CN105326808B - Capsule for clearing heat and eliminating phlegm removing toxic substances - Google Patents
Capsule for clearing heat and eliminating phlegm removing toxic substances Download PDFInfo
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- CN105326808B CN105326808B CN201510818007.9A CN201510818007A CN105326808B CN 105326808 B CN105326808 B CN 105326808B CN 201510818007 A CN201510818007 A CN 201510818007A CN 105326808 B CN105326808 B CN 105326808B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/35—Caprifoliaceae (Honeysuckle family)
- A61K36/355—Lonicera (honeysuckle)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/539—Scutellaria (skullcap)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
- A61K36/634—Forsythia
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The present invention relates to the capsule to detoxify for clearing heat and eliminating phlegm.The capsule, it includes capsule shells and is wrapped in the capsule shells and is in powder or granular filler.Wherein described capsule shells are selected from：Using capsule shells made of gelatin as key component, using capsule shells made of hydroxypropyl methyl cellulose as key component, using capsule shells made of algal polysaccharides as key component, using capsule shells made of pectin as key component or using capsule shells made of carboxymethyl cellulose as key component.The filler includes active material, diluent.The diluent be selected from starch, dextrin, carboxymethyl starch, hydroxypropul starch, modified starch, pregelatinized starch, lactose, Icing Sugar, microcrystalline cellulose, calcium phosphate, calcium monohydrogen phosphate, calcium carbonate etc., and combinations thereof.Capsule of the present invention has excellent biology effect in clearing heat and eliminating phlegm Jiedu Fang face.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicines, is related to a kind of Chinese medicine capsules available for clearing heat and eliminating phlegm removing toxic substances.
Background technology
Chinese traditional treatment febrile illness it is with a long history, mainly have typhoid fever school and epidemic febrile diease schools for a long time, they are each
Rich experience is have accumulated, also there is common theoretical foundation, for acute fever rapid onset, the characteristics of change of illness state is also fast,
They, which establish, closes the dialectical treatment method that typhoid fever and warm disease are integrated, symptom management, and then the purpose cured as early as possible,
Treat that this sick Chinese patent drug is although various in style now, but truly have efficiently quick-acting kinds also very in great shortage, existing swap buffers
Injection contains honeysuckle, radix scutellariae and Fructus Forsythiae, suitable for the wind-warm lung-heat exterior syndrome phase, although has the effect of certain to acute fever,
But to severe acute fever, i.e., to table interior symptom-complex's phase and interior symptom-complex's phase, then because seriously ill medicine is light, therefore curative effect difficulty is played.
Tuberculosis is one of main wind-warm lung-heat disease, is to invade lung system through mouth and nose by wind-heat disease and evil, with body heat, cough and asthma, thirsty
Deng a kind of acute external affection heat disease mainly to show.The disease winter and spring is multiple, often attacks lung system as starting symptom using heresy, easily enters
In the disease phase and there is gas symptom, such as the scorching resistance lung disease of phlegm, originally it is that heresy accumulates heat symptom-complex marquis person in lung stomach also to have.《Chinese medicine clinic refers to
Lead principle》Explicitly point out：Wind-warm lung-heat disease is experienced caused by wind-heat virus, and the four seasons all have, and how acute two season of Winter-Spring is
Fever caused by exogenous pathogenic factors., can also be on racing usually because fever with chilliness, cough, pectoralgia, asthma out of breath influence feed, sleep during this onste
Respiratory tract or the silt of lung system are swollen and inflammation infection.
Cao Chunlin discloses a kind of Jiawei double coptis medicament and its preparation in ZL94103391.0 in existing patent document
Method, the medicament have five kinds of scutelloside, total urso cholic acid, cornu caprae hircus hydrolysate, Honegsukle flower P.E, forsythia suspense extraction composition groups
Into.The pharmaceutical preparation has the effect of heat-clearing, removing toxic substances, resolving sputum, can clinically control the symptom of wind-warm lung-heat disease.Clinically lead at present
Parenteral solution often is made with radix scutellariae, bear gall powder, cornu caprae hircus, honeysuckle, Fructus Forsythiae gomi herbs to use.Due to safety of Chinese medicine injection
Problem generally existing, therefore it is with Great significance to develop with clinical efficacy and safe preparation such as oral formulations
's.
The content of the invention
It is an object of the invention to provide a kind of excellent capsule, especially it is to provide a kind of for clearing heat and eliminating phlegm removing toxic substances
Capsule.In the present invention, the capsule refers to hard capsule known to art of pharmacy, is usually known with being different from people
The soft capsule of dawn.
Hard capsule typically includes capsule shells (also commonly referred to as Capsules) and is wrapped in the capsule shells
Filler, the filler are usually in powder or graininess, wherein adding comprising active constituents of medicine and if necessary medicinal
Auxiliary material.
The object of the present invention is achieved like this：
A kind of capsule, it includes capsule shells and is wrapped in the capsule shells and is in powder or granular filler.
Known in pharmaceutical field technical staff, for capsule particularly hard capsule, its inside capsule shells is filled above-mentioned
Filler, is also known as " content ".
Capsule according to the present invention, it is the Chinese medicine or Chinese medicine composition for clearing heat and eliminating phlegm removing toxic substances.
Capsule according to the present invention, wherein the capsule shells are selected from：Using gelatin as capsule shells made of key component, with
Hydroxypropyl methyl cellulose is capsule shells made of key component, using capsule shells made of algal polysaccharides as key component, with fruit
Glue is capsule shells made of key component or using capsule shells made of carboxymethyl cellulose as key component.In the present invention,
Term " capsule shells " is also referred to as " Capsules " or similar appellation.It is well known that Capsules is usually by capsule body and glue
Capsule cap two parts form, after medicine is filled with that the two is closely sealed, become capsule.In the present invention, " the capsule referred to
Agent " each means hard capsule.
Capsule according to the present invention, wherein the capsule shells are using gelatin as capsule shells made of key component.It can
To be that the enteric gelatin that can either be dissolved in intestinal juice of the common gelatin hollow capsule that can be dissolved under the conditions of wide pH value is empty
Heart-soothing capsule.In the present invention, " gelatin hollow capsule " is referred to, if not otherwise indicated, each meaning can dissolve under the conditions of wide pH value
Common gelatin hollow capsule.And each mean enteric gelatin hollow capsule when being modified with " enteric ".In one embodiment,
The capsule shells are not the capsule shells of enteric gelatin hollow capsule.
Gelatin hollow capsule of the present invention has typically been recorded to version in 2010《Chinese Pharmacopoeia》Two, and have perhaps
Multi-product is ratified to list by state food pharmaceuticals administration general bureau, such as Chinese medicines quasi-word F20020009 (Shaoxing Renhe), state
The gelatin hollow capsule of the quasi- word F20020035 of medicine (life of Zhejiang enlightening) and Chinese medicines quasi-word F20030004 (the long standing grain in Jiangsu), in this hair
Its in bright can be described as common gelatin hollow capsule or similar appellation, to be different from following enteric gelatin hollow capsule.In addition,
In common gelatin hollow capsule is prepared enteric that is insoluble under one's belt but being dissolved in intestines is can obtain with formaldehyde impregnation
Gelatin hollow capsule, such as Chinese medicines quasi-word F20020030 (Shaoxing health can) and Chinese medicines quasi-word F20070003 (Xinchang Kangping)
Enteric gelatin hollow capsule.
It is of the present invention using hydroxypropyl methyl cellulose as capsule shells made of key component (its in this area usually also
Can be described as hydroxypropyl methylcellulose Capsules), using algal polysaccharides as capsule shells made of key component (its in this area usually also
Can be described as algal polysaccharides Capsules) ratify to list by state food pharmaceuticals administration general bureau, such as Chinese medicines quasi-word
The hydroxypropyl methylcellulose Capsules of F20090002 (Suzhou capsule) and Chinese medicines quasi-word F20120001 (Shaoxing health can), and
The algal polysaccharides Capsules of Chinese medicines quasi-word F20050002 (Qinhuangdao capsule for medicine).
It is of the present invention that using pectin as capsule shells made of key component, (it is hollow in this area usually also known as pectin
Capsule) developed and Preliminary Applications in some fields, (such as the easy Baeyer scientific ＆ technical corporation in Nanjing is on sale；In another example Chinese patent Shen
The Capsules containing 60~85% pectin that please be described in number 200910185990.X, with reference to the patent when being used in the present invention
The method of the document specification embodiments 1 of page 2 is prepared, and may be simply referred to as #990.X pectin capsule or similar appellation).
It is of the present invention that using carboxymethyl cellulose as capsule shells made of key component, (it usually can also claim in this area
For carboxymethyl cellulose Capsules, or CMC capsules or similar appellation) developed and Preliminary Applications in some fields (such as
The Capsules containing 80~90% carboxymethyl celluloses described in Chinese Patent Application No. 200910116242.6, in the present invention
Be prepared during middle use with reference to the method for the patent document specification embodiments 1 of page 3, may be simply referred to as #242.6CMC capsules or
Similar appellation).
Capsule according to the present invention, wherein the filler includes active material, diluent.
Capsule according to the present invention, wherein the diluent be selected from starch, dextrin, carboxymethyl starch, hydroxypropul starch,
Modified starch, pregelatinized starch, lactose, Icing Sugar, microcrystalline cellulose, calcium phosphate, calcium monohydrogen phosphate, calcium carbonate etc., and combinations thereof.
Capsule according to the present invention, wherein to be selected from starch (such as cornstarch, farina, big for the diluent
Rice starch, wheaten starch, tapioca), dextrin, carboxymethyl starch, hydroxypropul starch, modified starch, pregelatinized starch and its
Combination.
Capsule according to the present invention, wherein the diluent be selected from starch, dextrin, and combinations thereof.
Capsule according to the present invention, wherein other medicines can also be optionally included in the filler in addition to diluent
Use auxiliary material.
Capsule according to the present invention, wherein the active material is prepared by following material：
Bear gall powder or urso,
Cornu caprae hircus,
Radix scutellariae,
Honeysuckle,
Fructus Forsythiae.
Capsule according to the present invention, wherein the bear gall powder is the total urso cholic acid obtained with bear gall powder through saponification, purification
The form of (present invention is also referred to as Fel Ursi powder extract) is added in the filler.In one embodiment, it is described
Urso is included in total urso cholic acid.In one embodiment, urso (its molecule is included in the total urso cholic acid
Formula is C24H40O4) and chenodeoxycholic acid (its molecular formula is C24H40O4).In one embodiment, the Chinese medicine composition
The amount of middle urso is 2~30 times of the amount of chenodeoxycholic acid, and preferably 3-25 times, preferably 4-20 times, preferably 5-18 times are excellent
Select 5-16 times.
Capsule according to the present invention, wherein the cornu caprae hircus is with cornu caprae hircus water of the cornu caprae hircus through hydrolyzing, purifying
The form of solution thing (present invention is also referred to as goat's horn extraction) is added in the filler.In one embodiment,
Contain in the cornu caprae hircus hydrolysate and be selected from following amino acid：Aspartic acid, glutamic acid, serine, glycine, threonine,
Alanine, valine, phenylalanine, isoleucine, leucine, proline.These amino acid can be collectively referred to as total amino acid, count
It is that these amino acid respectively estimate one's own ability adduction during the amount of calculation total amino acid to obtain the final product.
Capsule according to the present invention, wherein the radix scutellariae is added in the form of Baical Skullcap root P.E in the filler
's.In one embodiment, scutelloside is included in the Baical Skullcap root P.E (its molecular formula is C21H18O11).In a reality
Apply in scheme, scutellarin (C21H18O12) is also included in the Baical Skullcap root P.E.In one embodiment, the radix scutellariae
The amount of glycosides is 20~200 times of the amount of scutellarin, preferably 30-180 times, preferably 40-160 times, preferably 50-150 times.
Capsule according to the present invention, wherein the honeysuckle is that the filling is added in the form of Honegsukle flower P.E
In thing.In one embodiment, included in the Honegsukle flower P.E and be selected from following organic acid：Chlorogenic acid, fresh green are former
Acid, Cryptochlorogenic acid, caffeic acid, bis- caffeic acid acyl chinic acids of 3,4-, bis- caffeic acid acyl chinic acids of 3,5-, bis- caffeic acid acyl Kuis of 4,5-
Buddhist nun's acid.In the present invention, these organic acids can be collectively referred to as total organic acids, or when describing their amount, the total scale of organic acid
Show the sum of amount of these organic acids.
Capsule according to the present invention, wherein the Fructus Forsythiae is added in the form of forsythia suspense extraction in the filler
's.In one embodiment, comprising forsythiaside A, (its molecular formula is C in the forsythia suspense extraction29H36O15) and forsythin
(its molecular formula is C27H35O11).Both forsythiaside A and forsythin can be described as the total glycosides of Fructus Forsythiae, calculate the amount of forsythia suspense extraction
When, can be with the summation meter of the two, and can be described as the total glycosides amount of Fructus Forsythiae, i.e. the total glycosides amount of Fructus Forsythiae=forsythiaside A amount+forsythin
Amount.
Capsule according to the present invention, wherein in the filler, comprising：Urso is (directly with urso
Form addition or from bear gall powder), total amino acid (coming from cornu caprae hircus), scutelloside (coming from radix scutellariae), total organic acids (come from
Honeysuckle) and the total glycosides of Fructus Forsythiae (coming from Fructus Forsythiae).
Capsule according to the present invention, wherein in the filler, comprising：
| Urso | 1-10 parts, |
| Total amino acid | 0.5-5 parts, |
| Scutelloside | 1-10 parts, |
| Total organic acids | 0.1-2 parts, |
| The total glycosides of Fructus Forsythiae | 0.25-10 parts. |
Capsule according to the present invention, wherein in the filler, comprising：
| Urso | 2-8 parts, |
| Total amino acid | 1-5 parts, |
| Scutelloside | 2-9 parts, |
| Total organic acids | 0.2-1.8 parts, |
| The total glycosides of Fructus Forsythiae | 0.5-9 parts. |
Capsule according to the present invention, wherein in the filler, comprising：
| Urso | 2.5-7 parts, |
| Total amino acid | 1.5-4 parts, |
| Scutelloside | 2-8 parts, |
| Total organic acids | 0.3-1.5 parts, |
| The total glycosides of Fructus Forsythiae | 1-9 parts. |
Capsule according to the present invention, wherein the urso, total amino acid, scutelloside, total organic acids and Fructus Forsythiae
Total glycosides (can they are referred to object herein) total amount accounts for the 10~90% of the filler gross weight, such as
15~75%, such as 20~75%.
Capsule according to the present invention, wherein the diluent accounts for the 2~60% of the filler gross weight, such as 2~
50%, such as 2~40%, such as 3~30%.
Capsule according to the present invention, wherein the total urso cholic acid is obtained with bear gall powder through saponification, purification.It can join
Examine the prior art to be prepared, made referring for example to the method for CN1947746B (Mu Laian, 2005) specification [0024] section
It is standby.It can also be prepared with reference to the method that CN1110150A (Cao Chunlin, 1994) Instructions Page 2 21-31 rows are recorded.In addition,
The method that may further reference the method such as wherein embodiment 1,2,3 in CN101890048A (Xue Dongsheng, 2009) obtains Xiong Zongdan
Acid, the amount of urso is the same up to 2~30 times of the amount of chenodeoxycholic acid in the total urso cholic acid that these methods obtain, excellent
Select 3-25 times, preferably 4-20 times, preferably 5-18 times, preferably 5-16 times.It has been found by the present inventors that what no matter which kind of method obtained
Total urso cholic acid is dosed into capsule of the present invention, is also whether directly dosed into urso in capsule of the present invention, only
Ursodeoxycholic acid content in capsule of the present invention is wanted to be shown with identical in the ratio range of capsule filler of the present invention
Therapeutic effect.The amount of urso is usually up to more than 40%, particularly example in the total urso cholic acid that above-mentioned each method obtains
As up to more than 50%.
Capsule according to the present invention, wherein the cornu caprae hircus hydrolysate is prepared according to following method：By goat
Angle add sulfuric acid (such as 8-12 times measured, the sulfuric acid of such as 8 times amount 4mol/L) be heated to reflux 16 it is small when or so, filtration, sediment is with 4 times
The water washing of amount is secondary, merging filtrate, washing lotion, dense to 5.5-7.0 (such as 6.0), filtration, filtrate with 16% milk of lime tune pH value
It is 1.04~1.1 (60 DEG C) to be reduced to relative density, adds 1% activated carbon decolorizing, filtration, is slowly added into ethanol under filtrate stirring, makes
Alcohol content is up to 70%, and when refrigeration 12 is small, hyperfiltration, recycles ethanol, cool, and stirring is lower plus ethanol makes alcohol content up to 80%, cold
Hide 12 it is small when, coarse filtration, hyperfiltration, recycles ethanol, and is concentrated into thick paste, and less than 60 DEG C are dried in vacuo into powder, obtain cornu caprae hircus
Hydrolysate.Contain in gained cornu caprae hircus hydrolysate of the invention and be selected from following amino acid：It is aspartic acid, glutamic acid, serine, sweet
Propylhomoserin, threonine, alanine, valine, phenylalanine, isoleucine, leucine, proline.In addition, it can also shine other existing
Method prepares cornu caprae hircus hydrolysate, referring for example to CN101084924B (Xue Dongsheng, 2006) specification [0026]-[0033]
It is prepared by the method for section embodiment 1-4.In addition, it can also shine CN1947746B (Mu Laian, 2005) specification [0025] section
Method prepares cornu caprae hircus hydrolysate.CN1110150A (Cao Chunlin, 1994) Instructions Page 3 2-18 rows can also be referred to record
Method prepare cornu caprae hircus hydrolysate.Further, these total amino acids in the cornu caprae hircus hydrolysate that above-mentioned each method obtains
Amount account for more than the 50% of cornu caprae hircus hydrolysate, such as up to more than 60%.
Capsule according to the present invention, wherein the Baical Skullcap root P.E is known in the art, it can be purchased from market
Obtain, such as it can refer to the method under " Baical Skullcap root P.E " item described in People's Republic of China's version one page 391 in 2010
It is prepared, and it can meet quality standard regulation.The method of other examples is for example recorded in CN1947746B and says
The method of bright book [0026] section.In the Baical Skullcap root P.E that these known methods obtain, the content of scutelloside can reach
More than 50%, it particularly can reach more than 65%.It has been found that sheet prepared by the Baical Skullcap root P.E obtained using distinct methods
Invention capsule is respectively provided with identical property, such as biology effect is identical, physical and chemical properties of drugs is identical；Therefore capsule of the present invention
The preparation method of Baical Skullcap root P.E used can be not particularly limited in agent.
Capsule according to the present invention, prepares wherein the Honegsukle flower P.E can shine the prior art.Such as it can join
Method that CN1110150A (Cao Chunlin, 1994) specification page 4 10-17 rows record is examined to prepare；Can also reference
It is prepared by the method for CN1947746B (Mu Laian, 2005) specification [0027] section；Can also be with reference to CN101084976A (Xue
East rises, 2006) prepared by the method for the specification embodiment of page 4.In the Honegsukle flower P.E that these known methods obtain, always have
The content of machine acid can reach more than 30%, particularly can reach more than 40%.In example of the present invention, institute
Honegsukle flower P.E is stated to be prepared according to following method：Extracting honeysuckle, adds water to cook secondary, first time plus 12 times of amount decoctings
Boil 1 it is small when, second plus 10 times of amount water, decoct 30 minutes, collecting decoction, filtration, filtrate is concentrated into relative density as 1.20 (70
DEG C), add 20% milk of lime tune pH value to be stirred, filtration, after precipitation adds 5 times of amount ethanol stirrings to be suspended, with 50% sulfuric acid tune to 11
PH value is to 2.0, and filtration, filtrate is again with 40% sodium hydroxide tune pH value to 6.8, and filtration, filtrate recycling ethanol, is concentrated into
100ml, extracts 4 times (60ml, 60ml, 40ml, 40ml) with n-butanol, divides and take n-butanol extracting liquid, recycle n-butanol, add water-soluble
Solution, when 5~10 DEG C of standings 48 are small, coarse filtration, hyperfiltration, takes filtrate to be concentrated into thick paste, 60 DEG C of vacuum drying, obtain honeysuckle extraction
Thing dry powder.
Capsule according to the present invention, prepares wherein the forsythia suspense extraction can shine the prior art.Such as it may be referred to
Prepared by the method that CN1110150A (Cao Chunlin, 1994) specification page 4 2-9 rows are recorded, can also with reference to CN1947746B
Prepared by the method for (Mu Laian, 2005) specification [0028] section, can also be with reference to CN101085043B (Xue Dongsheng, 2006)
Prepared by the method for specification [0026] section, can also refer to described in People's Republic of China (PRC) version one page 381 in 2010
" forsythia suspense extraction " item under method be prepared.In the forsythia suspense extraction that these known methods obtain, the total glycosides of Fructus Forsythiae
Content can reach more than 10%, particularly can reach more than 15%.In example of the present invention, the Fructus Forsythiae
Extract is prepared according to following method：Fructus Forsythiae adds water, and decoction is secondary, is extracted when decocting every time in volatile oil extractor
Volatile oil, obtains Forsythia volatile oil；When for the first time plus 10 times of amount water decoctions 1 are small, second plus 8 times of amount water, decoct 30 minutes, conjunction
And decocting liquid, filtration, it is 1.02~1.04 (60 DEG C) that filtrate, which is concentrated into relative density, adds ethanol alcohol content is stood 24 up to 70%
Hour, filtration, filtrate recycling ethanol, is concentrated into no alcohol taste, adds 1% activated carbon decolorizing, and filtration, filtrate is extracted 4 times with n-butanol
(each n-butanol dosage is the 50% of water phase volume), divides and takes n-butanol extracting liquid, recycle n-butanol, add 60% ethanol to dissolve, and 5
~10 DEG C are placed 3~5 days, and coarse filtration, hyperfiltration, takes filtrate to be concentrated into thick paste, and 60 DEG C of vacuum drying, obtain powder, its with it is foregoing
Forsythia volatile oil mixes, to obtain the final product.
Capsule according to the present invention, wherein the Baical Skullcap root P.E, Fel Ursi powder extract and associated extraction thing and
In the materials such as the filler of capsule of the present invention, contained chemical composition, the side that can be described according to following HPLC content determinations 1
Method is measured：
【HPLC content determinations 1】(it is available for the scutelloside, urso, chenodeoxycholic measured in various materials
The content of acid)：Measured according to high performance liquid chromatography (one annex VID of Chinese Pharmacopoeia version in 2010)；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler, with 0.05% trifluoro
Acetic acid solution is mobile phase A, and acetonitrile is Mobile phase B, and according to the form below carries out gradient elution；Use evaporative light scattering detector；Drift tube
95 DEG C of temperature.Number of theoretical plate is calculated by scutelloside peak, should be not less than 10000；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) | Flow velocity (ml/min) |
| 0~24 | 90→58 | 10→42 | 1.0 |
| 24~30 | 58→26 | 42→74 | 1.0 |
| 30~40 | 26→10 | 74→90 | 1.0 |
The preparation of reference substance solution：Precision weighs scutelloside reference substance, urso reference substance and chenodeoxycholic acid pair
According to product, (these reference substances and the other reference substances of the invention used can easily be bought from market, such as therefrom traditional Chinese medicines
Food calibrating research institute is savored to buy) in right amount, add propane diols and appropriate methanol, ultrasound makes to be completely dissolved, lets cool, and adds methanol dilution system
Into every 1ml 0.5mg containing scutelloside, urso 0.6mg, chenodeoxycholic acid 0.1mg mixed solution, to obtain the final product；
The preparation of test solution：Precision measures or takes test sample (to determine wherein respectively to contain according to trial test in right amount
To the amount of a great deal of grade of corresponding component in above-mentioned reference substance solution preparation process), put in 10ml measuring bottles, add methanol dissolving/
Be diluted to scale, shake up, filter if necessary, to obtain the final product；
Determination method：It is accurate respectively to draw 4 μ l of reference substance solution, 5 μ l of 8 μ l and test solution, liquid chromatograph is injected, is surveyed
It is fixed, content is calculated with external standard two-point method logarithmic equation, to obtain the final product, scutelloside, urso, goose deoxidation in test sample can be calculated to obtain
The content of cholic acid.The content can usually be represented with the mg numbers of contained scutelloside in every mg materials, represent the content of other materials
When there is similar implication.
Capsule according to the present invention, wherein the Baical Skullcap root P.E and associated extraction thing and capsule of the present invention
Contained chemical composition particularly scutellarin in the materials such as filler, the side that can be described according to following HPLC content determinations 2
Method is measured：
【HPLC content determinations 2】(it can be used for measuring the scutellarin in various materials)：According to high performance liquid chromatography
(one annex VID of Chinese Pharmacopoeia version in 2010) is measured；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler；Using acetonitrile as flowing
Phase A, using 0.1% formic acid solution as Mobile phase B, the regulation according to the form below carries out gradient elution；Detection wavelength is 280nm.It is theoretical
Plate number is calculated by scutellarin peak, should be not less than 3000；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) | Flow velocity (ml/min) |
| 0~30 | 15→30 | 85→70 | 1.0 |
| 30~60 | 30 | 70 | 1.0 |
The preparation of reference substance solution：It is appropriate that precision weighs scutellarin reference substance, adds methanol to dissolve and every 1ml is made containing 25
The solution of μ g, shakes up, to obtain the final product；
The preparation of test solution：Precision measures or takes test sample (to determine wherein respectively to contain according to trial test in right amount
To the amount of a great deal of grade of corresponding component in above-mentioned reference substance solution preparation process), put in measuring bottle, be dissolved in water/be diluted to
Scale, shakes up, and filters if necessary, to obtain the final product；
Determination method：Accurate absorption reference substance solution and each 10 μ l of test solution respectively, injection liquid chromatograph, measure,
The content of scutellarin (C21H18O12) in test sample can be calculated to obtain.
Capsule according to the present invention, wherein the goat's horn extraction and associated extraction thing and capsule of the present invention
The material such as filler in contained chemical composition particularly total amino acid, the description of following HPLC content determinations 3 can be shone
Method is measured：
【HPLC content determinations 3】(it can be used for measuring the single amino acid amount in various materials, can be especially useful for surveying
Determine total amino acid value)：Measured according to high performance liquid chromatography (one annex VID of Chinese Pharmacopoeia version in 2010)；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler (Hypersil-ODS
Chromatographic column, column length 20cm, internal diameter 4.6mm, 5 μm of particle diameter)；Mobile phase A：Sodium acetate (three crystallizations water) 7.00g is taken, adds water
4000ml makes dissolving, adds triethylamine 0.8ml, tetrahydrofuran 24ml, mixes, and pH value is adjusted to 7.2 with 2% glacial acetic acid solution；Stream
Dynamic phase B：Take sodium acetate (three crystallizations water) 10.88g, add water 800ml to make dissolving, with 2% glacial acetic acid solution adjust pH value to
7.2, add acetonitrile 1400ml, methanol 1800ml, mix, according to the form below carries out gradient elution；0~37.5 minute, Detection wavelength was
338nm, after 37.5 minutes, Detection wavelength 262nm；Column temperature：35℃；Number of theoretical plate is calculated by alanine peak to be not less than
40000；
| Time (min) | Mobile phase A (%) | Mobile phase B (%) | Flow velocity (ml/min) |
| 0~20 | 100→85 | 0→15 | 1.0 |
| 20~45 | 85→36 | 15→64 | 1.0 |
| 45~55 | 0 | 100 | 1.5 |
The preparation of reference substance solution：Precision weighs aspartic acid, glycine, glutamic acid, serine, threonine, phenylpropyl alcohol ammonia
Acid, isoleucine, proline, alanine, valine, leucine reference substance are appropriate, put in 10ml measuring bottles, add 0.1mol/L hydrochloric acid
Solution dissolves and is diluted to scale, shakes up, as reference substance stock solution (per 1ml respectively containing aspartic acid, glycine, glutamic acid,
Serine, threonine, isoleucine, proline, alanine, valine, leucine 1mg, phenylalanine 0.5mg)；Precision is drawn
Above-mentioned reference substance stock solution 2ml, puts in 10ml measuring bottles, is diluted with water to scale, shake up, (each per 1ml as reference substance solution
Containing aspartic acid, glycine, glutamic acid, serine, threonine, isoleucine, proline, alanine, valine, leucine
0.2mg, phenylalanine 0.1mg)；
The preparation of test solution：Accurate it can measure or take test sample (to determine wherein to distinguish according to trial test in right amount
Contain the amount to a great deal of grade of corresponding component in above-mentioned reference substance solution preparation process), put in measuring bottle, be dissolved in water/dilute
Release to scale, shake up, filter if necessary, to obtain the final product；
Determination method：It is accurate respectively to draw reference substance solution and each 1 μ L of test solution, liquid chromatograph is injected, using 1%
O-phthalaldehyde (OPA) solution and 0.5% 1 chloro-carbonic acid fluorenes methyl ester solution (FMOC) computer simulation pre-column derivatization, measure is simultaneously
Calculate the amount of above-mentioned each amino acid, and their total amount (for total amino acid amount).
" test solution and maneuver arrived involved in HPLC content determinations 3 " can shine following method and prepare or perform more than：
0.4mol/L borate buffers (pH10.2)：Boric acid is taken, is configured to the solution of 0.4mol/L, with 40% sodium hydroxide
Solution adjusts pH value to 10.2, up to (this liquid needs to refrigerate)；
1% o-phthalaldehyde (OPA) solution：O-phthalaldehyde (OPA) 80mg is weighed, adds borate buffer (pH10.2)
7ml, acetonitrile 1ml, 125 μ l of mercaptopropionic acid, mix, up to (this liquid needs to refrigerate)；
0.5% 1 chloro-carbonic acid fluorenes methyl esters (FMOC) solution：Chloro-carbonic acid fluorenes methyl esters (FMOC) 50mg is weighed, it is appropriate with acetonitrile
Make dissolving, and be diluted to 10ml (this liquid needs to refrigerate)；
Pre-column derivatization reacts：Test solution and reference substance solution in the borate buffer of pH10.2 first and OPA
Reaction, then derived with FMOC；
Pre-column derivatization injection procedure (bottle 1~5 is respectively OPA, FMOC, water, borate buffer solution, water)：Drawn from bottle 3
0 μ l (water, cleans syringe needle)；5 μ l (borate buffer solution) are drawn from bottle 4；0 μ l are drawn from bottle 3 (water, cleans syringe needle)；Inhaled from bottle 1
Take 1 μ l (OPA)；0 μ l are drawn from bottle 3 (water, cleans syringe needle)；1 μ l of pipette samples；0 μ l are drawn from bottle 3 (water, cleans syringe needle)；
" in atmosphere " 7 μ l of mixing, 10 times；1 μ l (FMOC) are drawn from bottle 2；0 μ l are drawn from bottle 3 (water, cleans syringe needle)；" in air
In " mixing 8 μ l, 30 times；32 μ l (water) are drawn from bottle 5；" in atmosphere " 20 μ l of mixing, maximal rate, 2 times；Sample introduction.
Capsule according to the present invention, wherein the Honegsukle flower P.E or total organic acids and capsule of the present invention are filled out
Contained chemical composition particularly total organic acids and its each specific organic acid in the materials such as thing are filled, following HPLC contents can be shone
The method that determination method 4 describes is measured：
【HPLC content determinations 4】(it can be used for measuring the single organic acid content in various materials, can be especially useful for surveying
Determine total organic acids value)：Measured according to high performance liquid chromatography (one annex VID of Chinese Pharmacopoeia version in 2010)；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler (column length 25cm, it is interior
Footpath is 4.6mm, and particle diameter is 5 μm)；Using acetonitrile as mobile phase A, using 0.1% formic acid solution as Mobile phase B, the regulation according to the form below
Carry out gradient elution (rinsing chromatographic column with a high proportion of acetonitrile after appearance)；Column temperature is 30 DEG C；Detection wavelength is 325nm；
Number of theoretical plate is calculated by caffeic acid peak should be not less than 50000；
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) | Flow velocity (ml/min) |
| 0~20 | 5→10 | 95→90 | 0.8 |
| 20~30 | 10 | 90 | 0.8 |
| 30~35 | 10→18 | 90→82 | 0.8→1.0 |
| 35~60 | 18 | 82 | 1.0 |
The preparation of reference substance solution：Take caffeic acid and chlorogenic acid reference substance appropriate, it is accurately weighed, add 50% methanol system respectively
Contain the solution of 30 μ g into every 1ml, to obtain the final product；
The preparation of test solution：Precision measures or takes test sample (to determine wherein respectively to contain according to trial test in right amount
To the amount of a great deal of grade of corresponding component in above-mentioned reference substance solution preparation process), put in measuring bottle, add methanol dissolving/dilution
To scale, shake up, filter if necessary, up to test solution；
Determination method：It is accurate respectively to draw reference substance solution and each 10 μ l of test solution, liquid chromatograph is injected, is measured,
Chromatographic peak is recorded, the content of caffeic acid and chlorogenic acid in tester can be calculated to obtain.
Further, it is possible to neochlorogenic acid, Cryptochlorogenic acid, 3,4-, bis- coffees in tester are calculated using following formula respectively
Sour acyl chinic acid, bis- caffeic acid acyl chinic acids of 3,5-, the content of bis- caffeic acid acyl chinic acids of 4,5-：
It is possible to further calculate the organic acid total amount (i.e. the amounts of total organic acids) in measure thing using the following formula：
Organic acid total amount=neochlorogenic acid content+
Chlorogenic acid content+
Cryptochlorogenic acid content+
Coffee acid content+
Bis- caffeic acid acyl chinic acid contents of 3,4-+
Bis- caffeic acid acyl chinic acid contents of 3,5-+
Bis- caffeic acid acyl chinic acid contents of 4,5-.
In the present invention, if not otherwise indicated, measure various materials such as forsythia suspense extraction or capsule of the present invention is filled out
It is reference when filling the total glycosides of specific chemical composition such as forsythiaside A and forsythin in thing either their summation i.e. Fructus Forsythiae
Chinese Pharmacopoeia contained " forsythia suspense extraction " project of version one page 381 in 2010【Assay】Method under carries out,
It can be appropriately adjusted when sample preparation and other concrete operations according to the standard empirical of those skilled in the art.Need what is illustrated
It is the specific chemical composition such as Fructus Forsythiae ester measured in various materials such as forsythia suspense extraction or capsule filler of the present invention
The method of other document reports also can be used in the method for glycosides A and forsythin either their the total glycosides of summation, that is, Fructus Forsythiae, such as can
With using the method for Cai Ying reports, (Cai Ying, HPLC method measure infantile lung heat cough and asthma product take containing for forsythin and forsythiaside A in liquid
Amount, Shandong medicine thing, 2012,31 (6):333).
In addition, either the special goat's horn extraction of associated extraction thing or total amino acid can shine capsule filler of the present invention
HPLC content determinations 3 of the present invention are measured, it has the typical liquid chromatographic figure as shown in Fig. 1 of the present invention, i.e., originally
Invention capsule filler either associated extraction thing particularly goat's horn extraction or total amino acid have Fig. 1 shown in fingerprint
Collection of illustrative plates (can be described as finger-print 1) in the present invention.When measuring finger-print 1, the preparation method of the reference solution used
For：Take alanine reference substance appropriate, it is accurately weighed, add water that solution of every 1ml containing 0.2mg is made, to obtain the final product.At one of the present invention
In embodiment, capsule filler of the present invention is measured gained finger-print according to HPLC content determinations 3 of the present invention
Compared with Fig. 1 finger-prints, except the later chromatographic peak of proline appearance, similarity software is simulated (in the present invention through computer
The middle traditional Chinese medicine fingerprint area of computer aided similarity evaluation software (version 2 004A) using those skilled in the art's routine) meter
Calculate, similarity is more than 0.90.
In addition, either the special Honegsukle flower P.E of associated extraction thing or total organic acids can shine capsule filler of the present invention
HPLC content determinations 4 of the present invention are measured, Detection wavelength 280nm, it, which has, is similar to shown in Fig. 2 of the present invention
Typical liquid chromatographic figure, i.e., capsule filler of the present invention either associated extraction thing particularly Honegsukle flower P.E or total organic
Acid has the feature of the finger-print (can be described as finger-print 2 in the present invention) shown in Fig. 2.When measuring finger-print 2, make
The preparation method of reference solution is：Take caffeic acid reference substance appropriate, it is accurately weighed, add 50% methanol that every 1ml is made and contain
The solution of 30 μ g, to obtain the final product.In one embodiment of the invention, capsule filler of the present invention contains according to HPLC of the present invention
Amount determination method 4 is measured finger-print obtained by (Detection wavelength 280nm) compared with finger-print 2, and phase is simulated through computer
Like degree software, (the traditional Chinese medicine fingerprint area of computer aided similarity evaluation that those skilled in the art's routine is used in the present invention is soft
Part (version 2 004A)) calculate, similarity is more than 0.90.
The preparation method of general hard capsule can be used to obtain for capsule of the present invention, it is however generally that, comprise the following steps：
(i) Capsules is provided；
(ii) following five kinds of materials are provided：Total urso cholic acid or urso, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, gold
Honeysuckle flower extract, forsythia suspense extraction, and determine the content of the object in each material；
(iii) ratio according to the object in formula, weighs five kinds of materials of step (ii) respectively；
(iv) five kinds of materials that step (iii) weighs are mixed with diluent and optional other pharmaceutic adjuvants, is filled out
Fill thing；Or five kinds of materials for weighing step (iii) mix, then mixed again with diluent and optional other pharmaceutic adjuvants
Close, obtain filler；
(v) filler obtained by step (iv) is filled into the Capsules, capsule body and capsule cap is closely sealed, i.e.,
.
Above-mentioned term " object ", refers to urso, for cornu caprae hircus hydrolysate for total urso cholic acid
Refer to total amino acid, scutelloside is referred to for Baical Skullcap root P.E, total organic acids are referred to for Honegsukle flower P.E, it is right
Refer to the total glycosides of Fructus Forsythiae for forsythia suspense extraction.
According to the above method, since the content of the object in five kinds of extracts can be by obtaining the methods of HPLC to measure
Know, it is thus determined that during the proportion scale of the filler in hard capsule of the present invention, can be directly with urso, total amino
The part by weight relation of acid, scutelloside, total organic acids, Fructus Forsythiae five kinds of (class) materials of total glycosides accurately determines, without examining
Consider the rate of charge of total urso cholic acid, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, Honegsukle flower P.E, forsythia suspense extraction these extracts,
Also without the concern for bear gall powder, cornu caprae hircus, radix scutellariae, honeysuckle, Fructus Forsythiae these medicinal materials rate of charge.Particularly, such as gold
For honeysuckle flower or Honegsukle flower P.E, the amount of the total organic acids contained between batches of medicinal material or extract might have change
The medicinal material of different batches or extract might have change when changing, therefore feeding intake in the actual production process, and between every batch of such as
For fruit with contained total organic acids timing in the material Honegsukle flower P.E that feeds intake, being calculated using this parameter as proportioning can usually keep permanent
It is fixed.
Thus, one embodiment of the invention provides the method for preparing capsule of the present invention, it includes above-mentioned steps (i)
To step (v).
In addition, the purposes present invention also offers capsule of the present invention in the medicine for preparing heat-clearing, resolving sputum, removing toxic substances.This
Invention additionally provides capsule of the present invention and is preparing for the purposes in the medicine of wind-warm lung-heat disease pulmonary retention of phlegmopyrexia card.The present invention is also
Provide capsule of the present invention prepare generate heat, cough, not well, abscess of throat of coughing up phlegm, thirsty, tongue is red, yellow tongue fur；Pneumonia early stage,
Acute bronchitis, acute exacerbation of chronic bronchitis and the infection of the upper respiratory tract belong to the purposes in the medicine of above-mentioned patient.
Each technical characteristic of each embodiment of the present invention can be combined in other embodiments, some implementation of the present invention
Scheme can also be with other combination of embodiment, as long as these combinations occur without contradiction.
When capsule of the present invention is applied to clinical, the dosages of usual adult patients can be 10 in terms of urso~
500mg/ days, such as 20~500mg/ days, such as 50~500mg/ days, when certain clinical practice also need to consider patient volume,
Age, gender, disease severity.In view of it is applied to clinic with the medicine that capsule of the present invention has similar prescription, therefore
The definite of the dosage of capsule of the present invention is that those skilled in the art are easy to implement.
Capsule of the present invention, for conventional hard capsule, the filler typically 100 that is included in its every 1~
750mg, is, for example, 150~500mg.
The capsule of the present invention is made, Huo Zheyou of five kinds of Chinese medicines (bear gall powder, cornu caprae hircus, radix scutellariae, honeysuckle, Fructus Forsythiae)
Four kinds of Chinese medicines (cornu caprae hircus, radix scutellariae, honeysuckle, Fructus Forsythiae) and directly addition can be synthesized chemically or biological synthesis pathway obtains
Urso be made.Each Chinese medicine is added in a manner of extracting to obtain extract respectively in the filler, bear gall powder,
Cornu caprae hircus, radix scutellariae, honeysuckle, the summation of five kinds of extracts of Fructus Forsythiae are properly termed as the active material of the present invention；Or cornu caprae hircus, Huang
A kind of reed mentioned in ancient books, honeysuckle, the summation of four kinds of extracts of Fructus Forsythiae and urso are properly termed as the active material of the present invention.It is in view of various
Quantitative object can be used for be measured by the above-mentioned various HPLC methods of the present invention in extract, such as goat's horn extraction
In the amount of total amino acid can measure to obtain by HPLC methods, the total glycosides of the Fructus Forsythiae in forsythia suspense extraction can be surveyed by HPLC methods
It is fixed.Therefore when preparing the filler of capsule of the present invention, can according in filler described above on urso, always
The part by weight relation of amino acid, scutelloside, total organic acids, Fructus Forsythiae five kinds of (class) materials of total glycosides, and this in various extracts
The content of five kinds of (class) materials, the extract comprising five kinds of (class) materials is added (i.e. into the filler or active material
Total urso cholic acid, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, Honegsukle flower P.E, forsythia suspense extraction), can be straight for total urso cholic acid
Connect and added in the form of urso.
, can be first by total urso cholic acid (or directly with ursodeoxycholic in addition, when preparing the filler of capsule of the present invention
Acid addition), cornu caprae hircus hydrolysate, Baical Skullcap root P.E, Honegsukle flower P.E, forsythia suspense extraction mix in proportion, form one
Kind can be described as the material of active material in the present invention, then again by the material and diluent of the present invention and optionally other
Pharmaceutic adjuvant mixes, and obtains the filler of the present invention, and temporarily foring one kind during this manner of formulation is referred to as
The intermediate material of " active material ".
Alternatively, when preparing the filler of capsule of the present invention, directly total urso cholic acid (or directly can be deoxygenated with bear
Cholic acid adds), cornu caprae hircus hydrolysate, Baical Skullcap root P.E, Honegsukle flower P.E, forsythia suspense extraction and of the present invention dilute
Release agent and the mixing of optional other pharmaceutic adjuvants mix in proportion, directly obtain can as the material of filler of the present invention,
This manner of formulation will not independently form the material only assembled by five kinds of active matters, i.e., will not independently form as described above " living
Property material ".
In view of as described above in the present invention, filler of the present invention includes active material, diluent and optional its
Its pharmaceutic adjuvant.Therefore, in the present invention, term " active material ", the total urso cholic acid for referring to there are special ratios (or directly
Added with urso), cornu caprae hircus hydrolysate, Baical Skullcap root P.E, five kinds of Honegsukle flower P.E, forsythia suspense extraction components it is total
With, should " active material " can be the intermediate material that is specifically formd in preparation process as described above or not specific
Formed but directly mix five kinds of components for forming it with pharmaceutic adjuvant.That is, term " active material ", refers to there is spy
The total urso cholic acid (or directly being added with urso) of certainty ratio, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, honeysuckle extraction
The general name of five kinds of thing, forsythia suspense extraction components.
In the present invention, the diluent used it is especially preferential be starch and/or dextrin.Starch and dextrin loaded 2010
Year version《Pharmacopoeia of People's Republic of China》Two.The pharmacopeia of other countries such as American Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan
Deng, starch and dextrin are also recorded, such as recorded cornstarch, farina, rice in beautiful, Deng states pharmacopeia
The starch of the separate sources such as starch, wheaten starch, tapioca.Since these starch and dextrin are to be added to the present invention with prototype
In filler, therefore these dilutions can be detected by the common detection methods of starch and dextrin in filler of the present invention
The presence of agent, such as can be carried out by using for reference pharmacopeia is recorded plus iodine solution development process, or by petrographic microscope detection method
Detection, to judge the presence of starch in the present invention；The present invention can also be calculated for example, by the colour developing depth of iodine solution development process to fill out
Fill the amount of starch and dextrin in thing.
Capsule of the present invention has effects that heat-clearing, resolving sputum, removing toxic substances, clinically available for wind-warm lung-heat disease pulmonary retention of phlegmopyrexia
Card, symptoms include：Generate heat, cough, not well, abscess of throat of coughing up phlegm, thirsty, tongue is red, yellow tongue fur；It is pneumonia early stage, acute bronchitis, chronic
Bronchitis acute attack and the infection of the upper respiratory tract belong to above-mentioned patient.
Brief description of the drawings
Fig. 1 is the typical fingerprint collection of illustrative plates of the total amino acid of capsule filler of the present invention.The corresponding component in each peak number in figure
It is as follows：1st, aspartic acid, 2, glutamic acid, 3, serine, 4, glycine, 5, threonine, 6, alanine, 7, valine, 8, phenylpropyl alcohol
Propylhomoserin, 9, isoleucine, 10, leucine, 11, proline.
Fig. 2 is the typical fingerprint collection of illustrative plates of the total organic acids of capsule filler of the present invention.The corresponding component in each peak number in figure
It is as follows：1st, neochlorogenic acid, 2, Forsythoside D, 3, chlorogenic acid, 4, Cryptochlorogenic acid, 5, caffeic acid, 6, scutellarin, 7,3,4- bis-
Caffeic acid acyl chinic acid, 8,3,5-, bis- caffeic acid acyl chinic acids, 9,4,5-, bis- caffeic acid acyl chinic acids.
Embodiment
The present invention is further described with specific example below.Extract preparation example part below, it is such as in addition not special
Illustrate, the every batch of inventory at least 1kg of medicinal material and meet the needs of later tests reagent when preparing extract.Test below
In, when directly being fed intake with urso, urso is directly to buy and supervised by state food medicine from the market
Superintend and direct the bulk pharmaceutical chemicals of the pharmaceutical grade of management general bureau approval listing.
First, extract preparation example part
Preparation example 1a：The preparation of total urso cholic acid
Total urso cholic acid is obtained according to the method for CN101890048A specifications [0093]-[0094] section, that is, embodiment 1, through surveying
It is fixed, wherein containing 76.6% urso and 11.6% chenodeoxycholic acid (bear/goose=6.6；Below in each example, system
In the total urso cholic acid obtained, ursodeoxycholic acid content：The ratio of chenodeoxycholic acid content is in the range of 5-16).
Preparation example 1b：The preparation of total urso cholic acid
Total urso cholic acid is prepared according to CN1947746B specification [0024] section case method, containing 64.6% ursodeoxycholic
Acid.
Preparation example 1c：The preparation of total urso cholic acid
Total urso cholic acid is prepared according to the method for CN1110150A Instructions Page 2 21-31 rows record, is gone containing 56.3% bear
Oxycholic acid.
Preparation example 2a：The preparation of cornu caprae hircus hydrolysate
By cornu caprae hircus plus sulfuric acid (8 times of amounts, 4mol/L sulfuric acid) be heated to reflux 16 it is small when or so, filtration, sediment is measured with 4 times
Water washing it is secondary, merging filtrate, washing lotion, with 16% milk of lime tune pH value to 6.0, filtration, filtrate is concentrated into relative density
For 1.04~1.1 (60 DEG C), add 1% activated carbon decolorizing, filter, be slowly added into ethanol under filtrate stirring, make alcohol content up to 70%,
Refrigerate 12 it is small when, hyperfiltration, recycles ethanol, cools, and stirring is lower plus ethanol makes alcohol content up to 80%, when refrigeration 12 is small, coarse filtration,
Hyperfiltration, recycles ethanol, and is concentrated into thick paste, and less than 60 DEG C vacuum drying obtain cornu caprae hircus hydrolysate into powder.
Through【HPLC content determinations 3】Measure, contain following amino acid in the cornu caprae hircus hydrolysate：Aspartic acid, paddy
Propylhomoserin, serine, glycine, threonine, alanine, valine, phenylalanine, isoleucine, leucine, proline, and
The total amount (also referred to as total amino acid amount) of these amino acid accounts for the 84.5% of cornu caprae hircus hydrolysate, which has
Finger-print as shown in Figure 1.
Complementary testing is found, using can be as capsule filler of the present invention made of the hereafter dispensing of filler example 2
Mixture, it is passed through【HPLC content determinations 3】Measure, has the chromatogram of Fig. 1, contains following amino acid in chromatogram：My god
Winter propylhomoserin, glutamic acid, serine, glycine, threonine, alanine, valine, phenylalanine, isoleucine, leucine, dried meat
Propylhomoserin, and the finger-print of gained collection of illustrative plates (except the later chromatographic peak of proline appearance) and above-mentioned cornu caprae hircus hydrolysate, warp
Computer simulation similarity software calculates, and similarity is not less than 0.90, and similarity is up to 0.95.This result shows that, other 4 kinds/classes
The addition of component does not interfere with the HPLC fingerprint characteristics of total amino acid in mixture.
Preparation example 2b：The preparation of cornu caprae hircus hydrolysate
Prepare, pass through according to the method for CN101084924B (Xue Dongsheng, 2006) specification [0027] section, that is, embodiment 1
【HPLC content determinations 3】Measure, contain following amino acid in the cornu caprae hircus hydrolysate：Aspartic acid, glutamic acid, silk ammonia
Acid, glycine, threonine, alanine, valine, phenylalanine, isoleucine, leucine, proline, and these amino acid
Total amount (also referred to as total amino acid amount) account for the 74.2% of cornu caprae hircus hydrolysate.
Preparation example 2c：The preparation of cornu caprae hircus hydrolysate
Cornu caprae hircus hydrolysate is prepared according to the method for CN1947746B (Mu Laian, 2005) specification [0025] section, is passed through
【HPLC content determinations 3】Measure, contain following amino acid in the cornu caprae hircus hydrolysate：Aspartic acid, glutamic acid, silk ammonia
Acid, glycine, threonine, alanine, valine, phenylalanine, isoleucine, leucine, proline, and these amino acid
Total amount (also referred to as total amino acid amount) account for the 66.7% of cornu caprae hircus hydrolysate.
Preparation example 3a：The preparation of Baical Skullcap root P.E
It is prepared into according to the method under " Baical Skullcap root P.E " item described in People's Republic of China's version one page 391 in 2010
To Baical Skullcap root P.E, after measured, wherein containing 85.2% scutelloside.
Preparation example 3b：The preparation of Baical Skullcap root P.E
Baical Skullcap root P.E is prepared according to the method for CN1947746B specification [0026] section, after measured, wherein containing
67.1% scutelloside.
Preparation example 3c：The preparation of Baical Skullcap root P.E
It is prepared into according to the method under " Baical Skullcap root P.E " item described in People's Republic of China's version one page 391 in 2010
To extract, then it is dissolved in hot ether, filters, cool down to be recrystallized, removes solvent, it is dry, obtain radix scutellariae extraction
Thing, after measured, wherein containing 91.8% scutelloside.
In addition, the scutellarin in above-mentioned preparation example 3a to Baical Skullcap root P.E made from preparation example 3c also measured were, as a result
Scutelloside in three extracts：The ratio of scutellarin is in the range of 50-150, such as Huang in preparation example 3a Baical Skullcap root P.Es
A kind of reed mentioned in ancient books glycosides：Scutellarin=93：1.
Preparation example 4a：The preparation of Honegsukle flower P.E
Extracting honeysuckle, add water to cook it is secondary, for the first time plus 12 times of amount water decoct 1 it is small when, second plus 10 times of amount water, decoct
30 minutes, collecting decoction, filtration, it was 1.20 (70 DEG C) that filtrate, which is concentrated into relative density, adds 20% milk of lime tune pH value to be stirred to 11
Mix, filter, precipitation plus 5 times of amount ethanol are stirred after being suspended, and with 50% sulfuric acid tune pH value to 2.0, filtration, filtrate is again with 40%
Sodium hydroxide tune pH value is to 6.8, and filtration, filtrate recycling ethanol, is concentrated into 100ml, with n-butanol extract 4 times (60ml, 60ml,
40ml, 40ml), divide and take n-butanol extracting liquid, recycle n-butanol, be dissolved in water, when 5~10 DEG C of standings 48 are small, coarse filtration, ultra micro mistake
Filter, takes filtrate to be concentrated into thick paste, 60 DEG C of vacuum drying, obtain Honegsukle flower P.E dry powder.
The Honegsukle flower P.E shines【HPLC content determinations 4】Measure, contain following organic acid in chromatogram：Green original
Acid, neochlorogenic acid, Cryptochlorogenic acid, caffeic acid, bis- caffeic acid acyl chinic acids of 3,4-, bis- caffeic acid acyl chinic acids of 3,5-, 4,5- bis-
Caffeic acid acyl chinic acid, and the total amount (also referred to as total organic acids amount) of these organic acids accounts for Honegsukle flower P.E
62.6%, the chromatogram of the Honegsukle flower P.E includes the chromatographic peak of seven kinds of above-mentioned organic acids described in Fig. 2.
Complementary testing find, using above-mentioned Honegsukle flower P.E prepare containing following component can be as capsule of the present invention
The mixture of filler：Total urso cholic acid (preparation example 1a) 6.5mg, cornu caprae hircus hydrolysate (preparation example 2b) 4mg, Baical Skullcap root P.E
(preparation example 3b) 8.9mg, Honegsukle flower P.E (preparation example 4a) 1.4mg, forsythia suspense extraction (preparation example 5a) 9.3mg, corn form sediment
Powder 5mg.
Gained mixture passes through【HPLC content determinations 4】Measure, is shown in Fig. 2, contains following organic acid in chromatogram：Green original
Acid, neochlorogenic acid, Cryptochlorogenic acid, caffeic acid, bis- caffeic acid acyl chinic acids of 3,4-, bis- caffeic acid acyl chinic acids of 3,5-, 4,5- bis-
Caffeic acid acyl chinic acid, and the finger-print of gained collection of illustrative plates and above-mentioned Honegsukle flower P.E are soft through computer simulation similarity
Part calculates, and similarity is not less than 0.90, and similarity is up to 0.97.This result shows that, the addition of other 4 kinds/class components does not interfere with
The HPLC fingerprint characteristics of total organic acids in mixture.
Preparation example 4b：The preparation of Honegsukle flower P.E
Prepare according to the method for CN1110150A (Cao Chunlin, 1994) specification 10-17 rows record of page 4, after measured, have
The total amount (also referred to as total organic acids amount) of machine acid accounts for the 49.4% of Honegsukle flower P.E.
Preparation example 4c：The preparation of Honegsukle flower P.E
Prepared according to the method for CN1947746B (Mu Laian, 2005) specification [0027] section, after measured, organic acid
Total amount (also referred to as total organic acids amount) accounts for the 71.1% of Honegsukle flower P.E.
Preparation example 5a：The preparation of forsythia suspense extraction
Fructus Forsythiae adds water, and decoction is secondary, and volatile oil is extracted in volatile oil extractor when decocting every time, obtains Fructus Forsythiae volatilization
Oil；When for the first time plus 10 times of amount water decoctions 1 are small, second plus 8 times of amount water, decoct 30 minutes, collecting decoction, filter, filtrate is dense
It is 1.02~1.04 (60 DEG C) to be reduced to relative density, and adding ethanol to make alcohol content, when standing 24 is small, filtration, filtrate is recycled up to 70%
Ethanol, is concentrated into no alcohol taste, adds 1% activated carbon decolorizing, filtration, and filtrate n-butanol extracts that 4 times (each n-butanol dosage is water
Phase volume 50%), point take n-butanol extracting liquid, recycle n-butanol, add 60% ethanol to dissolve, 5~10 DEG C are placed 3~5 days, slightly
Filter, hyperfiltration, takes filtrate to be concentrated into thick paste, 60 DEG C of vacuum drying, obtain powder, it is mixed with foregoing Forsythia volatile oil, to obtain the final product
Forsythia suspense extraction.After measured, the total glycosides of 32.1% Fructus Forsythiae is contained in the forsythia suspense extraction.
Preparation example 5b：The preparation of forsythia suspense extraction
Prepared with reference to the method that CN1110150A (Cao Chunlin, 1994) specification 2-9 rows of page 4 are recorded, obtain Fructus Forsythiae and carry
Take thing.After measured, the total glycosides of 19.4% Fructus Forsythiae is contained in the forsythia suspense extraction.
Preparation example 5c：The preparation of forsythia suspense extraction
The method system under " forsythia suspense extraction " item with reference to described in People's Republic of China's version one page 381 in 2010
It is standby, the spray-dried obtained dry powder water of 5 times of amounts is dissolved, adds 1% activated carbon decolorizing, filters, filtrate is carried with n-butanol
4 times (each n-butanol dosage is the 50% of water phase volume) are taken, divides and takes n-butanol extracting liquid, recycle n-butanol, add 60% ethanol
Dissolving, 5~10 DEG C are placed 3~5 days, coarse filtration, hyperfiltration, take filtrate to be concentrated into thick paste, 60 DEG C of vacuum drying, obtain powder to connect
Stick up extract.After measured, the total glycosides of 44.6% Fructus Forsythiae is contained in the forsythia suspense extraction.
2nd, the instance section of capsule filler is prepared
Filler example 1：Prepare filler
Component proportion：
| Component | Amount |
| Urso | 5g (is fed intake, inventory 6.527g, wherein 5g containing urso, also there is same implication below) with preparation example 1a, |
| Total amino acid | 3g (is fed intake) with preparation example 2b, |
| Scutelloside | 6g (is fed intake) with preparation example 3b, |
| Total organic acids | 1g (is fed intake) with preparation example 4c, |
| The total glycosides of Fructus Forsythiae | 3g (is fed intake) with preparation example 5a, |
| Note：5 kinds of materials of the above add up to 30.26g, and (wherein 5 kinds of object gross weight 18g, they account for the pact of filler gross weight 53%) | |
| Cornstarch | 3.4g (notes：Account for filler gross weight 10%). |
| Note：Whole materials add up to 33.66g (this is the amount of 100 capsules of preparation, every capsule 's content 336.6mg). |
Total material 33.66g in above list of ingredients, but fed intake when actually preparing with 100 times of material shown in table；Under
In each example in face, suitably double to be amplified to 10000 capsule manufacture amounts throwing grains.
Preparation method：Total urso cholic acid, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, Honegsukle flower P.E, Fructus Forsythiae are weighed by said ratio
Extract, is uniformly mixed, and adds diluent and other auxiliary materials (if there is when), is uniformly mixed, to obtain the final product.
Filler example 2：Prepare filler
Component proportion：
Preparation method：Total urso cholic acid, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, Honegsukle flower P.E, Fructus Forsythiae are weighed by said ratio
Extract, diluent and other auxiliary materials (if there is when), are uniformly mixed, to obtain the final product.
Filler example 3：Prepare filler
Component proportion：
Preparation method：Filler example 1.
Filler example 4：Prepare filler
Component proportion：
Preparation method：Filler example 1.
Filler example 5：Prepare filler
Component proportion：
Preparation method：Filler example 2.
Filler example 6：Prepare filler
Component proportion：
Preparation method：Filler example 1.
Filler example 7：Prepare filler
Component proportion：
Preparation method：Filler example 1.
Filler example 8：Prepare filler
Component proportion：
Preparation method：Filler example 1.
3rd, prepared by capsule
The various fillers being prepared in the upper and lower each example of text of the present invention are filled into the Capsules of suitable size
In, the content is filled substantially with capsule body, then capsule cap fitting is sealed.The material of Capsules is selected according to specific experiment
Select.Obtaining different capsules can be marked with " filler-Capsules type " or be marked with similar other manner.
4th, capsule shells employment and suitability test (E ＆ ST)
By 8 batches of fillers obtained by above filler example 1 to filler example 8, it is filled into respectively different types of hollow
In capsule, certain material be filled into obtained in certain Capsules capsule amount be no less than 400, and take appropriate capsule into
Row capsule shells employment and suitability test (E ＆ ST).
Elasticity is carried out to Capsules with reference to Chinese Pharmacopoeia version two page 1205 in 2010 and friability detection method is come
Check capsule of the present invention, it is as follows to having wrapped up the capsule particular exam method of filler in the present invention：
Elasticity：The capsule every batch of 100 for having wrapped up filler is taken, it is 2cm directly to be fallen in thickness in the eminence of 1m by grain
Plank on, count leakage powder capsule number simultaneously calculate the powder leakage rate (%) of this batch of capsule；
Friability：The capsule every batch of 100 for having wrapped up filler is taken, is put into by grain stands upright on plank (thickness respectively
In glass tube (internal diameter 24mm, a length of 200mm) on 2cm), by cylindrical counterweight (polytetrafluoroethylene (PTFE) material, diameter 22mm,
Weight 20g ± 0.1g) freely fallen at the glass mouth of pipe, count the capsule number of rupture and calculate the rupture rate of this batch of capsule
(%).
Measure the elasticity (being characterized with powder leakage rate) after each batch of filler is filled into different types of Capsules and crisp
Broken degree (being characterized with rupture rate), which places without long-term, therefore can be described as the result of 0 month.
Then, by the capsule of preparation with can completely cut off air and four layers of compound membrane bag that aqueous vapor penetrates through (aluminium-modeling-aluminium-
Modeling) pack (ensure them during experiment from external environment change influence, capsule workshop phase before sealing
To humidity about 42%), then they are placed in 40 DEG C of insulating boxs and place 3 months (referred to herein as " 40 degree of March "), at 3
Capsule is taken out after month.Measure each batch of filler and be filled into different types of Capsules and obtain different capsules and through 40 degree
Elasticity and friability, this result after disposal in March can be described as the result in 40 degree of March.Filler example 1 and the gained of filler example 2
The testing result of capsule sees below table 1.
Table 1：
The result shows that for filler example 1, no matter it is filled into the Capsules of which kind of material, the powder leakage rate at 0 month
It is with rupture rate<2%, it is qualified to show the Capsules used.However, the sealing listed in these capsules in simulation
Under terms of packing, stability of drug products accelerated test method routinely is after 40 degree of March are disposed, the Capsules institute of unlike material
Capsule show very different as a result, be specifically：The capsule obtained for common gelatin hollow capsule, at 40 degree 3
Powder leakage rate and rupture rate are equal after moon disposal<3%, fully meet in production general requires (this two parameter in production<5% is usual
It is qualified)；But the Capsules of other species is used, even if being equally the hollow glue of enteric gelatin that main material is gelatin
Capsule, the capsule of acquisition, powder leakage rate and rupture rate are equal after being disposed 40 degree of March>15%, show the hollow glue of these other materials
Capsule is not suitable for filler (this two parameter in production of the parcel present invention>5% is particularly>It is that cannot make us connecing completely when 10%
Receive).
The filler of filler example 2 is using capsule obtained by different Capsuleses, in above-mentioned capsule shells employment and suitability test (E ＆ ST)
Show it is essentially identical with the capsule of filler example 1 as a result, i.e. be only in gelatin hollow capsule capsule have it is good
Good elasticity and friability, and in the Capsules of other species when, is respectively provided with completely unsatisfactory result.
Method according to above-mentioned table 1 for result described in filler example 1,8 each filler of measure filler 3~filler of example example
It is filled into the elasticity and friability of gained capsule in unlike material Capsules.The results show is directed to filler example 1 with table 1
Result it is essentially identical, be specially：
This 6 kinds of fillers are filled into the Capsules of 10 kinds of materials respectively, the elasticity and friability measured at 0 month
It is equal with powder leakage rate and rupture rate respectively<2%；
After 40 degree of March are disposed, 6 kinds of fillers are filled into powder leakage rate and rupture rate in common gelatin hollow capsule respectively
<3%；
After 40 degree of March are disposed, 6 kinds of fillers are filled into enteric gelatin hollow capsule, HPMC Capsuleses, seaweed respectively
Polysaccharide empty capsule, pectin Capsules, the powder leakage rate in CMC Capsuleses and rupture rate are equal>10%, in 16~28% models
In enclosing.
As it can be seen that 8 each filler of filler 1~filler of example example is filled into capsule shells when in common gelatin hollow capsule above
It is with good stability, and when being filled into the Capsules of other materials display entirely without decree people receive as a result, to the greatest extent
The Capsules for managing these other materials is also that those skilled in the art are commonly used when preparing hard capsule.Show common
Gelatin hollow capsule is suitable for filler of the present invention, and the Capsules of other materials is not suitable for filler of the present invention, uncomfortable
Together in preparation capsule of the present invention.
5th, capsule filler and capsule shells employment and suitability test (E ＆ ST) are prepared
Filler example 21：
Respectively refer to the formula and preparation method of filler 1~filler of example example 8, different be only by starch therein and/or
Dextrin get rid of and without using, i.e., the dosage of starch and/or dextrin be 0%, obtain filler 211~filler of example example 218 totally 8
Sample.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler 211~filler of example example 218 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.8 fillers of the results show are made respectively
It is standby into 8 kinds of capsules, they：
What is measured at 0 month is equal with powder leakage rate and rupture rate<2%, display Capsules is qualified；
After 40 degree of March are disposed, the powder leakage rate and rupture rate of all categories capsule of each filler are equal>13%, exist
In the range of 15~31%.
As it can be seen that the capsule of the above-mentioned each filler preparation for being not added with starch and/or dextrin, no matter which kind of material is hollow
Capsule its result receives entirely without decree people, even common gelatin hollow capsule also it is not acceptable that.Show
Starch and/or dextrin is added in filler of the present invention to be necessary for obtaining stable capsule.
Filler example 22：
Respectively refer to the formula and preparation method of filler 1~filler of example example 8, different be only by starch therein and/or
Dextrin dosage is reduced, and is reduced to starch and/or dextrin and is accounted for the 1.5% of filler gross weight, obtains filler 221~filler of example
Totally 8 samples of example 228.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler 221~filler of example example 228 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.8 fillers of the results show are made respectively
It is standby into 8 kinds of capsules, they：
The powder leakage rate and rupture rate measured at 0 month is equal<2%, display Capsules is qualified；
After 40 degree of March are disposed, the powder leakage rate and rupture rate of all categories capsule of each filler are equal>14%, exist
In the range of 14~27%.
As it can be seen that capsule prepared by each filler of above-mentioned addition relatively low amount starch and/or dextrin, no matter which kind of material
Capsules its result receives entirely without decree people, even common gelatin hollow capsule also it is not acceptable that.Table
It is bright enough starch and/or dextrin are added in filler of the present invention to be necessary for obtaining stable capsule.
Filler example 23：
Respectively refer to filler example 1, the formula of filler 3~filler of example example 8 and preparation method, different be only will be therein
Starch and/or the adjustment of dextrin dosage, adjust to starch and/or dextrin and account for the 3% of filler gross weight, obtain filler example 231
Totally 7 samples of~filler example 237.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler 231~filler of example example 237 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.7 fillers of the results show are made respectively
It is standby into 8 kinds of capsules, they：
The powder leakage rate and rupture rate measured at 0 month is equal<2%, display Capsules is qualified；
After 40 degree of March are disposed, 7 kinds of fillers are filled into powder leakage rate and rupture rate in common gelatin hollow capsule respectively
<3%；
After 40 degree of March are disposed, 7 kinds of fillers are filled into enteric gelatin hollow capsule, HPMC Capsuleses, seaweed respectively
Polysaccharide empty capsule, pectin Capsules, the powder leakage rate in CMC Capsuleses and rupture rate are equal>15%, in 15~33% models
In enclosing.
As it can be seen that 237 these starch of filler 231~filler of example example and/or dextrin dosage are fitted up to 3% filler above
Common gelatin hollow capsule is used to, but the Capsules of other materials does not apply to.
Filler example 24：
Respectively refer to filler 2~filler of example example 5, the formula of filler example 8 and preparation method, different be only will be therein
Starch and/or the adjustment of dextrin dosage, adjust to starch and/or dextrin and account for the 10% of filler gross weight, obtain filler example 241
Totally 5 samples of~filler example 245.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler 241~filler of example example 245 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.5 fillers of the results show are made respectively
It is standby into 8 kinds of capsules, they：
The powder leakage rate and rupture rate measured at 0 month is equal<2%, display Capsules is qualified；
After 40 degree of March are disposed, 5 kinds of fillers are filled into powder leakage rate and rupture rate in common gelatin hollow capsule respectively
<3%；
After 40 degree of March are disposed, 5 kinds of fillers are filled into enteric gelatin hollow capsule, HPMC Capsuleses, seaweed respectively
Polysaccharide empty capsule, pectin Capsules, the powder leakage rate in CMC Capsuleses and rupture rate are equal>15%, in 15~33% models
In enclosing.
As it can be seen that the filler of 245 these starch of filler 241~filler of example example and/or dextrin dosage up to 10% above
It is suitable for common gelatin hollow capsule, but the Capsules of other materials does not apply to.
Filler example 25：
Respectively refer to filler example 1, filler example 2, filler example 6, the formula of filler example 7 and preparation method, it is different only
It is by starch therein and/or the adjustment of dextrin dosage, adjusts to starch and/or dextrin and account for the 25% of filler gross weight, obtain
Totally 4 samples of filler 251~filler of example example 254.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler 251~filler of example example 254 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.4 fillers of the results show are made respectively
It is standby into 8 kinds of capsules, they：
The powder leakage rate and rupture rate measured at 0 month is equal<2%, display Capsules is qualified；
After 40 degree of March are disposed, 4 kinds of fillers are filled into powder leakage rate and rupture rate in common gelatin hollow capsule respectively
<3%；
After 40 degree of March are disposed, 4 kinds of fillers are filled into enteric gelatin hollow capsule, HPMC Capsuleses, seaweed respectively
Polysaccharide empty capsule, pectin Capsules, the powder leakage rate in CMC Capsuleses and rupture rate are equal>15%, in 15~33% models
In enclosing.
As it can be seen that the filler of 254 these starch of filler 251~filler of example example and/or dextrin dosage up to 25% above
It is suitable for common gelatin hollow capsule, but the Capsules of other materials does not apply to.
Filler example 26：
The formula and preparation method of filler example 1 are respectively referred to, different is only to use starch therein instead equivalent respectively：Breast
This five kinds of common diluents of those skilled in the art of sugar, Icing Sugar, microcrystalline cellulose, calcium monohydrogen phosphate, calcium carbonate, respectively obtain and fill out
Fill totally 5 samples of thing 261~filler of example example 265.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler 261~filler of example example 265 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.
8 kinds of capsules that 5 fillers of the results show are prepared into respectively, they：
What is measured at 0 month is equal with powder leakage rate and rupture rate<2%, display Capsules is qualified；
After 40 degree of March are disposed, the powder leakage rate and rupture rate of all categories capsule of each filler are equal>15%, exist
In the range of 15~37%.
As it can be seen that it is above-mentioned use instead the common diluent of other those skilled in the art cannot but obtain it is gratifying as a result,
Also fail to obtain and gratifying result even with common gelatin hollow capsule.
Filler example 27：
According to the formula and method of CN1754542A specifications embodiments 1 of page 13, adding appropriate amount of starch in a final step makes
Its content in final filler is 10% or 20%, and capsule filler example 271, filler example 272 is prepared.
Method according to above-mentioned table 1 for result described in filler example 1, measure filler example 271, filler example 272 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.
8 kinds of capsules that 2 fillers of the results show are prepared into respectively, they：Measured at 0 month with powder leakage rate and broken
It is equal to split rate<2%, display Capsules is qualified；After 40 degree of March are disposed, all categories capsule of each filler
Powder leakage rate and rupture rate are equal>18%, in the range of 18~39%.Use other those skilled in the art instead as it can be seen that above-mentioned and commonly use
Diluent cannot but obtain it is gratifying as a result, also failing to obtain even with common gelatin hollow capsule and making us full
The result of meaning.Peppermint is included in the formula of the CN1754542A embodiments 1, it there may be the effect of capsule starch of the present invention
Harmful effect.Therefore in one embodiment of the invention, wherein not including peppermint in the active material.
Filler example 28：
It is [0050] section formula with reference to CN102784203A specifications 1 core tablet formulas of embodiment of page 4, will wherein forms sediment if necessary
Powder dosage adjusts, and the formula is made uniformly mixed powder by grinding, it is directly encapsulated, obtains two formulas, point
Not Wei filler example 281 and filler example 282, the two starch dosage be respectively 3.8% (it is identical with [0050] section formula) and
15%,
Method according to above-mentioned table 1 for result described in filler example 1, measure filler example 281, filler example 282 are respectively filled out
Fill thing be filled into 8 kinds of unlike material Capsuleses (F20020009 (gelatin, common), F20020035 (gelatin, common),
F20030004 (gelatin, common), F20020030 (gelatin, enteric), F20090002 (HPMC), (seaweed is more by F20050002
Sugar), #990.X pectin, #242.6CMC) in gained capsule elasticity and friability.
8 kinds of capsules that 2 fillers of the results show are prepared into respectively, they：Measured at 0 month with powder leakage rate and broken
It is equal to split rate<2%, display Capsules is qualified；After 40 degree of March are disposed, all categories capsule of each filler
Powder leakage rate and rupture rate are equal>18%, in the range of 15~34%.Use other those skilled in the art instead as it can be seen that above-mentioned and commonly use
Diluent cannot but obtain it is gratifying as a result, also failing to obtain even with common gelatin hollow capsule and making us full
The result of meaning.Substantial amounts of mannitol, hydroxypropyl methyl cellulose, hydroxyl second are included in the formula of the CN102784203A embodiments 1
Base cellulose, it may have harmful effect to the effect of capsule starch of the present invention.Therefore in one embodiment of the invention,
Include mannitol, hydroxypropyl methyl cellulose, hydroxyethyl cellulose three when different in wherein described other pharmaceutic adjuvants.
6th, uniformity is filled to investigate
It is the capsule filling machine in stainless steel when being filled into Capsules to filler in each experiment of the invention
Upper progress, filler is slowly discharged in feed hopper and inserted in Capsules.
The use of suitable starch and/or dextrin is beneficial the inventors discovered that for the present composition, but
It is when starch and/or dextrin is excessively used, capsule obtained by the starting stage and bear in capsule obtained by ending phase can be caused
The content difference of deoxycholic aicd is larger.Specific experiment is as follows：
When the filler of every batch at least 5kg carries out encapsulated, capsule is continuously filled, after 0.2kg materials are filled with,
Take the capsule 100 in this stage, the sample as first section capsule；In filler residue about 0.2kg, the glue in this stage is taken
Wafer 100, the sample as latter end capsule.
By the present invention【HPLC content determinations 1】Method, measures the content of urso in just section capsule filling
(C0, three times measured value be averaged, per 1g fillers in the urso weight g numbers that measure, g/g, similarly hereinafter), and measure end
The content (C1, three times measured value be averaged) of urso in section capsule filling.It is calculated as follows content deviant
(%)：
Content deviant (%)=(C1 ÷ C0) × 100%
The content deviant represents the ursodeoxycholic acid content in starting stage and end stage material closer to 100%
Quite, it is desirable；The content deviant is more than 100%, represents the ursodeoxycholic acid content phase in end stage material
Added for the content in starting stage material, offset it is more big, increase it is bigger, this be it is undesirable in production as a result, because
For urso in end stage capsule can be caused higher, and the relatively low content of urso in starting stage capsule
Non-uniform problem；Otherwise content deviant can cause urso in end stage capsule relatively low when being less than 100%, and
The non-uniform problem of the higher content of urso in starting stage capsule.Test method and result are as follows：
(1) filler obtained by the formula of 1~filler of filler example above example 8 and method is filled into respectively bright
In glue Capsules (No. 2, F20020009), their content deviant is measured, the results show that the content deviant of 8 samples
In the range of 98~102%, this is entirely satisfactory.
(2) filler obtained by the formula of 231~filler of filler example above example 237 and method is filled respectively
Into gelatin hollow capsule (No. 2, F20020009), their content deviant is measured, the results show that the content of 7 samples is inclined
In the range of 98~102%, this is entirely satisfactory shifting value.
(3) 241~filler of filler example above example 245 and filler 251~filler of example example 254 will be passed through respectively
Formula and method obtain filler be filled into gelatin hollow capsule (No. 2, F20020009), the content for measuring them is inclined
Shifting value, the results show that the content deviant of 9 samples, in the range of 98~102%, this is entirely satisfactory.
(4) formula and method of filler 1~filler of example example 8 are respectively referred to, unlike by starch therein and/or
The amount of dextrin increase to its account for filler gross weight 40%, obtain 8 kinds of fillers, by this 8 kinds of fillers be filled into gelatin sky
In heart-soothing capsule (No. 2, F20020009), their content deviant is measured, the results show that the content deviant of 8 samples exists
In the range of 126~142%, the content that urso is higher in end stage capsule is shown, although the present inventor still cannot
Explain the low early and high after phenomenon of this ursodeoxycholic acid content, but it is this result is that entirely without decree people receiving, it will agent
Measure it is uneven and the problem of bring the effect of huge unstable.
(5) formula and method of filler 1~filler of example example 8 are respectively referred to, unlike by starch therein and/or
The amount of dextrin increase to its account for filler gross weight 60%, obtain 8 kinds of fillers, by this 8 kinds of fillers be filled into gelatin sky
In heart-soothing capsule (No. 2, F20020009), their content deviant is measured, the results show that the content deviant of 8 samples exists
In the range of 133~167%.The amount of starch and/or dextrin caused active component content after increasing to 40% in visible inlays
The problem of serious offset, this can not make us receiving.
7th, biological test example part
Biological test example 1：The refrigeration function research of capsule of the present invention
Some of weight 2~3kg healthy rabbits are taken, laboratory temperature is controlled at 25 DEG C or so.The 3d before experiment, it is daily to survey
Normally anus temperature 2 times, choose rabbit 50 of the body temperature variation not higher than 0.3 DEG C, are randomly divided into 5 groups.3 anus temperature of measure before administration
(often 30min 1 time), using body temperature average value as basic body temperature.
Test sample and packet：Filler 1~filler of example 5 five kinds of filler powder of example above of the invention, each test sample agent
Amount is converted to urso meter 5mg/kg weight, and gastric infusion is taken orally after being dissolved/be suspended with suitable quantity of water；
Normal group (referred to as CONL) gives isometric(al) water with method；
Using aspirin, (referred to as ASPL, is dissolved/is suspended with suitable quantity of water positive control, oral administration gavage administration, 25mg/
Kg weight).In animal auricular vein injection (iv) endotoxin 5EU/kg after each group administration.L, 2,3,4,5h after endotoxin challenge
Measure rabbit anus temperature.2 are the results are shown in Table, each body temperature value only provides average, and SD values are within ± 0.2 DEG C.
Table 2：
Through statistical test, each minute point when 1-5 is small, positive controls and each composition group of the present invention with it is opposite
The negative control group at time point is compared and is respectively provided with significant difference (P<0.05).By result in table as it can be seen that being used to prepare the present invention
The filler of capsule is respectively provided with good refrigeration function with the common drug with refrigeration function.
Biological test example 2：The antitussive action research of capsule of the present invention
With reference to CN101890048A specifications [0063] to [0066] section the method, animal is randomly divided into 5 groups, is respectively
Three administration groups of filler of filler 1~filler of example example 3 of preparation capsule of the present invention (convert by each test sample dosage
Into urso meter 5mg/kg body weight/days, gastric infusion, 1 time a day, totally 5 days are taken orally after being dissolved/be suspended with suitable quantity of water), phosphorus
Sour codeine parenteral solution group, Normal group.Tested in accordance with the law.It is well known that in the test model, R values are more than 130%
Indicate antitussive action, and, then there is notable antitussive action in when R values are more than 150.
As a result, codeine phosphate injection group R value=179.3%, R value=171.5% of 1 filler of filler example, is filled out
R value=162.7% of 1 filler of thing example is filled, R value=168.4% of 1 filler of filler example, shows capsule tool of the present invention
There is significant antitussive action.
Claims (21)
1. a kind of capsule, it includes capsule shells and is wrapped in the capsule shells and is in powder or granular filler；Its
In：
The capsule shells are using gelatin as gelatin hollow capsule made of key component；
The filler includes active material, diluent and optional other pharmaceutic adjuvants, different in other pharmaceutic adjuvants
When include mannitol, hydroxypropyl methyl cellulose, hydroxyethyl cellulose three；
The active material is prepared by following material：Bear gall powder or urso, cornu caprae hircus, radix scutellariae, honeysuckle,
Fructus Forsythiae；The bear gall powder is to be added in the form of the total urso cholic acid that bear gall powder is obtained through saponification, purification in the filler,
The cornu caprae hircus is to be added in the form of cornu caprae hircus hydrolysate of the cornu caprae hircus through hydrolyzing, purifying in the filler,
The radix scutellariae is added in the form of Baical Skullcap root P.E in the filler, and the honeysuckle is with Honegsukle flower P.E
Form is added in the filler, and the Fructus Forsythiae is added in the form of forsythia suspense extraction in the filler；
Include urso in total urso cholic acid made from the bear gall powder, and in total urso cholic acid urso amount up to 50%
More than；
Contain in the cornu caprae hircus hydrolysate and be selected from following amino acid：Aspartic acid, glutamic acid, serine, glycine, Soviet Union's ammonia
Acid, alanine, valine, phenylalanine, isoleucine, leucine, proline, 11 kinds of amino acid are known as total amino acid, and
The amount of total amino acid accounts for more than the 60% of cornu caprae hircus hydrolysate in cornu caprae hircus hydrolysate；
Scutelloside is included in the Baical Skullcap root P.E；
Included in the Honegsukle flower P.E and be selected from following organic acid：Chlorogenic acid, neochlorogenic acid, Cryptochlorogenic acid, caffeic acid, 3,
Bis- caffeic acid acyl chinic acids of 4-, bis- caffeic acid acyl chinic acids of 3,5-, bis- caffeic acid acyl chinic acids of 4,5-；Seven kinds of organic acids are known as
Total organic acids；
Forsythiaside A and forsythin are included in the forsythia suspense extraction；Two kinds of glycosides are known as the total glycosides of Fructus Forsythiae；
In the filler, comprising：1-10 parts of urso, 0.5-5 parts of total amino acid, 1-10 parts of scutelloside, total organic acids
0.1-2 parts, total glycosides 0.25-10 parts of Fructus Forsythiae；
The diluent be selected from starch, dextrin, and combinations thereof；
The diluent accounts for the 3 ~ 30% of the filler gross weight.
2. capsule according to claim 1, wherein the starch is selected from cornstarch, farina, rice starch, wheat
Starch, tapioca.
3. capsule according to claim 1, urso and chenodeoxycholic acid are included in the total urso cholic acid, wherein bear goes
The amount of oxycholic acid is 5-16 times of the amount of chenodeoxycholic acid.
4. capsule according to claim 1, scutellarin is also included in the Baical Skullcap root P.E, the amount of scutelloside is wild radix scutellariae
50-150 times of the amount of glycosides.
5. capsule according to claim 1, wherein in the filler, comprising：2-8 parts of urso, total amino acid 1-5
Part, 2-9 parts of scutelloside, 0.2-1.8 parts of total organic acids, total glycosides 0.5-9 parts of Fructus Forsythiae.
6. capsule according to claim 1, wherein in the filler, comprising：2.5-7 parts of urso, total amino acid
1.5-4 parts, 2-8 parts of scutelloside, 0.3-1.5 parts of total organic acids, total glycosides 1-9 parts of Fructus Forsythiae.
7. capsule according to claim 1, wherein the urso, total amino acid, scutelloside, total organic acids and company
Stick up total glycosides total amount accounts for the filler gross weight 10 ~ 90%.
8. capsule according to claim 1, wherein the urso, total amino acid, scutelloside, total organic acids and company
Stick up total glycosides total amount accounts for the filler gross weight 15 ~ 75%.
9. capsule according to claim 1, wherein the urso, total amino acid, scutelloside, total organic acids and company
Stick up total glycosides total amount accounts for the filler gross weight 20 ~ 75%.
10. according to the capsule of any one of claim 1 to 9, it is conventional hard capsule, the filling included in its each grain
Thing is 100 ~ 750mg.
11. according to the capsule of any one of claim 1 to 9, it is conventional hard capsule, the filling included in its each grain
Thing is 150 ~ 500mg.
12. according to the capsule of any one of claim 1 to 9, do not include peppermint in the active material.
13. according to the capsule of any one of claim 1 to 9, it is prepared using the preparation method of hard capsule, should
Method comprises the following steps：
(i) Capsules is provided；
(ii) following five kinds of materials are provided：Total urso cholic acid or urso, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, honeysuckle
Extract, forsythia suspense extraction, and determine the content of the object in each material；
(iii) ratio according to the object in formula, weighs five kinds of materials of step (ii) respectively；
(iv) five kinds of materials that step (iii) weighs are mixed with diluent and optional other pharmaceutic adjuvants, obtains filler；
Or five kinds of materials for weighing step (iii) mix, then mix, obtain with diluent and optional other pharmaceutic adjuvants again
Filler；
(v) filler obtained by step (iv) is filled into the Capsules, capsule body and capsule cap is closely sealed, to obtain the final product.
14. preparing the method for the capsule of any one of claim 1 to 12, it comprises the following steps：
(i) Capsules is provided；
(ii) following five kinds of materials are provided：Total urso cholic acid or urso, cornu caprae hircus hydrolysate, Baical Skullcap root P.E, honeysuckle
Extract, forsythia suspense extraction, and determine the content of the object in each material；
(iii) ratio according to the object in formula, weighs five kinds of materials of step (ii) respectively；
(iv) five kinds of materials that step (iii) weighs are mixed with diluent and optional other pharmaceutic adjuvants, obtains filler；
Or five kinds of materials for weighing step (iii) mix, then mix, obtain with diluent and optional other pharmaceutic adjuvants again
Filler；
(v) filler obtained by step (iv) is filled into the Capsules, capsule body and capsule cap is closely sealed, to obtain the final product.
15. purposes of the capsule of any one of claim 1 to 13 in the medicine for preparing heat-clearing, resolving sputum, removing toxic substances.
16. the capsule of any one of claim 1 to 13 is being prepared for the use in the medicine of wind-warm lung-heat disease pulmonary retention of phlegmopyrexia card
On the way.
17. the capsule of any one of claim 1 to 13 is generated heat, coughed, not well, abscess of throat of coughing up phlegm, thirsty, tongue preparing
Red, yellow tongue fur；Pneumonia early stage, acute bronchitis, acute exacerbation of chronic bronchitis and the infection of the upper respiratory tract belong to above-mentioned syndrome
Purposes in the medicine of person.
18. measure the scutelloside in the filler of the capsule of any one of claim 1 to 13, urso, chenodeoxycholic
The method of the content of acid, it includes the following steps：
According to Chinese Pharmacopoeia one contained high effective liquid chromatography for measuring of annex VID of version in 2010；
Chromatographic condition and system suitability：It is molten with 0.05% trifluoroacetic acid using octadecylsilane chemically bonded silica as filler
Liquid is mobile phase A, and acetonitrile is Mobile phase B, and according to the form below carries out gradient elution；Use evaporative light scattering detector；Drift tube temperature 95
DEG C, number of theoretical plate is calculated by scutelloside peak, should be not less than 10000；
The preparation of reference substance solution：Precision weighs scutelloside reference substance, urso reference substance and chenodeoxycholic acid reference substance
In right amount, add propane diols and appropriate methanol, ultrasound makes to be completely dissolved, lets cool, add methanol dilution be made every 1ml 0.5mg containing scutelloside,
The mixed solution of urso 0.6mg, chenodeoxycholic acid 0.1mg, to obtain the final product；
The preparation of test solution：Precision measures or takes test sample appropriate, puts in 10ml measuring bottles, adds methanol to dissolve/be diluted to
Scale, shakes up, and filters if necessary, to obtain the final product；
Determination method：It is accurate respectively to draw 4 μ l of reference substance solution, 5 μ l of 8 μ l and test solution, liquid chromatograph is injected, is measured,
Content is calculated with external standard two-point method logarithmic equation, to obtain the final product, calculates to obtain scutelloside in test sample, urso, chenodeoxycholic acid
Content.
19. measuring the method for the content of the scutellarin in the filler of the capsule of any one of claim 1 to 13, it includes
Following steps：
According to Chinese Pharmacopoeia one contained high effective liquid chromatography for measuring of annex VID of version in 2010；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler；Using acetonitrile as mobile phase A,
Using 0.1% formic acid solution as Mobile phase B, the regulation according to the form below carries out gradient elution；Detection wavelength is 280nm, and number of theoretical plate is pressed
Scutellarin peak calculates, and should be not less than 3000；
The preparation of reference substance solution：Precision weighs that scutellarin reference substance is appropriate, adds methanol to dissolve and every 1ml is made containing 25 μ g
Solution, shakes up, to obtain the final product；
The preparation of test solution：Precision measures or takes test sample appropriate, puts in measuring bottle, be dissolved in water/scale is diluted to, shake
It is even, filter if necessary, to obtain the final product；
Determination method：It is accurate respectively to draw reference substance solution and each 10 μ l of test solution, liquid chromatograph is injected, measure, is calculated
The content of scutellarin in test sample.
20. the single amino acid content and total amino acid in the filler of the capsule of any one of measure claim 1 to 13 contain
The method of amount, it includes the following steps：
According to Chinese Pharmacopoeia one contained high effective liquid chromatography for measuring of annex VID of version in 2010；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler；Mobile phase A：Take three water vinegar
Sour sodium 7.00g, adds water 4000ml to make dissolving, adds triethylamine 0.8ml, tetrahydrofuran 24ml, mixes, and is adjusted with 2% glacial acetic acid solution
PH value is to 7.2；Mobile phase B：Take Sodium acetate trihydrate 10.88g, add water 800ml to make dissolving, with 2% glacial acetic acid solution adjust pH value to
7.2, add acetonitrile 1400ml, methanol 1800ml, mix, according to the form below carries out gradient elution；0~37.5 minute, Detection wavelength was
338nm, after 37.5 minutes, Detection wavelength 262nm；Column temperature：35℃；Number of theoretical plate is calculated by alanine peak to be not less than
40000；
The preparation of reference substance solution：Precision weighs aspartic acid, glycine, glutamic acid, serine, threonine, phenylalanine, different
Leucine, proline, alanine, valine, leucine reference substance are appropriate, put in 10ml measuring bottles, add 0.1mol/L hydrochloric acid solutions
Dissolve and be diluted to scale, shake up, as reference substance stock solution, wherein per 1ml respectively containing aspartic acid, glycine, glutamic acid,
Serine, threonine, isoleucine, proline, alanine, valine, leucine 1mg, phenylalanine 0.5mg；Precision is drawn
Above-mentioned reference substance stock solution 2ml, puts in 10ml measuring bottles, is diluted with water to scale, shake up, as reference substance solution, wherein often
1ml is respectively containing aspartic acid, glycine, glutamic acid, serine, threonine, isoleucine, proline, alanine, valine, bright
Propylhomoserin 0.2mg, phenylalanine 0.1mg；
The preparation of test solution：Accurate it can measure or take test sample appropriate, put in measuring bottle, be dissolved in water/be diluted to quarter
Degree, shakes up, filters if necessary, to obtain the final product；
Determination method：It is accurate respectively to draw reference substance solution and each 1 μ L of test solution, liquid chromatograph is injected, using 1% adjacent benzene
Dicarbaldehyde solution and 0.5% 1 chloro-carbonic acid fluorenes methyl ester solution computer simulation pre-column derivatization, measure and calculate above-mentioned each amino acid
Amount, and their total amount, is total amino acid amount；
Following method can be shone in the test solution and maneuver arrived involved in above HPLC content determinations to prepare or perform：
The 0.4mol/L borate buffers of pH10.2：Boric acid is taken, is configured to the solution of 0.4mol/L, with 40% sodium hydroxide solution
PH value is adjusted to 10.2, to obtain the final product, refrigeration；
1% o-phthalaldehyde solution：O-phthalaldehyde 80mg is weighed, adds the borate buffer 7ml of pH10.2, acetonitrile 1ml, sulfydryl
125 μ l of propionic acid, mix, to obtain the final product, refrigeration；
0.5% 1 chloro-carbonic acid fluorenes methyl ester solution：A chloro-carbonic acid fluorenes methyl esters 50mg is weighed, makes dissolving in right amount with acetonitrile, and be diluted to
10ml, refrigeration；
Pre-column derivatization reacts：Test solution and reference substance solution in the borate buffer of pH10.2 first and O-phthalic
Aldehyde reaction, then derived with a chloro-carbonic acid fluorenes methyl esters；
Pre-column derivatization injection procedure, bottle 1~5 be respectively o-phthalaldehyde, a chloro-carbonic acid fluorenes methyl esters, water, borate buffer solution,
Water：0 μ l are drawn from bottle 3；5 μ l are drawn from bottle 4；0 μ l are drawn from bottle 3；1 μ l are drawn from bottle 1；0 μ l are drawn from bottle 3；Pipette samples 1
μl；0 μ l are drawn from bottle 3；" in atmosphere " 7 μ l of mixing, 10 times；1 μ l are drawn from bottle 2；0 μ l are drawn from bottle 3；" in atmosphere " mix
Close 8 μ l, 30 times；32 μ l are drawn from bottle 5；" in atmosphere " 20 μ l of mixing, maximal rate, 2 times；Sample introduction.
21. the single organic acid content and total organic acids in the filler of the capsule of any one of measure claim 1 to 13 contain
The method of amount, it includes the following steps：
According to Chinese Pharmacopoeia one contained high effective liquid chromatography for measuring of annex VID of version in 2010；
Chromatographic condition and system suitability：Using octadecylsilane chemically bonded silica as filler；Using acetonitrile as mobile phase A,
Using 0.1% formic acid solution as Mobile phase B, the regulation according to the form below carries out gradient elution, is rushed after appearance with a high proportion of acetonitrile
Wash chromatographic column；Column temperature is 30 DEG C；Detection wavelength is 325nm；Number of theoretical plate is calculated by caffeic acid peak is not less than 50000；
The preparation of reference substance solution：Take caffeic acid and chlorogenic acid reference substance appropriate, accurately weighed, respectively plus 50% methanol is made often
1ml contains the solution of 30 μ g, to obtain the final product；
The preparation of test solution：Precision measure or take test sample appropriate, according to trial test determine wherein respectively contain with it is upper
The amount of a great deal of grade of corresponding component in reference substance solution preparation process is stated, puts in measuring bottle, adds methanol to dissolve/be diluted to quarter
Degree, shakes up, filters if necessary, up to test solution；
Determination method：It is accurate respectively to draw reference substance solution and each 10 μ l of test solution, liquid chromatograph is injected, is measured, record
Chromatographic peak, can calculate to obtain the content of caffeic acid and chlorogenic acid in tester；
Respectively neochlorogenic acid, Cryptochlorogenic acid, bis- caffeic acid acyl chinic acids of 3,4-, 3,5- in tester are calculated using following formula
The content of two caffeic acid acyl chinic acids, bis- caffeic acid acyl chinic acids of 4,5-：
,
,
,
,
,
The amount of the organic acid total amount, i.e. total organic acids in measure thing is calculated using the following formula：
Organic acid total amount=neochlorogenic acid content+
Chlorogenic acid content+
Cryptochlorogenic acid content+
Coffee acid content+
Bis- caffeic acid acyl chinic acid contents of 3,4-+
Bis- caffeic acid acyl chinic acid contents of 3,5-+
Bis- caffeic acid acyl chinic acid contents of 4,5-.
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| CN201510818007.9A CN105326808B (en) | 2013-12-02 | 2013-12-02 | Capsule for clearing heat and eliminating phlegm removing toxic substances |
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| CN201510818007.9A CN105326808B (en) | 2013-12-02 | 2013-12-02 | Capsule for clearing heat and eliminating phlegm removing toxic substances |
| CN201310632658.XA CN103599188B (en) | 2013-12-02 | 2013-12-02 | For the capsule of clearing heat and eliminating phlegm removing toxic substances |
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| CN103599188B (en) * | 2013-12-02 | 2016-05-18 | 北京三泉医药技术有限公司 | For the capsule of clearing heat and eliminating phlegm removing toxic substances |
| CN104523653B (en) * | 2015-02-06 | 2017-03-29 | 杭州朱养心药业有限公司 | Acarbose capsules agent pharmaceutical composition |
| CN104546795B (en) * | 2015-02-06 | 2018-02-02 | 杭州朱养心药业有限公司 | Acarbose capsules agent and preparation method |
| CN109633011A (en) * | 2018-12-29 | 2019-04-16 | 中山百灵生物技术有限公司 | A kind of detection method of new Glycine Levels |
| CN110187041B (en) * | 2019-07-11 | 2021-03-26 | 上海凯宝药业股份有限公司 | Method for establishing fingerprint of phlegm-heat clearing injection |
| CN111617138A (en) * | 2020-07-07 | 2020-09-04 | 上海凯宝药业股份有限公司 | Application of phlegm-heat clearing medicine in preparation of medicine for treating acute exacerbation of chronic obstructive pulmonary disease |
| CN114081934B (en) * | 2022-01-20 | 2022-04-12 | 江西省中医药研究院 | Traditional Chinese medicine composition and quality detection method thereof |
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| Publication number | Publication date |
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| CN103599188A (en) | 2014-02-26 |
| CN103599188B (en) | 2016-05-18 |
| CN105326808A (en) | 2016-02-17 |
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