 μ g/ml.

2. dissolution rate recovery test

Scullcap total-flavonoid is weighed by prescription proportion precision and blank mixed accessories carry out rate of recovery experiment, measures average recycling Rate is 97.36%.RSD=1.59%.It is shown in Table 18.

18. dissolution rate rate of recovery result of table

Average recovery rate: X=97.36%RSD%=1.59

3. blank interference test: 0.54% lauryl sodium sulfate aqueous solution of the blank auxiliary of scarce Scullcap total-flavonoid is taken, In 200~400nm length scanning, discovery is slightly absorbed in 276.5nm wave and strong point, but negligible.Separately take without 12 0.54% lauryl sodium sulfate aqueous solution of the blank auxiliary of sodium alkyl sulfate exists in 200~400nm length scanning, discovery 276.5nm wave and strong point it can thus be appreciated that the disturbing factor in blank auxiliary is lauryl sodium sulfate, but can be ignored not without absorption Meter, is shown in Figure 10,11.

4. assay: taking Scullcap total-flavonoid dispersible tablet powder about 0.01g to set 50ml volumetric flask, add 95% ethyl alcohol 40ml super Sound extracts 30min, is settled to scale with 95% ethyl alcohol after letting cool, and filters, and precision draws 1ml into 10ml volumetric flask, with 95% Ethyl alcohol is diluted to scale, measures trap at 276nm wavelength with ultraviolet spectrophotometry, calculates the content of Scullcap total-flavonoid.

5. the measurement of dissolution rate: measuring Scullcap total-flavonoid dispersible tablet according to Chinese Pharmacopoeia version annex dissolution method in 2000 Dissolution rate (n=6), using slurry processes, medium is 0.54% lauryl sodium sulfate aqueous solution, revolving speed 100r/min, and temperature is 37±0.5℃.5ml, the isometric dissolution medium of supplement isothermal are sampled respectively at 2,5,10,20,30,45min.It is used when sampling 0.8 μm of miillpore filter filtration, takes filtrate 0.25ml in 5ml volumetric flask, is settled to scale with dissolution medium, in 276.5nm wave Strong point surveys trap.

6. dissolving out the processing of data:

According to Weibull (Weibull) distribution function F (t)=e^-(t-α)m/t0, lnln (1/ (1-F is obtained after Mathematical treatment (t))=mln (t-a)-lnt₀, bibliography goes out T with Visual Basic6.0 program calculation₅₀, 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 suitable work The process route that industry metaplasia produces pelletizes to wetting, and three kinds of method of granulating of fast Speed mixer and fluidized bed granulation obtained Grain and tablet quality compare.

(1) Scullcap total-flavonoid dispersible tablet quality evaluation index

Disintegration time: it is provided by Chinese Pharmacopoeia 2000 editions, measures disintegration in 19-21 DEG C of water.

Dispersed homogeneous degree: according to 93 years version regulations of British Pharmacopoeia, two panels Scullcap total-flavonoid dispersible tablet test sample is put into In 100ml water, stirs to being completely dispersed, the sieve of 710 μ should be passed through.

Dissolution rate: it is measured according to dissolution determination method.

Tablet hardness: with the measurement of tablet hardness tester, replication 10 times, its average value is taken.

Tablet weight variation: by the regulation of Chinese Pharmacopoeia second annex of version in 2000,20 calculating average values are measured.

Tablet appearance: visually observing the unilateral smoothness of dispersible tablet, and whether there is or not situations such as piebald, loose pieces, sliver to occur.

(2) composition of Scullcap total-flavonoid dispersible tablet

Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), sodium carboxymethyl starch, crospovidone, dodecyl sulphur Sour sodium, superfine silica gel powder, 5%NT aqueous solution.

(3) different method of granulating tablettings

1. squeezing granulation: pressing recipe quantity for Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), sodium carboxymethyl starch It mixing well, 5%NP (pyrrolones) aqueous solution dissolved with lauryl sodium sulfate is added, softwood is made, 30 meshes are pelletized, and 70 DEG C drying, 30 mesh sieves of dry particl are added PVPP and superfine silica gel powder, are pressed into the dispersible tablet of the every 160mg containing general flavone.

2. High Shear Mixer Granulator: Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), carboxymethyl forming sediment by recipe quantity Powder sodium is set HLY-10 type and is mixed in granulator, first mixes, the 5%NP (pyrrolones) containing lauryl sodium sulfate is then added Aqueous solution is that adhesive is pelletized, and superfine silica gel powder is added in 70 DEG C of dryings, 30 mesh sieves of dry particl, and PVPP is pressed into every and contains The dispersible tablet of medicine 160mg.

3. fluidized bed granulation: by 2 times of recipe quantity by Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), carboxymethyl Sodium starch is set in FL-5 type boiling granulating device, using 5%NP (pyrrolones) aqueous solution containing lauryl sodium sulfate as adhesive system Superfine silica gel powder is added in grain, 70 DEG C of dryings, 30 mesh sieves of dry particl, and PVPP is pressed into the dispersible tablet of every drug containing 160mg.

(4) semi-finished granules quality compares

1. angle of repose: angle of repose is to indicate one of main method of interparticle force.The size at angle of repose can reflect The quality of grain mobility.The measurement at angle of repose uses fixed funnel method: funnel is fixed on to the top one of horizontal positioned drawing paper Set a distance, height of the mouth away from drawing paper is H under funnel, carefully pours into particle in funnel, until the circle formed under funnel Until the nib contacts of cone to the lower mouth of funnel, the diameter at cone bottom is 2R, then tg α=H/R, the angle α are angle of repose.Three The angle of repose that the different method of granulating of kind are made pellet is shown in Table 19.The result shows that mobility of particle obtained by fluidized bed granulation is best, Secondary is High Shear Mixer Granulator.It is poor to squeeze granulation gained mobility of particle.

The angle of repose that 19 3 kinds of table different method of granulating are made pellet

2. the size distribution that three kinds of different method of granulating are made pellet

Different method of granulating has apparent influence to particle size distribution, if fine powder particulate is excessive, when tabletting is also easy to produce Sliver, loose pieces, corner hair lack and phenomena such as stickings, therefore should control the granularity of particle.Test result shows: squeezing the thin of granulation Powder amount (< 100 mesh) is up to 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%.Granule fines made from High Shear Mixer Granulator are more moderate, are conducive to tabletting.And squeeze granulation and fluidized bed granulation Fine powder amount is higher.It is shown in Table 20,21,22 and Figure 12,13,14.

Table 20. squeezes granulation particle diameter distribution

21. High Shear Mixer Granulator particle diameter distribution of table

22. fluidized bed granulation particle diameter distribution of table

(5) influence of the different method of granulating to Scullcap total-flavonoid dispersion tablet quality

Particle obtained by different method of granulating has apparent influence, high speed to the quality of Scullcap total-flavonoid dispersible tablet Stirring is pelletized, and tablet hardness obtained is big, and good appearance, completely, and disintegration time limited meets the requirements, and dissolution is rapid.Squeeze granulation system The tablet mobility obtained is poor, and tablet hardness made from fluidized bed granulation does not reach requirement, and has capping phenomenon.It is shown in Table 21.

The different method of granulating of table 23. influence Scullcap total-flavonoid dispersion tablet quality

The Comparative Study on Dissolution of (6) three kinds of different method of granulating tablets

Granular mass made from different method of granulating is different, we use uniform pressure tabletting, then carries out dissolution rate ratio Compared with.

1. the measurement of the cumulative defaultlogic of three kinds of different method of granulating

The measurement of cumulative defaultlogic uses paddle method: taking 0.54% lauryl sodium sulfate aqueous solution 1000ml to be molten Medium out carries out 2,5,10,20,30,45min samplings 5ml (filling into isothermal equivalent medium immediately), warp in dissolution test respectively 0.8 μm of membrane filtration, precision measurement 0.25ml are quantitative dilute with 0.54% lauryl sodium sulfate aqueous solution in 5ml volumetric flask It releases to 5ml, using 0.54% lauryl sodium sulfate aqueous solution as blank control, absorbance is measured at 276.5nm wavelength, It calculates cumulative defaultlogic (%).The cumulative defaultlogic of tablet made from three kinds of result different method of granulating is without obvious Difference, be shown in Table 24 and Figure 15.

The cumulative defaultlogic of 24. 3 kinds of table different method of granulating

2. three kinds of different made Scullcap total-flavonoids of method of granulating disperse tablet dissolution T₅₀Single factor analysis

With dissolution rate T₅₀For index, one-way analysis of variance is carried out to dispersible tablet made from three kinds of different method of granulating, The result shows that three kinds of method of granulating are shown in Table 25 without apparent difference.

The T of the made dispersible tablet of the different method of granulating of table 25.₅₀

26. analysis of variance table of table

By the comparison of three of the above method of granulating, determine the High Shear Mixer Granulator method that uses, and to granulating process parameter into Row is investigated.

2, the research of High Shear Mixer Granulator technological parameter

Influence High Shear Mixer Granulator because being known as: the revolving speed of agitating paddle, granulating cutter, stir and Granulation time.Because of dispersible tablet Required particle is smaller, therefore we select paddle to open low speed, and granulating cutter opens high speed.

(1) determination of incorporation time: the mixing between solid cannot reach complete evenly distributed, can only achieve the equal of macroscopic view Even property, therefore usually with the method for statistical analysis.We use standard deviation sigma or variances sigma herein², it is more common simple side Method.

σ=[1/ (n-1) ∑ (x_i-x)²]^1/2

σ²=1/ (n-1) ∑ (x_i-x)²

N indicates frequency in sampling, x_iIndicate point rate that a certain component is sampled in I time, a certain component is flat in x expression sample Equipartition rate, with x=1/n ∑ x_iTheory instead of a certain component divides rate.In σ, σ²Calculating process in, by sampling number, sample position It sets, the influence for dividing rate etc. is added, there is random error.

Calculated result: σ or σ²Be worth it is smaller, closer to average value；When these values are 0, this mixture, which reaches, to be thoroughly mixed.

Test method: in different time, three different parts samplings, sampling amount about 0.01g measure content from container, count Calculate σ value.The result shows that σ, σ after 3 minutes²Value is smaller, therefore incorporation time is set to 3 minutes.It is shown in Table 27.

σ, σ of the different incorporation times of table 27.²Value

(2) determination of Granulation time: ocular estimate, particle obtained of being subject to are uniform.

Test method: weighing main ingredient and auxiliary material blanking by prescription, and vessel is closed up progress and is quickly stirred 3 minutes, so Paddle is opened into low speed afterwards, granulating cutter opens high speed, then 5%NP (pyrrolones) aqueous solution is added from form, from form, works as grain It is shut down when spending uniform, pours out wet granular, it is dry in 70 DEG C of baking ovens.

3, the determination of glidant dosage

In order to improve the mobility of particle, appropriate glidant can be added, dosage can be determined by measurement angle of repose. The general dosage that superfine silica gel powder makees glidant is 0.15%-3%, and the angle of repose of superfine silica gel powder different amounts is shown in Table 28 and Figure 16.

Influence of the 28. superfine silica gel powder different amounts of table to stream effect is helped

As shown in Figure 16, after the dosage of superfine silica gel powder is up to 1%, the mobility of particle is preferable, is further added by dosage to stopping Angle influence is smaller,.The disintegration that can accelerate tablet when the dosage of superfine silica gel powder is 1% or more, is conducive to the absorption of drug, therefore It is 1.3% that we, which select glidant dosage,.

4, the hygroscopicity of particle is investigated

The hygroscopicity of particle has important influence to tabletting, therefore determines the balance Moisture absorption rate of dry particl.

The measuring method of balance Moisture absorption rate: precision weighs dry particl about 1.0g, is respectively placed in 12 open titles for totally 12 parts In the weighing bottle for determining weight and number, it is paved into the thickness of 2mm or so.Then weighing bottle is put into the sulphur for filling certain relative humidity In the drier of the saturated solution of acid or salt, drier is set to save 7 days in 25 DEG C of constant incubators reaches equilibrium state, take The rapid precise weighing of weighing bottle out, calculated equilibrium hydroscopicity (%) the results are shown in Table 29, table 30.

Particle weight × 100% before balance Moisture absorption rate (%)=(particle weight before particle weight-moisture absorption after moisture absorption)/moisture absorption

Relative humidity of the saturated solution of 29. various concentration sulfuric acid of table or different salt at 25 DEG C

The balance Moisture absorption rate of dry particl under the different relative humidity of table 30.

Using balance Moisture absorption rate as ordinate, using relative humidity as abscissa, moisture equilibrium at dry side curve, the result is shown in Figure 17 are drawn.

The result shows that: dry particl hygroscopicity is not strong, and when relative humidity is less than 60%, hygroscopic capacity variation is unobvious, when When greater than 60%, hygroscopic capacity is obviously increased, therefore the relative humidity in workshop should control below 60%.

5, influence of the tablet hardness to Scullcap total-flavonoid dispersible tablet disintegration time

Find that the disintegration time of Scullcap total-flavonoid dispersible tablet and hardness have apparent relationship in test.When hardness is larger, piece The appearance of agent is preferable, but disintegration time is also longer；When hardness is small, and phenomena such as be easy to happen loose pieces, sliver.It investigates thus With a batch particle in the disintegration of different pressures under the conditions of institute compressed tablets, suitable briquetting pressure is found out, the results showed that, hardness Control disintegration time between 4-5 Kgfs is proper, is shown in Table 31.

Influence of 31. hardness of table to tablet disintegration times

6, preparation process: by the studies above, determine Scullcap total-flavonoid dispersible tablet preparation process: Scullcap total-flavonoid powder with Auxiliary material sieves with 100 mesh sieve respectively, and filler is added and Nei Jia disintegrating agent adds and contains in mixing 3min in High Speed Stirring Machine container There are 5%NP (pyrrolones) aqueous solution 160ml, the granulation of Surfactant, additional disintegrating agent is added in 70 DEG C of dryings, 30 mesh sieves With glidant be uniformly mixed, tabletting to get.

7, the process conditions of formed product

Tablet press machine: ZDY₈Heavy single-punch tablet press

Piece type: round

Punch die:

Particle water content: 2~5%

Slice weight: 0.35g is checked once every fixing time

Institute's medication powder and auxiliary material sieve with 100 mesh sieve, and unilateral color is relatively uniform, binder concn 5%.Dosage is 160ml, It makes pellet uniformly, fine powder is less, and drying temperature is 70 DEG C.

8, the selection of packaging material

By the moisture equilibrium at dry side test of particle it is found that when relative humidity is greater than 60%, hygroscopic capacity is obviously increased, therefore, The production environment relative humidity of tablet should control below 60%.The tablet suppressed is placed in the weighing apparatus that relative humidity is 75% After placing one month in wet environment, discovery tablet has the case where softening, hardness become smaller, therefore tablet must have packaging, using double In Aluminium Foil Packing.

(6) pilot scale

Pilot scale three batches are carried out by determining prescription and technique, every batch of feeds intake 10,000.

1, composition

Scullcap total-flavonoid 45%, disintegrating agent (CMS-Na, PVPP) 8%, filler (microcrystalline cellulose, TY (l-tyrosine)) 42.6%, lauryl sodium sulfate 0.5%, NP (pyrrolones) 5%, superfine silica gel powder 1.3%.

2, preparation method: take Scullcap total-flavonoid fine powder, microcrystalline cellulose, TY (l-tyrosine), CMS-Na in high-speed stirred In granulator container, after mixing 3min, 5%NP (pyrrolones) the aqueous solution granulation containing SLS is poured into form, until particle is equal Until even, wet granular is dry, whole grain is added PVPP, superfine silica gel powder, rushes after mixing in 21 and be pressed into every in rotary tablet machine The circular piece of the 160mg containing Scullcap total-flavonoid, piece weigh about 0.35g.

3, scale up test result

Semi-finished granules are carried out to three batches of pilot scale Scullcap total-flavonoid dispersible tablets and dispersible tablet checks, the results showed that Grain good fluidity, fine powder amount are moderate.Appearance, disintegration time, dispersed homogeneous degree, hardness, dissolution rate, content and the piece method of double differences of tablet Different equal qualification, is shown in Table 32,33.

Table 32, semi-finished granules quality measurements

33. dispersible tablet quality measurements of table

34. lab scale of table and pilot scale dispersible tablet dissolve out parameter T₅₀、T_dCompare

35. dispersible tablet T of table₅₀、T_dVariance analysis

The result shows that: there was no significant difference for the dissolution rate of pilot scale and lab scale.

One, prescription

Scullcap total-flavonoid aglycone: 160g；Microcrystalline cellulose: 84g；Pregelatinized starch: 62.48g；

Sodium carboxymethyl starch: 21g；Crospovidone: 7g；Lauryl sodium sulfate: 1.75g；

Polyoxyethylene sorbitan monoleate: 1.22g；Talcum powder: 4.55g；30 POVIDONE K 30 BP/USP 3:8g；Distilled water: appropriate.

1000 are made altogether

Two, preparation method

Weigh the Scullcap total-flavonoid aglycone sieved with 100 mesh sieve, add microcrystalline cellulose and pregelatinized starch, sodium carboxymethyl starch in In mixer-granulator, agitating paddle keeps off mixing 1 to 3 minute fastly, then opens to slow gear；Granulating cutter is opened to fast gear and is added from feed opening The 5% PVP K30 liquid containing surfactant stirs 3 to 4 minutes, and distilled water is added to stir 3 to 4 minutes.Wet granular is taken out in 70 DEG C drying after 30 mesh sieves of dry particl, is added crospovidone and talcum powder sieving is uniformly mixed, and adjustment slice weight is 0, 35g, tabletting to get.

Three, process flow

Process flow is as shown in figure 18.

Four, preparations shaping Journal of Sex Research

Test material, reagent and instrument

Test material:

Scullcap total-flavonoid aglycone (pharmaceutical technology center picks up by oneself in river)；

Pregelatinized starch pharmaceutical grade, purchased from the chemical pharmaceutcal corporation, Ltd's lot number of Zhejiang Huzhou prospect: 20010405；

Microcrystalline cellulose pharmaceutical grade, purchased from Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong's lot number: 19990110；

Sodium carboxymethyl starch pharmaceutical grade, purchased from the upper macro Chemical Co., Ltd.'s lot number of sea-freight: 20010115；

Lot number is sold in lauryl sodium sulfate pharmaceutical grade, Tianjin chemical reagent wholesale department: 20000504；

Two, the Primary Study of quality standard

(1) material and instrument

1, sample: Scullcap total-flavonoid dispersible tablet (self-control, lot number: 010618,010620,010625)

2, reference substance: radix scutellariae B component (river Chinese medicine is provided)

3, key instrument: Waters 600E system (including Waters 600 Contrdler, Waters 600Pump, 486 detector of Qaters), 800 work station of WATERS PC, 1/10000 balance of Switzerland (METTLER AE240)

4, reagent: methanol used, ethyl alcohol, phosphoric acid are to analyze pure, and acetonitrile is chromatographically pure.

(2) research of quality standard

1, character: test agent is yellowish-brown in three batches, and gas is micro-, mildly bitter flavor, therefore the character of this product is set to yellowish-brown color chips Agent, gas is micro-, mildly bitter flavor.

2, identify: (summary)

3, it checks

(1) inspection of moisture content: according to the first method in " (Pharmacopoeia of People's Republic of China) 2000 editions, one, Ⅸ H of annex " (oven drying method) measurement, water content must not exceed 7.0%.This product powder 4g or so is taken, it is accurately weighed, it is operated according to this method, measurement Example weight after drying calculates water content in test sample.Water content meets the requirements between 3~5%.The inspection of three batches of samples It looks into and the results are shown in Table 36.

36. 3 batches of sample moisture determination results of table

(2) disintegration time limited: by being tested under disintegration time limit test (one annex of " Chinese Pharmacopoeia " version in 2000) item, It is disintegration medium with water, controls 20 ± 1 DEG C of temperature.It should be in being disintegrated completely in 3min.Three batches of sample measurement results are shown in Table 37.

The disintegration time measurement result of 37 3 batches of samples of table

(3) dispersed homogeneous degree: taking this product two panels, sets in 100ml water, and stirring inclines to 24 mesh screens to complete disintegration dispersion On, it should all pass through sieve.As a result the dispersed homogeneous degree of three batches of samples meets the requirements.

(4) disperse tablet dissolution: using paddle method (see one annex of " Chinese Pharmacopoeia " version in 2000): taking the 12 of 0.54% Alkylsurfuric acid sodium water solution 1000ml is dissolution medium, and ultrasonic degassing 15 divides a clock, carries out 2,5,10 in dissolution test respectively, 20,30,45min samplings 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 with 0.54% lauryl sodium sulfate aqueous solution, with 0.54% lauryl sodium sulfate water Solution measures absorbance as blank control at 276.5nm wavelength, calculates dissolution rate T₅₀It the results are shown in Table 38.

The dissolution rate T of 38, three batches of samples of table₅₀Measurement result

(5) it tablet weight variation: shines under tablet weight variation inspection technique (" Chinese Pharmacopoeia " 2000 editions I D of annex) item and carries out Test, three batches of sample measurement results are shown in Table 39.

The tablet weight variation measurement result of 39. 3 batches of samples of table

It can be seen that meeting regulation within defined ± 5%.

(6) health examination: according in microbial decolorization (" Chinese Pharmacopoeia " version in 2000, one, Ⅹ III C of annex) Inspection technique item under test, pathogenic bacteria, mite living must not detect, and bacterial population must not exceed 100/gram, and fungi count must not exceed 100 A/gram, three batches of sample inspection results are shown in Table 40.

40. 3 batches of sample health examination results of table

4, assay

(1) instrument and reagent

Instrument: Waters 600E system (including Waters 600 Contrdler, Waters 600Pump, Qaters 486 detectors), 800 work station of WATERS PC, 1/10000 balance of Switzerland (METTLER AE240)

Reagent: methanol used, ethyl alcohol, phosphoric acid are to analyze pure, and acetonitrile is chromatographically pure.

Reference substance: radix scutellariae B component (river Chinese medicine is provided)

Sample: Scullcap total-flavonoid dispersible tablet (self-control: lot number: 010618,010620,010625)

(2) method and result:

1. chromatographic condition

A, chromatographic condition: NOVA-PAKC₁₈(3.9mm × 150mm) chromatographic column, 20 DEG C of column temperature, flow velocity 1.0ml/min.Flowing Phase: acetonitrile-water (35:65) is 4 with phosphoric acid tune pH value.Sensitivity 0.1AUFS.20 η l of sample volume.

B, the determination of Detection wavelength: radix scutellariae B methanol solution is taken, in 200-400nm spectral scan, maximum absorption wave is a length of 277nm。

2. the preparation of contrast solution: precision weighs radix scutellariae B component 0.98mg, is placed in 100ml volumetric flask, and it is dilute that methanol is added It releases to scale, shakes up to get reference substance solution.

3. the preparation of test solution: taking Scullcap total-flavonoid dispersible tablet 20, set finely ground in mortar, precision weighs about 0.1g is placed in 250ml round-bottomed flask, is added 95% ethyl alcohol 30ml refluxing extraction 3 hours, and 5ml95% ethyl alcohol is used in filtration respectively Washing residue 3 times, merging filtrate, constant volume in 50ml volumetric flask, shake up to get.

4. the preparation of negative control solution: taking the sample of scarce Scullcap total-flavonoid, press " preparation of test solution " method system At negative control solution.

Negative control solution, reference substance solution, sample solution HPLC figure see Figure 19,20,21.

5. the investigation of linear relationship: precision draws reference substance solution 0.1,0.3,1,3,10, ml in 10ml volumetric flask, uses 95% ethyl alcohol is settled to scale, the ethanol solution of 0.098,0.294,0.98,2.94,9.8 μ g/ml is made into, by above-mentioned chromatostrip Part measures peak area.Linear regression is made to integrating peak areas value A with sample introduction concentration C (μ g/ml), obtains regression equation: A= (364597C+10731.84 r=0.9995).The result shows that radix scutellariae B component has well in 0.098~9.8 μ g/ml concentration range Linear relationship.It is shown in Table 41.

41. reference substance peak area measurement result of table

6. Precision Experiment: precision is drawn 20 μ l of radix scutellariae B component reference substance solution and is repeated sample introduction 5 times, relative standard deviation It is 1.87%, precision is high.It the results are shown in Table 42.

The continuous 5 secondary peak area estimation result of 42. same sample of table

7. repetitive test: precision weighs 6 parts of sample, every part of about 0.1g of same lot number (001068), presses " test solution Preparation " item operation, 20 μ l of sample introduction, peak area is converted into content, relative standard deviation 1.85%, favorable reproducibility.As a result It is shown in Table 43.

43. 6 parts of sample size measurement results of same lot number of table

8. stability experiment: 20 μ l of test solution sample introduction is taken, it is primary every 2h sample introduction, total sample introduction 5 times, RSD%= 1.28%, show that test liquid is stablized in 10h.It is shown in Table 44.

44. stability test result of table

9. the rate of recovery is tested: using sample-adding recycling measuring method.As a result average recovery rate 99.04%, relative standard deviation 0.92%, it meets the requirements, is shown in Table 45.

45. radix scutellariae B component sample recovery rate result of table

10. the measurement of sample: pressing above-mentioned content assaying method, carried out assay to test agent in 3 batches.The result is shown in Table 46.

The assay of three batches of table 46, pilot scale middle test agents

(3) quality standard

Scullcap total-flavonoid dispersible tablet

Huangqin Fensan Pian

[composition] Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), sodium carboxymethyl starch, crospovidone, Lauryl sodium sulfate, superfine silica gel powder, 5%NP (pyrrolones) aqueous solution

Scullcap total-flavonoid, microcrystalline cellulose, TY (l-tyrosine), sodium carboxymethyl starch are placed in high-speed stirring mixing by [preparation method] It in the container of grain machine, is first uniformly mixed, then 5%NP (pyrrolones) aqueous solution 160ml containing SLS is added by form, pelletizes, until Until grain is uniform.Wet granular, 70 DEG C of dryings are taken out, additional disintegrating agent and glidant, tabletting is added in 30 mesh sieves, and packaging is ?.

[character] this product is yellowish-brown tablet, and gas is micro-, mildly bitter flavor.

[inspection]

(1) inspection of moisture content: according to the first method in " (Pharmacopoeia of People's Republic of China) 2000 editions, one, Ⅸ H of annex " (oven drying method) measurement, water content must not exceed 7.0%.This product powder 4g or so is taken, it is accurately weighed, it is operated according to this method, measurement Example weight after drying calculates water content in test sample.Water content controls between 3~5%.

(2) disintegration time limited: by being tested under disintegration time limit test (one annex of " Chinese Pharmacopoeia " version in 2000) item, It is disintegration medium with water, controls 20 ± 1 DEG C of temperature.It should be in being disintegrated completely in 3min.Three batches of sample measurement results are shown in Table 34.

(3) dispersed homogeneous degree: taking this product two panels, sets in 100ml water, and stirring inclines to 24 mesh screens to complete disintegration dispersion On, it should all pass through sieve.

(4) disperse tablet dissolution: using paddle method (see one annex of " Chinese Pharmacopoeia " version in 2000): taking the 12 of 0.54% Alkylsurfuric acid sodium water solution 1000ml is dissolution medium, and ultrasonic degassing 15 divides a clock, carries out 2,5,10 in dissolution test respectively, 20,30,45min samplings 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 with 0.54% lauryl sodium sulfate aqueous solution, with 0.54% lauryl sodium sulfate water Solution measures absorbance as blank control at 276.5nm wavelength, calculates dissolution results T₅₀。

(5) it tablet weight variation: shines under tablet weight variation inspection technique (" Chinese Pharmacopoeia " 2000 editions I D of annex) item and carries out Test, tablet weight variation should control within 5%.

(6) health examination: according in microbial decolorization (" Chinese Pharmacopoeia " version in 2000, one, Ⅹ III C of annex) Inspection technique item under test, pathogenic bacteria, mite living must not detect, and bacterial population must not exceed 1000/gram, and fungi count must not exceed 100/gram.

[assay]

1, chromatographic condition

NOVA-PAKC₁₈(3.9mm × 150mm) chromatographic column, 20 DEG C of column temperature, flow velocity 1.0ml/min.Mobile phase: acetonitrile-water (35:65) is 4 with phosphoric acid tune pH value.Sensitivity 0.1AUFS.20 μ l of sample volume.Detection wavelength 277nm.

2, the preparation of contrast solution

Precision weighs radix scutellariae B component 0.98mg, is placed in 100ml volumetric flask, and methanol dilution is added to scale, shakes up, i.e., Obtain reference substance solution.

3, the preparation of test solution

Scullcap total-flavonoid dispersible tablet 20 are taken, sets finely ground in mortar, precision weighs about 0.1g, is placed in 250ml round-bottomed flask In, it being added 95% ethyl alcohol 30ml refluxing extraction 3 hours, filtration is used 5ml95% ethanol washing residue 3 times, merging filtrate respectively, Constant volume in 50ml volumetric flask, shake up to get.

4, the measurement of sample

Precision draws 20 μ l of test solution, injects high performance liquid chromatograph, chromatogram is recorded, by external standard method with peak area Calculate to get.

[usage and dosage] is oral, and 3 times a day, one at a time, warm water takes.

[specification] every 0.16g containing Scullcap total-flavonoid.

Three, Scullcap total-flavonoid dispersible tablet primary stability is tested

According to present invention determine that prescription, technique preparation three batches of Scullcap total-flavonoid dispersible tablets (010618,010620, 010625) primary stability test is carried out.Specific test method and result are as follows:

Room temperature reserved sample observing method

Drug: lot number 010618,010620,010625, river Chinese medicine is provided.

Experimental procedure: three batches of samples (double aluminum foil packaging) are set under normal room temperature, at 0 month, 1 month, 2 months, 3 months Indices are inspected periodically at interval, the results are shown in Table 47, table 48, table 49.

47. room temperature reserved sample observing of table report sample lot number: 010618

48. room temperature reserved sample observing of table report sample lot number: 010620

49. room temperature reserved sample observing of table report sample lot number: 010625

Conclusion: according to the room temperature reserved sample observing to three batches of samples as a result, showing Scullcap total-flavonoid dispersible tablet in three months It is stable.

Low temperature Acceleration study

Drug: lot number 010618,010620,010625, river Chinese medicine is provided.

Experimental procedure: 3 are saved under conditions of this product (double aluminum foil packaging) is set constant temperature (37-40 DEG C), relative humidity 75% A month, monthly (0,1,2, March) timing sampling, examined indices, the results are shown in Table 50, table 51.

50. low temperature accelerated test of table report sample lot number: 010618

51. low temperature accelerated test of table report sample lot number: 010620

The result shows that this product was stablized in 3 months low temperature accelerated tests, therefore can fix tentatively its validity period is 2 years, but it has The effect phase should determine again after the final result according to continuation room temperature reserved sample observing.

It should be understood by those skilled in the art that foregoing description and the embodiment of the present invention shown in the drawings are only used as illustrating And it is not intended to limit the present invention.The purpose of the present invention has been fully and effectively achieved.Function and structural principle of the invention exists It shows and illustrates in embodiment, under without departing from the principle, embodiments of the present invention can have any deformation or modification.

Claims (20)

1. a kind of Scullcap total-flavonoid dispersible tablet, which is characterized in that including radix scutellariae total flavone extract and auxiliary material, the wherein accessory package The disintegrating agent not less than the Scullcap total-flavonoid dispersible tablet gross weight 8% is included, not less than the Scullcap total-flavonoid dispersible tablet gross weight 42.6% Filler, not less than the pyrrolones of the Scullcap total-flavonoid dispersible tablet gross weight 5%, residual components are extractive of general flavone, wherein at this In extractive of general flavone, the ingredient of Scullcap total-flavonoid is not less than 45%, and wherein the disintegrating agent includes that sodium carboxymethyl starch and crosslinking are poly- Vinylpyrrolidone, the filler include microcrystalline cellulose and l-tyrosine, and wherein the Scullcap total-flavonoid dispersible tablet passes through high speed Stirring granulation is made.

2. Scullcap total-flavonoid dispersible tablet as described in claim 1, which is characterized in that the auxiliary material still further comprise lubricant and Glidant.

3. Scullcap total-flavonoid dispersible tablet as claimed in claim 2, which is characterized in that the lubricant is hydrophilic lubricant, should Glidant is superfine silica gel powder, and wherein the hydrophilic lubricant accounts for the 0.3%~0.9% of the Scullcap total-flavonoid dispersible tablet gross weight, this is micro- Powder silica gel accounts for the 1%~1.3% of the Scullcap total-flavonoid dispersible tablet gross weight.

4. Scullcap total-flavonoid dispersible tablet as claimed in claim 3, which is characterized in that it is always yellow that the hydrophilic lubricant accounts for the radix scutellariae The 0.5% of ketone dispersible tablet gross weight.

5. the Scullcap total-flavonoid dispersible tablet as described in claim 1,2,3 or 4, which is characterized in that wherein the Scullcap total-flavonoid mentions Object and the auxiliary material is taken first to be made into particle of the granularity less than 30 mesh, then the particle again by the granularity less than 30 mesh is mixed with disintegrating agent After conjunction, it is pressed into dispersible tablet.

6. Scullcap total-flavonoid dispersible tablet as described in claim 1, which is characterized in that further comprise always yellow not less than the radix scutellariae The lauryl sodium sulfate of ketone dispersible tablet gross weight 0.5% and superfine silica gel powder higher than the Scullcap total-flavonoid dispersible tablet gross weight 1.3%.

7. a kind of Scullcap total-flavonoid dispersible tablet, which is characterized in that including Scullcap total-flavonoid and auxiliary material, wherein the auxiliary material includes not low In the disintegrating agent of the Scullcap total-flavonoid dispersible tablet gross weight 8%, not less than the Scullcap total-flavonoid dispersible tablet gross weight 42.6% filler, Not less than the pyrrolones of the Scullcap total-flavonoid dispersible tablet gross weight 5%, residual components are general flavone, and wherein the disintegrating agent includes carboxylic first Base sodium starch and crosslinked polyvinylpyrrolidone, the filler include microcrystalline cellulose and l-tyrosine, and wherein the radix scutellariae is always yellow Ketone dispersible tablet is made up of High Shear Mixer Granulator method.

8. Scullcap total-flavonoid dispersible tablet as claimed in claim 7, which is characterized in that the auxiliary material still further comprise lubricant and Glidant.

9. Scullcap total-flavonoid dispersible tablet as claimed in claim 8, which is characterized in that the lubricant is hydrophilic lubricant, should Glidant is superfine silica gel powder, and wherein the hydrophilic lubricant accounts for the 0.3%~0.9% of the Scullcap total-flavonoid dispersible tablet gross weight, this is micro- Powder silica gel accounts for the 1%~1.3% of the Scullcap total-flavonoid dispersible tablet gross weight.

10. Scullcap total-flavonoid dispersible tablet as claimed in claim 9, which is characterized in that it is total that the hydrophilic lubricant accounts for the radix scutellariae The 0.5% of flavones dispersible tablet gross weight.

11. the Scullcap total-flavonoid dispersible tablet as described in claim 7,8,9 or 10, which is characterized in that the wherein Scullcap total-flavonoid First it is made into particle of the granularity less than 30 mesh with the auxiliary material, then the particle again by the granularity less than 30 mesh is mixed with disintegrating agent Afterwards, it is pressed into dispersible tablet.

12. Scullcap total-flavonoid dispersible tablet as claimed in claim 7, which is characterized in that further comprise total not less than the radix scutellariae The lauryl sodium sulfate of flavones dispersible tablet gross weight 0.5% and superfine silica gel powder higher than the Scullcap total-flavonoid dispersible tablet gross weight 1.3%.

13. a kind of manufacturing method of Scullcap total-flavonoid dispersible tablet, which comprises the following steps:

A) by high-speed stirring mixing machine, Baical Skullcap root P.E and auxiliary material are stirred mixing granulation, wherein the auxiliary material includes disintegration Agent, filler, lauryl sodium sulfate, pyrrolones, wherein the disintegrating agent includes sodium carboxymethyl starch and crosslinked polyethylene pyrroles Alkanone, the filler include microcrystalline cellulose and l-tyrosine, and wherein the Scullcap total-flavonoid in the Baical Skullcap root P.E is not less than 45%, which is not less than the 8% of the Scullcap total-flavonoid dispersible tablet gross weight, which is not less than the Scullcap total-flavonoid dispersible tablet Gross weight 42.6%, lauryl sodium sulfate not less than the Scullcap total-flavonoid dispersible tablet gross weight 0.5%, pyrrolones be not less than the Huang The 5% of a kind of reed mentioned in ancient books total flavones dispersible tablet gross weight；With

B it) by obtained particle drying, and through 30 mesh sieve whole grains, obtains that crosslinked polyethylene pyrroles is added no more than 30 mesh particles Alkanone, superfine silica gel powder and disintegrating agent are mixed, and compacting obtains Scullcap total-flavonoid dispersible tablet, and wherein the disintegrating agent includes that carboxymethyl forms sediment Powder sodium and crosslinked polyvinylpyrrolidone, wherein superfine silica gel powder is not less than the 1.3% of the Scullcap total-flavonoid dispersible tablet gross weight.

14. manufacturing method as claimed in claim 13, which is characterized in that the granularity of radix scutellariae total flavone extract and auxiliary material is small In 100 mesh.

15. manufacturing method as claimed in claim 13, which is characterized in that the auxiliary material still further comprises lubricant, wherein should Lubricant is hydrophilic lubricant, and wherein the hydrophilic lubricant accounts for the 0.3%~0.9% of the Scullcap total-flavonoid dispersible tablet gross weight.

16. manufacturing method as claimed in claim 14, which is characterized in that the auxiliary material still further comprises lubricant, wherein should Lubricant is hydrophilic lubricant, and wherein the hydrophilic lubricant accounts for the 0.3%~0.9% of the Scullcap total-flavonoid dispersible tablet gross weight.

17. a kind of manufacturing method of Scullcap total-flavonoid dispersible tablet, which comprises the following steps:

A) by high-speed stirring mixing machine, Scullcap total-flavonoid and auxiliary material are stirred mixing granulation, which includes disintegrating agent, fills out Agent, lauryl sodium sulfate, pyrrolones are filled, wherein the disintegrating agent includes sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone, The filler includes microcrystalline cellulose and l-tyrosine, and wherein the disintegrating agent is not less than the Scullcap total-flavonoid dispersible tablet gross weight 8%, it is always yellow not less than the radix scutellariae which is not less than the 42.6% of the Scullcap total-flavonoid dispersible tablet gross weight, lauryl sodium sulfate Ketone dispersible tablet gross weight 0.5%, pyrrolones be not less than the Scullcap total-flavonoid dispersible tablet gross weight 5%；With

B it) by obtained particle drying, and through 30 mesh sieve whole grains, obtains that crosslinked polyethylene pyrroles is added no more than 30 mesh particles Alkanone, superfine silica gel powder and disintegrating agent are mixed, and compacting obtains Scullcap total-flavonoid dispersible tablet, and wherein the disintegrating agent includes that carboxymethyl forms sediment Powder sodium and crosslinked polyvinylpyrrolidone, wherein superfine silica gel powder is not less than the 1.3% of the Scullcap total-flavonoid dispersible tablet gross weight.

18. manufacturing method as claimed in claim 17, which is characterized in that the granularity of Scullcap total-flavonoid and auxiliary material is respectively less than 100 Mesh.

19. manufacturing method as claimed in claim 17, which is characterized in that the auxiliary material still further comprises lubricant, wherein should Lubricant is hydrophilic lubricant, and wherein the hydrophilic lubricant accounts for the 0.3%~0.9% of the Scullcap total-flavonoid dispersible tablet gross weight.

20. manufacturing method as claimed in claim 18, which is characterized in that the auxiliary material still further comprises lubricant, wherein should Lubricant is hydrophilic lubricant, and wherein the hydrophilic lubricant accounts for the 0.3%~0.9% of the Scullcap total-flavonoid dispersible tablet gross weight.