CN108938654A - A kind of injection preparation of anemoside B4 - Google Patents
A kind of injection preparation of anemoside B4 Download PDFInfo
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- CN108938654A CN108938654A CN201710551726.8A CN201710551726A CN108938654A CN 108938654 A CN108938654 A CN 108938654A CN 201710551726 A CN201710551726 A CN 201710551726A CN 108938654 A CN108938654 A CN 108938654A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The present invention provides a kind of injection preparation of anemoside B4, including anemoside B4 and pharmaceutically acceptable auxiliary material, the preparation are liquid drugs injection or freeze drying powder injection, more preferable freeze drying powder injection.The present invention also provides the preparation methods of the anemoside B4 liquid drugs injection and anemoside B4 freeze drying powder injection.The effective dose of the injection preparation of anemoside B4 of the present invention, injury of kidney caused by revert cisplatin is low, significantly improves the drug safety of packet header father-in-law's saponin(e B4, is expected to provide new selection for clinical treatment injury of kidney, kidney failure.
Description
Technical field
The invention belongs to pharmaceutics fields, and in particular to a kind of using anemoside B4 as the injection of active constituent
Preparation.
Background technique
The Chinese medicine Chinese bulbul is the Ranunculaceae Pulsatilla plant Chinese bulbul (Pulsatilla chinensis (Bge.)
Regel dry root) is conventional Chinese medicine first recorded in Shennong's Herbal.There is its taste bitter and cold clearing heat and detoxicating, cool blood to stop
Dysentery, removing dampness and destroying parasites and other effects, for treating toxic-heat and blood stasis, a kind of malaria fever and chills, nosebleed epistaxis, bleeding.By modern pharmacological studies have shown that white
Head father-in-law has extensive antibacterial activity, to staphylococcus aureus, shigella dysenteriae, dermatophyte, saccharomycete, Candida albicans etc.
There is inhibiting effect.The antitumor action of the Chinese bulbul is also the hot spot of research.In addition, the Chinese bulbul also has anti-inflammatory, enhancing body
The effects of immune function.
The Chinese bulbul has triterpenoid saponins abundant.Anemoside B4 belongs to the pentacyclic triterpene soap of lupinane type
Glycosides, the structure with formula 1.
Anemoside B4 has stronger activity, such as publication number CN105213410A (publication date on January 6th, 2016)
Chinese invention patent application discloses application of the anemoside B4 as immunomodulator in treatment acute inflammation drug, institute
Stating acute inflammation includes acute kidney injury, acute liver damage and acute lung injury caused by being over-expressed due to inflammatory factor.Again
As the Chinese invention patent application of publication number CN105535004A (publication date on May 4th, 2016) discloses the compound conduct
EV71 viral inhibitors are preparing the application in anti-hand-foot-and-mouth-disease drug.
There are five glycosyl, good water solubilities for anemoside B4 tool.Some researches show that if the compound is using oral administration
(stomach-filling of such as animal experiment), then effective dose is big, causes security window narrow.Therefore, it is necessary to study anemoside B4s
Non-oral administration preparation meets clinical medical demand so that it plays active function in safe-dosaging limits.But
So far there is not yet the relevant report of anemoside B4 injection type.
Summary of the invention
For overcome the deficiencies in the prior art, the present invention provides a kind of preparation of injection anemoside B4.The system
Agent is stablized, and preparation process is easy.Compared with oral administration, the preparation revert cisplatin of injection anemoside B4 of the invention
The effective dose of caused injury of kidney reduces 20 times, improves drug safety, is expected to provide for clinical treatment injury of kidney, kidney failure
New selection.
In order to achieve the above-mentioned object of the invention, present invention employs the following technical solutions:
A kind of injection preparation of anemoside B4, including anemoside B4 and pharmaceutically acceptable auxiliary material,
The preparation is liquid drugs injection or freeze drying powder injection.
Preferably, the injection preparation of the anemoside B4, by anemoside B4, pharmaceutically acceptable is auxiliary
Material and inevitable impurity are constituted.
Preferably, the injection preparation of the anemoside B4 is intramuscular dose and/or intravenous injection；More preferably
For intravenous injection.
Preferably, the injection preparation of the anemoside B4 is liquid drugs injection, the pharmaceutically acceptable auxiliary material
It is water for injection.
Preferably, in the liquid drugs injection, the mass percent of anemoside B4 is 0.5%~5%, more preferably 2~
3%.
The present invention also provides the preparation method of above-mentioned liquid drugs injection, including dissolution, active carbon decoloring, filtering, constant volume, packing and
Sterilizing.
Preferably, the preparation method of the liquid drugs injection, concrete operations are as follows:
The anemoside B4 of recipe quantity is taken, it is accurately weighed, partial syringe water is added, stirring makes anemoside B4
After dissolution completely, the active carbon of liquid drugs injection gross mass 0.1%~0.5% is added into solution, is heated to boiling, stirs 15min,
It is settled to final volume with water for injection, is mixed, active carbon is removed through 0.22 μm of filtering with microporous membrane while hot, obtains intermediate medicine
Liquid；Packing, sterilizing to get.
In the preparation method of above-mentioned liquid drugs injection, packing and sterilizing are operated using the conventional method of this field.Wherein, sterilizing can
Sterilize the 15min that sterilizes at 30min or 121 DEG C to use pressure sterilizing, at 115 DEG C.
It is furthermore preferred that the injection preparation of anemoside B4 of the present invention is freeze drying powder injection, it is described pharmaceutically
It is a variety of selected from one of lactose, sucrose and mannitol or arbitrary proportion using the auxiliary material of receiving as freeze-dried excipient.
Preferably, in the freeze drying powder injection, the mass ratio of anemoside B4 and the freeze-dried excipient are as follows: the Chinese bulbul
Saponin(e B4: freeze-dried excipient=3:10~3:16.
It is furthermore preferred that in the freeze drying powder injection, the mass ratio of anemoside B4 and the freeze-dried excipient are as follows: hoary hair
Father-in-law's saponin(e B4: freeze-dried excipient=3:14.
It is also preferred that the freeze-dried excipient is mannitol.
The present invention also provides the preparation methods of above-mentioned freeze drying powder injection, and the preparation steps including intermediate medical fluid and freezing are dry
Dry step.
Preferably, the preparation steps of the intermediate medical fluid, concrete operations are as follows:
Anemoside B4 is dissolved in water for injection, is stirred to dissolve, the freeze-drying figuration is added according to quality proportioning
PH to 6.0~8.5 is adjusted in agent, stirring, and the active carbon of the intermediate quality of liquid medicine 0.05%~0.1% is added, adds at 100 DEG C
10~20min of thermal agitation, is cooled to room temperature, and the concentration that water for injection is added to anemoside B4 is 0.5%~5%, 0.22 μ
M filtering with microporous membrane is to get the intermediate medical fluid.
It is furthermore preferred that the preparation steps of the intermediate medical fluid, concrete operations are as follows:
Anemoside B4 is dissolved in water for injection, is stirred to dissolve, the freeze-drying figuration is added according to quality proportioning
Agent, stirring adjust pH to 6.5~8.0, the active carbon of the intermediate quality of liquid medicine 0.05%, heating stirring 10 at 100 DEG C are added
~20min, is cooled to room temperature, and the concentration that water for injection is added to anemoside B4 is 2%~3%；0.22 μm of miillpore filter
Filtering is to get the intermediate medical fluid.
Preferably, the freeze-drying step includes pre-freeze, distillation and parsing-desiccation；Pre-freezing temperature is -30 DEG C~-15
℃；The vacuum pressure of sublimation stage and parsing drying stage is 0.5~10Pa；Sublimation temperature is -10 DEG C~0 DEG C；Parsing-desiccation
Temperature is 25 DEG C~30 DEG C.
It is furthermore preferred that the vacuum pressure of sublimation stage and parsing drying stage is 5~10Pa.
It is furthermore preferred that sublimation temperature is -10 DEG C.
As a preferred embodiment, the freeze-drying step, concrete operations are as follows:
Intermediate medical fluid is dispensed, is transferred in freezing equipment, with 3.0 DEG C~5.0 DEG C/min or 1.0 DEG C~1.5 DEG C/
The rate of min is cooled to -30 DEG C~-15 DEG C, and temperature is kept to freeze 8~10 hours；It is subsequently placed in closed container, vacuum pressure
Under 0.5~10Pa of power, it is at the uniform velocity warming up to -10 DEG C~0 DEG C with the rate of 25 DEG C~30 DEG C/3h, keeps the temperature 8~10h, keeps vacuum degree
It is constant, 25 DEG C~30 DEG C are warming up to the rate of 1.0 DEG C~1.5 DEG C/min, keeps the temperature 4~6h.
As a further preferred embodiment, the freeze-drying step, concrete operations are as follows:
Intermediate medical fluid is dispensed, is transferred in freezing equipment, with 3.0 DEG C~5.0 DEG C/min or 1.0 DEG C~1.5 DEG C/
The rate of min is cooled to -30 DEG C~-20 DEG C, and temperature is kept to freeze 8 hours；It is subsequently placed in closed container, vacuum pressure 5
Under~10Pa, be at the uniform velocity warming up to -10 DEG C with the rate of 25 DEG C~30 DEG C/3h, keep the temperature 8h, keep the vacuum constant, with 1.0 DEG C~
The rate of 1.5 DEG C/min is warming up to 25 DEG C~30 DEG C, keeps the temperature 4h.
The present invention also provides the anemoside B4 freeze drying powder injections being prepared by the above method.
In addition, the present invention also provides the anemoside B4 injection preparations, or are prepared by the above method
Anemoside B4 liquid drugs injection or anemoside B4 freeze drying powder injection prepare acute kidney injury, chronic renal failure and/or
Application in the drug of renal insufficiency.
" inevitable impurity " described in description of the invention, the object for generation of degrading on a small quantity including anemoside B4
A small amount of moisture in matter and anemoside B4 freeze drying powder injection.Although above-mentioned inevitable impurity is in the presence of content
It all should comply with the limitation regulation in pharmacopeia.
The injection preparation of anemoside B4 of the present invention, granting object is mammal, in particular to people.When
The preparation grants object when being people, and in terms of the adult of weight 60kg, daily dosage is 2~120mg.
Anemoside B4 liquid drugs injection or anemoside B4 freeze drying powder injection of the present invention, realize pulchinenoside
The intramuscular injection or intravenous injection administration of B4 ensure that active constituent enters the circulatory system with original form and is distributed to each in vivo
Internal organs, especially kidney, lungs etc., this is achieved anemoside B4 with the ideal drug effect of relatively low-dose performance, thus
The security window for increasing treatment ensure that the safety of medication.
Anemoside B4 good water solubility, convenient for being prepared into liquid drugs injection；But its stability in different media is different,
Therefore the solvent needs of liquid drugs injection are carefully studied and is selected.
Anemoside B4 itself and its aqueous solution are more sensitive to temperature and illumination；For example, anemoside B4 water
Solution is placed 14 days at 60 DEG C, and the purity of anemoside B4 just drops to about 93% from the 98.90% of the 0th day, total impurities from
The 0.64% of 0th day rises to 0.94%.Freeze-dried powder is more advantageous to the stability of preparation since water content is low, therefore is excellent
The injection type of the anemoside B4 of choosing.
But in view of the complexity of freeze-drying disperse system, it is not easy to meet the powder-injection that injection requires to efficient quick obtaining
Thing, not yet forms that the maturation that freeze-drying formula is chosen is theoretical so far, needs on may influence each of freeze-drying behavior and effect
Factor is investigated alone or in combination.Wherein excipient and other additives can interact with main ingredient in freeze-drying formula,
The type and concentration of formula can significantly affect system freeze to solidify and the dehydration behavior that distils, such as maximum Freeze concentration vitrifying turn
Temperature (important indicator whether collapsed when measuring dry), rate of temperature fall, freezes annealing time etc. at minimum solidification point.This
Outside, the type and concentration of additive can also significantly affect the time of drying stage and the character of final products.The present invention is to freeze-drying
Categories of excipients and dosage, the pH of intermediate medical fluid, pre-freezing temperature, pre-freeze mode, sublimation temperature, vacuum pressure, parsing-desiccation
The parameters such as temperature respectively or are combined and are investigated, excellent to have selected optimal technological parameter, have obtained appearance and solubility is good, matter
Measure stable anemoside B4 freeze drying powder injection.
Specific embodiment
The present invention is described below with reference to specific embodiments.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, do not limit the scope of the invention in any way.
Experimental method in following embodiments is unless otherwise specified conventional method.Medicine as used in the following examples
Material raw material, reagent material etc. are commercially available products unless otherwise specified.Wherein, portion of reagent and supplementary material buy situation
It is as follows:
Anemoside B4: self-control, HPLC detect purity and are not less than 98%；
Mannitol (injection stage): F949A, Guangxi Nanning Chemical Pharmaceutical Ltd.；
Glucose (injection stage): P20160118, Beijing wind gift essence are sought medical advice medicine limited liability company；
Sucrose (injection stage): lot number 20150701, J.TBaker；
Water for injection: self-control；
Magnetic stirring apparatus: IKA Model:R015PS25；
Freeze drying box: GZLY-1.0, Beijing development in science and technology Co., Ltd of Song Yuan Huaxing.
The assay of anemoside B4 involved in test example and embodiment below, is all made of following method:
Chromatographic condition
Chromatographic column: C18, 250mm × 4.6mm, 5 μm
Mobile phase: acetonitrile-water (26:74) (volume ratio)
Flow velocity: 1.0ml/min
Wavelength: 201nm
The preparation of reference substance solution
Take anemoside B4 reference substance appropriate, it is accurately weighed, it sets in 10ml measuring bottle, adds methanol to dissolve and be diluted to quarter
Degree, shakes up, and filters, makes the 1mg of reference substance containing anemoside B4 in every 1ml solution.
The preparation of test solution
Sample to be tested about 25mg is taken, it is accurately weighed, it sets in 25ml measuring bottle, flowing phased soln is added, and be diluted to scale, shakes
It is even, 0.22 μm of filtering with microporous membrane, take subsequent filtrate to get.
Measuring method
It takes in 10 μ l test solutions injection liquid chromatograph, records chromatogram.
Calculation formula
Wherein:
CIt is right- reference substance concentration (mg/ml)；
SIt is right- reference substance purity；
AIt is rightThe main peak area of-reference substance solution；
ASampleThe main peak area of-test solution.
Test example 1The comparison of anemoside B4 different way of administration drug effect
Two ways is parallel with intravenous injection is administered with oral, investigates different way of administration anemoside B4 to cis-platinum
(CDDP) after stimulating in mice serum the index of acute nephritis influence.
1. test material
1.1 animals: ICR mouse, 16-18g, male, Hunan SJA Laboratory Animal Co. , Ltd, credit number:
SCXK (Hunan) 2016-0002.
1.2 reagents: cis-platinum, it is standby that stoste 5mg/kg takes cis-platinum that appropriate physiological saline is added to be configured to 1.5mg/ml solution before use
With.
1.3 drugs: anemoside B4 (self-control, hereinafter referred to as " B4 "), lot number: 20161107；Dexamethasone, 0.75g/
Piece, Anhui Jintaiyang Biochemical Medicine Co., Ltd., lot number: 15032521.
Above-mentioned test medicine is configured to the solution of normal concentration under " test method " item with distilled water, according to the side of regulation
Formula administration.
1.4 instrument table-type low-speed centrifuges；Automatic clinical chemistry analyzer
2. test method
All animals are numbered for preparation before 2.1 modelings, then weigh the weight of animal.
2.2 modeling methods press the dosage modeling of cis-platinum 15ml/kg, normally organize intraperitoneal injection of saline, other group of abdominal cavity
Inject cisplatin injections.
2.3 groupings are administered animal being randomly divided into seven groups, every group of 10-12 only:
1. normal group, stomach-filling distilled water 20ml/kg weight；
2. model group, tail vein injection isometric(al) physiological saline；
3. dexamethasone positive group (0.5mg/kg weight), by 20ml/kg weight stomach-filling dexamethasone solution；
4. B4 is injected intravenously high dose group (5mg/kg weight), by 5ml/kg weight tail vein injection B4 solution；
5. B4 is injected intravenously low dose group (2.5mg/kg weight), by 5ml/kg weight tail vein injection B4 solution；
6. B4 stomach-filling high dose group (100mg/kg weight), by 20ml/kg weight stomach-filling B4 solution；
7. B4 stomach-filling low dose group (50mg/kg weight), by 20ml/kg weight stomach-filling B4 solution.
Successive administration 4 days on the day of modeling.
2.4 Indexs measure
Urine is taken within 0.5 hour after the last administration, surveys Urine proteins；Administration takes blood in eyeball in 1 hour, by the Mouse whole blood room of taking-up
Temperature stand 2 hours, 3500rpm/min, be centrifuged 15min, take 200 μ l automatic clinical chemistry analyzer of supernatant detection total protein (TP),
Urea nitrogen (BUN), creatinine (Cre).
3. test result
The indices testing result of each group, is shown in Table 1.
Influence (SD ± Mean) of the table 1B4 to each index of induced by Cisplatin acute kidney injury
#: the P < 0.05 compared with normal group；*: the P < 0.05 compared with model group.
The data of table 1 are shown:
1. model group compares normal group, Urine proteins and serum urea nitrogen (BUN) and creatinine (Cre) are horizontal significant
It increases (P < 0.05), illustrates modeling success.
2. the urea nitrogen (BUN) and urine protein level of positive controls are remarkably decreased (P < 0.05) compared with model group.
3. compared with model group, 5mg/kg weight B4 intravenous injection administration can be substantially reduced urea nitrogen (BUN) and flesh
Acid anhydride (Cre) level (P < 0.05), although urine protein level has a declining tendency without significant difference.
4. 100mg/kg weight B4 gastric infusion, only the horizontal decline of urea nitrogen (BUN) is obvious for mouse compared with model group
(P < 0.05).
4. conclusion (of pressure testing)
Anemoside B4 has the function of anti-renal damage caused by cis-platinum, and prompting it clinically has exploitation treatment anxious slow
Property ephritis, renal failure drug prospect.And administration route plays active function to anemoside B4 and has a major impact, vein note
The effect for penetrating abnormal renal function index caused by 5mg/kg weight B4 revert cisplatin is better than 100mg/kg weight gastric infusion, agent
Amount reduces at least 20 times.Therefore, drug administration by injection, especially intravenous injection administration, for improving the curative effect of anemoside B4
It is significant with safety.
Embodiment 1A kind of liquid drugs injection of anemoside B4
The prescription of liquid drugs injection 100ml described in the present embodiment are as follows:
It is prepared via a method which:
The anemoside B4 raw material of recipe quantity is taken, it is accurately weighed, the water for injection of part (appropriate) is added, is stirred in magnetic force
After keeping anemoside B4 dissolution of raw material complete under the effect of mixing, the active carbon of solution quality 0.10% is added into solution, 100
15min is heated and stirred under DEG C water bath condition, 100ml is diluted to water for injection, shakes up, removed through 0.22 μm of filtering with microporous membrane
Deactivation charcoal, precision measure 2ml intermediate medical fluid and are fitted into the ampoule bottle of 5ml, after the 30min that sterilizes under the conditions of 115 DEG C, i.e.,
?.
Test example 2The research of anemoside B4 freeze-dried powder technique
1.1 supplementary material compatibility tests
By anemoside B4 raw material respectively with each auxiliary material (water for injection, physiological saline, mannitol, lactose, sucrose, Portugal
Grape sugar) in 1:5 (quality) ratio after mixing, be respectively placed in high temperature (60 DEG C, 40 DEG C), illumination (4500Lux ± 500) item
Under part, anemoside B4 purity and related substance situation are investigated in sampling in the 0th day, the 7th day and the 14th day, the results are shown in Table 2, table
3, table 4.
Table 2 supplementary material compatibility test, 0 day result
*: API table shows anemoside B4, the same below.
The data of table 2 are shown, and at the 0th day of investigation, the purity of the anemoside B4 in each supplementary material combination was suitable, are had
The content for closing substance does not have significant difference.
Table 3 supplementary material compatibility test, 7 days results
The data of table 3 show, anemoside B4 itself and its with after the mixing of the various auxiliary materials of investigation, to temperature and light
According to more sensitive, high temperature (60 DEG C) stability is particularly subject to the influence of water for injection, physiological saline and glucose.
Table 4 supplementary material compatibility test, 14 days results
Compared with the 7th day investigation result, at 60 DEG C anemoside B4 itself and its with mannitol, sucrose and lactose
In mixture, the purity of saponin(e is not substantially reduced further, illustrates that saponin(e has tended towards stability；But saponin(e B4 is in injection
In water, physiological saline and in the mixture of saponin(e B4 and glucose, the purity of saponin(e is further decreased, and saponin(e is still being degraded.
Supplementary material compatibility test the result shows that, anemoside B4 is compatible with each auxiliary material under 40 DEG C, illumination condition
Property is preferable, and purity and related substance have no significant change, more stable.But under 60 DEG C of hot conditions, anemoside B4
After raw material is mixed with water for injection, physiological saline or glucose, different degrees of degradation occurs for main ingredient；Therefore, Chinese bulbul soap
The water for injection injection or freeze drying powder injection of glycosides B4 should avoid prolonged high temperature in production, storage, transport.
The screening of 1.2 categories of excipients
Common freeze-dried excipient has lactose, mannitol, sucrose, glucose.According to Chinese bulbul soap is weighed shown in table 5 respectively
Glycosides B4 and mannitol, lactose, glucose, sucrose prepare medical fluid intermediate by following technical process, and are lyophilized:
Anemoside B4 is dissolved in appropriate water for injection, is stirred to dissolve, the freeze-dried excipient is added, is stirred,
PH to~7.0 is adjusted, the active carbon of 0.05g is added, heating stirring 15min, is cooled to room temperature at 100 DEG C, and water for injection is added extremely
100g；0.22 μm of filtering with microporous membrane is to get the intermediate medical fluid.Precision measures the west that 2ml intermediate medical fluid is packed into 10ml
In woods bottle, in freezing equipment, -20 DEG C is cooled to the rate of 5.0 DEG C/min, temperature is kept to freeze 8 hours；It is subsequently placed in cold
In lyophilizer, under vacuum degree 5Pa, -10 DEG C is at the uniform velocity warming up to the rate of 25 DEG C/3h, 8h is kept the temperature, keeps the vacuum constant,
25 DEG C are warming up to the rate of 1.0 DEG C/min, keeps the temperature 6h.
Observe dried frozen aquatic products character made from each prescription, at the same investigate anemoside B4 purity and related content of material,
It the results are shown in Table 6.
5 Formulation of table
| Composition | F1 | F2 | F3 | F4 |
| API | 1.5g | 1.5g | 1.5g | 1.5g |
| Mannitol | 5.0g | --- | --- | --- |
| Sucrose | --- | 5.0g | --- | --- |
| Lactose | --- | --- | 5.0g | --- |
| Glucose | --- | --- | --- | 5.0g |
| Water for injection | Add to 100g | Add to 100g | Add to 100g | Add to 100g |
6 categories of excipients the selection result of table
By the result shown in table 6 it is found that using lactose, sucrose, glucose as this product excipient, Chinese bulbul soap after freeze-drying
Different degrees of degradation occurs for glycosides B4, and the sequence of palliating degradation degree is: glucose > sucrose > lactose；And use mannitol as tax
After shape agent, significant change does not occur for content and related substance.It is therefore preferable that sucrose, lactose or mannitol are freeze-drying figuration
Agent, most preferably mannitol.
The screening of 1.3 amount of excipient
Anemoside B4 and mannitol are weighed respectively according to prescription shown in table 7, are prepared in medical fluid by following technical process
Mesosome, and be lyophilized:
Anemoside B4 is dissolved in appropriate water for injection, is stirred to dissolve, be added mannitol, stirring, adjust pH to~
7.0, the active carbon of 0.05g is added, heating stirring 15min, is cooled to room temperature at 100 DEG C, and water for injection is added to 100g；0.22
μm filtering with microporous membrane is to get the intermediate medical fluid.Precision measures 2ml intermediate medical fluid and is fitted into the cillin bottle of 10ml,
In freezing equipment, -20 DEG C are cooled to the rate of 5 DEG C/min, temperature is kept to freeze 8 hours；It is subsequently placed in freeze drier,
Under vacuum degree 5Pa, -10 DEG C are at the uniform velocity warming up to the rate of 25 DEG C/3h, 8h is kept the temperature, keeps the vacuum constant, with 1 DEG C/min's
Rate is warming up to 25 DEG C, keeps the temperature 6h.
The intermediate medical fluid of each prescription preparation and the character of freeze-dried products are observed, and investigates the purity of anemoside B4
Amount, related content of material, test result are shown in Table 7.
7 amount of excipient of table screens Formulation and the selection result
It, need to be in a suitable interval range by the result shown in table 7 it is found that the dosage of mannitol is not The more the better.
When B4 and mannitol mass ratio are between 3:10~3:14, as the dosage of mannitol increases, what the stability of B4 was improved
Trend；Later, with the increase of mannitol dosage, B4 degradation aggravation in dried frozen aquatic products.Therefore, currently preferred pulchinenoside
The quality of B4 and mannitol is than range: 3:10~3:16, most preferably 3:14.
The screening of 1.4 intermediate medical fluid pH value
Anemoside B4 is more sensitive to pH value, and palliating degradation degree changes with pH value.Therefore, midbody solution has been investigated
The degradation situation of pulchinenoside, filters out optimum PH range under condition of different pH.Specific test procedure are as follows:
According to the prescription F8 in table 7,8 parts of anemoside B4s and mannitol are weighed respectively；Anemoside B4 is dissolved
It in appropriate water for injection, being stirred to dissolve, mannitol is added, stirring adjusts pH according to shown in table 8, the active carbon of 0.05g is added,
Heating stirring 15min, is cooled to room temperature at 100 DEG C, and water for injection is added to 100g；0.22 μm of filtering with microporous membrane is to get institute
State intermediate medical fluid.Precision measures 2ml intermediate medical fluid and is fitted into the cillin bottle of 10ml, in freezing equipment, with 5 DEG C/min's
Rate is cooled to -20 DEG C, and temperature is kept to freeze 8 hours；It is subsequently placed in freeze drier, under vacuum degree 5Pa, with 25 DEG C/3h
Rate be at the uniform velocity warming up to -10 DEG C, keep the temperature 8h, keep the vacuum constant, be warming up to 25 DEG C with the rate of 1.0 DEG C/min, heat preservation
6h。
It the results are shown in Table 8.
8 condition of different pH of table investigates test result
From the result shown in table 8: using related content of material as index, the pH value of intermediate medical fluid is preferably 6.0~
8.5, most preferably 6.5~8.0.
The screening of 1.5 activated carbon dosages
Investigate the influence of activated carbon dosage, adsorption time to main ingredient, specific test procedure are as follows:
According to the prescription F8 in table 7,3 parts of anemoside B4s and mannitol are weighed respectively；Anemoside B4 is dissolved
It in appropriate water for injection, is stirred to dissolve, mannitol is added, stirring is added water for injection to 100ml, adjusts pH~7, measure white
The purity of head father-in-law's saponin(e B4；Then according to active carbon is added shown in table 8, heating stirring 15min at 100 DEG C, 0.22 μm of micropore is filtered
Film filtration fraction medical fluid, measures the pH value of filtrate and the purity of anemoside B4；Remaining medical fluid continuation is stirred at 100 DEG C
It is 30min to total adsorption time, 0.22 μm of filtering with microporous membrane part medical fluid measures the pH value and anemoside B4 of filtrate
Purity.
It the results are shown in Table 9.
The influence test result of 9 different activities charcoal dosage of table and adsorption time to main ingredient
The result of table 9 is shown, and activated carbon dosage increases, adsorption time extends, and can all lead to anemoside B4 purity
It reduces.Therefore, based on the volume of intermediate medical fluid, preferred activated carbon dosage (quality) is 0.05%~0.1%, more excellent
It is selected as 0.05%.
The research of 1.6 freeze drying process
Lyophilized technique directly influences the appearance of product, redissolves rate, moisture and stability.Therefore, high spot reviews pre-freeze
The parameters such as temperature, pre-freeze mode, sublimation temperature, vacuum pressure, parsing-desiccation temperature, specific test procedure are as follows:
According to the prescription F8 in table 7,4 parts of anemoside B4s and mannitol are weighed respectively；Anemoside B4 is dissolved
It in appropriate water for injection, is stirred to dissolve, mannitol is added, pH~7 are adjusted in stirring, and the active carbon of 0.05g is added, adds at 100 DEG C
Thermal agitation 15min, is cooled to room temperature, and water for injection is added to 100g；0.22 μm of filtering with microporous membrane is to get the intermediate medicine
Liquid.Precision measures 2ml intermediate medical fluid and is fitted into the cillin bottle of 10ml, in freezing equipment, according to parameter shown in table 10 and item
Part carries out pre-freeze；It is subsequently placed in freeze drier, carries out distillation and parsing-desiccation according to parameter shown in table 10 and condition.Respectively
The appearance of each dried frozen aquatic products is observed, measurement wherein in relation to the content of substance, carries out redissolution test, and record redissolves the time.It the results are shown in Table
10。
The influence test result to product of the different parameters of freeze-drying process of table 10
From the result shown in table 10 it is found that vacuum pressure is crucial parameter, vacuum pressure in distillation and parsing drying process
Power is too small (0.1Pa of technique 3), obtained dried frozen aquatic products poor appearance, and moisture is high, the production in relation to the obvious more other techniques of content of material
Product are high, prompt anemoside B4 degradation more.Accordingly, it is preferred that vacuum pressure is 0.5~10Pa, more preferably 5~10Pa.
Preferably, freeze-drying step of the present invention, concrete operations are as follows:
Intermediate medical fluid is dispensed, with the rate of 3 DEG C~5 DEG C/min or 1.0 DEG C~1.5 DEG C/min be cooled to -30 DEG C~-
15 DEG C, temperature is kept to freeze 8~10 hours；Be subsequently placed in closed container, under 0.5~10Pa of vacuum pressure, with 25 DEG C~
The rate of 30 DEG C/3h is at the uniform velocity warming up to -10 DEG C~0 DEG C, keeps the temperature 8~10h, keeps the vacuum constant, with 1.0 DEG C~1.5 DEG C/
The rate of min is warming up to 25 DEG C~30 DEG C, keeps the temperature 4~6h.
It is furthermore preferred that the freeze-drying step, concrete operations are as follows:
Intermediate medical fluid is dispensed, in freezing equipment, with 3.0 DEG C~5.0 DEG C/min or 1.0 DEG C~1.5 DEG C/min's
Rate is cooled to -30 DEG C~-20 DEG C, and temperature is kept to freeze 8 hours；It is subsequently placed in closed container, 5~10Pa of vacuum pressure
Under, be at the uniform velocity warming up to -10 DEG C with the rate of 25 DEG C~30 DEG C/3h, keep the temperature 8h, keep the vacuum constant, with 1.0 DEG C~1.5 DEG C/
The rate of min is warming up to 25 DEG C~30 DEG C, keeps the temperature 4h.
Cumulated volume test example as a result, anemoside B4 freeze drying powder injection of the present invention, including anemoside B4,
Freeze-dried excipient, freeze-dried excipient are selected from a variety of of one of mannitol, sucrose or lactose or arbitrary proportion, preferably sweet dew
Alcohol；The mass ratio of anemoside B4 and freeze-dried excipient is 3:10~3:16, more preferably 3:14.
Preferably, the anemoside B4 freeze drying powder injection includes the anemoside B4 that mass ratio is 3:10~3:16
And mannitol；It can also include a small amount of inevitable impurity, such as moisture, the catabolite of anemoside B4.
Anemoside B4 freeze drying powder injection of the present invention the preparation method comprises the following steps:
I. the preparation of intermediate medical fluid
Anemoside B4 is dissolved in appropriate water for injection, is stirred to dissolve, the freeze-drying figuration is added according to the proportion
PH to 6.0~8.5 is adjusted in agent, stirring, and the active carbon of the intermediate quality of liquid medicine 0.05%~0.1% is added, adds at 100 DEG C
10~20min of thermal agitation, is cooled to room temperature, and the concentration that water for injection is added to anemoside B4 is 0.5%~5%；0.22μ
M filtering with microporous membrane is to get the intermediate medical fluid；
II. it is freeze-dried
The intermediate medical fluid packing that step I is prepared；Be transferred in freezing equipment, with 3.0 DEG C~5.0 DEG C/
The rate of min or 1.0 DEG C~1.5 DEG C/min is cooled to -30 DEG C~-15 DEG C, and temperature is kept to freeze 8~10 hours；It is subsequently placed in
In closed container, under 0.5~10Pa of vacuum pressure, it is at the uniform velocity warming up to -10 DEG C~0 DEG C with the rate of 25 DEG C~30 DEG C/3h, is protected
8~10h of temperature, keeps the vacuum constant, and is warming up to 25 DEG C~30 DEG C with the rate of 1.0 DEG C~1.5 DEG C/min, keeps the temperature 4~6h.
Above-mentioned preparation method, preferred technical solution are as follows:
I. the preparation of intermediate medical fluid
Anemoside B4 is dissolved in water for injection, is stirred to dissolve, the freeze-drying figuration is added according to quality proportioning
Agent, stirring adjust pH to 6.5~8.0, the active carbon of the intermediate quality of liquid medicine 0.05%, heating stirring 10 at 100 DEG C are added
~20min, is cooled to room temperature, and the concentration that water for injection is added to anemoside B4 is 2%~3%；0.22 μm of miillpore filter
Filtering is to get the intermediate medical fluid；
II. it is freeze-dried
The intermediate medical fluid packing that step I is prepared, is transferred in freezing equipment, with 3.0 DEG C~5.0 DEG C/
The rate of min or 1.0 DEG C~1.5 DEG C/min is cooled to -30 DEG C~-20 DEG C, and temperature is kept to freeze 8 hours；It is subsequently placed in closed
Container in, under 5~10Pa of vacuum pressure, be at the uniform velocity warming up to -10 DEG C with the rate of 25 DEG C~30 DEG C/3h, keep the temperature 8h, keep true
Reciprocal of duty cycle is constant, is warming up to 25 DEG C~30 DEG C with the rate of 1.0 DEG C~1.5 DEG C/min, keeps the temperature 4h.
Embodiment 2A kind of freeze drying powder injection of anemoside B4
The prescription of intermediate medical fluid:
It is prepared via a method which:
I. the preparation of intermediate medical fluid
Take the pulchinenoside B of recipe quantity4Raw material, it is accurately weighed, suitable water for injection is added, is acted in magnetic agitation
Under make pulchinenoside B4After dissolution of raw material is complete, the mannitol of recipe quantity is added into the solution, stirring keeps mannitol complete
Dissolution continues stir about 10 minutes, and 0.05g active carbon is added, 15min is heated and stirred under 100 DEG C of water bath conditions, is cooled to
Room temperature is added water for injection to 100ml, shakes up, through 0.22 μm of filtering with microporous membrane remove active carbon to get；
II. it is freeze-dried
The intermediate medical fluid that step I is prepared dispenses: precision measures 2ml intermediate medical fluid and is packed into 10ml
Cillin bottle in；It is transferred in freezing equipment, is cooled to -20 DEG C at full speed, keep temperature 8h；It is then transferred to freeze drier
In, vacuum pressure 5Pa is at the uniform velocity warming up to -10 DEG C with the rate of 25 DEG C/3h, keeps -10 DEG C of 8h, be then at the uniform velocity warming up to 25 DEG C,
Keep 4h to get.
The anemoside B4 freeze drying powder injection being prepared is the block of white puff, and water redissolves time 6s, moisture
1.3%, anemoside B4 purity is 99.74%, largest single impurity content 0.12%, total miscellaneous content 0.26%.
Embodiment 3A kind of freeze drying powder injection of anemoside B4
The prescription of intermediate medical fluid:
It is prepared via a method which:
I. the preparation of intermediate medical fluid
The anemoside B4 raw material of recipe quantity is taken, it is accurately weighed, suitable water for injection is added, is acted in magnetic agitation
Under keep anemoside B4 dissolution of raw material complete after, into the solution be added recipe quantity lactose, stirring be completely dissolved lactose,
Continue stir about 10 minutes, 0.1g active carbon be added, 20min is heated and stirred under 100 DEG C of water bath conditions, is cooled to room temperature,
Water for injection is added to 100ml, shakes up, through 0.22 μm of filtering with microporous membrane remove active carbon to get；
II. it is freeze-dried
The intermediate medical fluid that step I is prepared dispenses: precision measures 2ml intermediate medical fluid and is packed into 10ml
Cillin bottle in；It is transferred in freezing equipment, is cooled to -30 DEG C with the rate of 3 DEG C/min, keeps temperature 10h；It is then transferred to
In freeze drier, vacuum pressure 10Pa is at the uniform velocity warming up to -10 DEG C with the rate of 25 DEG C/3h, keeps -10 DEG C of 10h, then with
The rate of 1.5 DEG C/min is warming up to 30 DEG C, keep 6h to get.
The anemoside B4 freeze drying powder injection being prepared is the block of white puff, and water redissolves time 6s, moisture
1.07%, anemoside B4 purity is 99.61%, largest single impurity content 0.28%, total miscellaneous content 0.39%.
Embodiment 4A kind of freeze drying powder injection of anemoside B4
The prescription of intermediate medical fluid:
It is prepared via a method which:
I. the preparation of intermediate medical fluid
The anemoside B4 raw material of recipe quantity is taken, it is accurately weighed, suitable water for injection is added, is acted in magnetic agitation
Under keep anemoside B4 dissolution of raw material complete after, into the solution be added recipe quantity sucrose, stirring be completely dissolved sucrose,
Continue stir about 10 minutes, 0.15g active carbon be added, 15min is heated and stirred under 100 DEG C of water bath conditions, is cooled to room temperature,
Water for injection is added to 100ml, shakes up, through 0.22 μm of filtering with microporous membrane remove active carbon to get；
II. it is freeze-dried
The intermediate medical fluid that step I is prepared dispenses: precision measures 2ml intermediate medical fluid and is packed into 10ml
Cillin bottle in；It is transferred in freezing equipment, is cooled to -15 DEG C with the rate of 5 DEG C/min, keeps temperature 9h；It is then transferred to
In freeze drier, vacuum pressure 0.5Pa is at the uniform velocity warming up to 0 DEG C with the rate of 30 DEG C/3h, keeps 0 DEG C of 8h, then with 1 DEG C/
The rate of min is warming up to 25 DEG C, keep 5h to get.
The anemoside B4 freeze drying powder injection being prepared is the block of white puff, and water redissolves time 6s, moisture
1.39%, anemoside B4 purity is 99.68%, largest single impurity content 0.22%, total miscellaneous content 0.32%.
In short, the present invention provides the preparation of injection anemoside B4, including liquid drugs injection and freeze drying powder injection.With mouth
Clothes administration is compared, and ejection preparation provided by the invention significantly reduces the effective of injury of kidney caused by anemoside B4 revert cisplatin
Dosage improves drug safety.In addition, by the preferred of preparation process parameter, so that injection preparation of the present invention is each
Item index is stable and controllable.
Claims (10)
1. a kind of injection preparation of anemoside B4, including anemoside B4 and pharmaceutically acceptable auxiliary material, institute
Stating preparation is liquid drugs injection or freeze drying powder injection；
Preferably, the injection preparation of the anemoside B4, by anemoside B4, pharmaceutically acceptable auxiliary material and
Inevitable impurity is constituted.
2. the injection preparation of anemoside B4 according to claim 1, which is characterized in that the anemoside B4
Injection preparation be intramuscular dose and/or intravenous injection；More preferably intravenous injection.
3. the injection preparation of anemoside B4 according to claim 1, which is characterized in that the anemoside B4
Injection preparation be liquid drugs injection, the pharmaceutically acceptable auxiliary material is water for injection；
Preferably, in the liquid drugs injection, the mass percent of anemoside B4 is 0.5%~5%, more preferably 2~3%.
4. the injection preparation of anemoside B4 according to claim 1, which is characterized in that the anemoside B4
Injection preparation be freeze drying powder injection, the pharmaceutically acceptable auxiliary material be freeze-dried excipient, selected from lactose, sucrose and
One of mannitol or arbitrary proportion it is a variety of；
Preferably, in the freeze drying powder injection, the mass ratio of anemoside B4 and the freeze-dried excipient are as follows: pulchinenoside
B4: freeze-dried excipient=3:10~3:16；
It is furthermore preferred that in the freeze drying powder injection, the mass ratio of anemoside B4 and the freeze-dried excipient are as follows: Chinese bulbul soap
Glycosides B4: freeze-dried excipient=3:14.
5. the injection preparation of anemoside B4 according to claim 4, which is characterized in that the freeze-dried excipient is
Mannitol.
6. a kind of preparation method of the liquid drugs injection of anemoside B4, the liquid drugs injection of the anemoside B4 such as claim 3
Middle definition, including dissolution, active carbon decoloring, filtering, constant volume, packing and sterilizing；
Preferably, the preparation method of the liquid drugs injection, concrete operations are as follows:
The anemoside B4 of recipe quantity is taken, it is accurately weighed, partial syringe water is added, stirring dissolves anemoside B4
After completely, the active carbon of liquid drugs injection gross mass 0.1%~0.5% is added into solution, is heated to boiling, 15min is stirred, with note
It penetrates and is settled to final volume with water, mix, remove active carbon through 0.22 μm of filtering with microporous membrane while hot, obtain intermediate medical fluid；Point
Dress, sterilizing to get.
7. a kind of preparation method of the freeze drying powder injection of anemoside B4, the freeze drying powder injection of anemoside B4 such as right are wanted
It asks and is defined in 4 or 5, the preparation steps including intermediate medical fluid and freeze-drying step；
Preferably, the preparation steps of the intermediate medical fluid, concrete operations are as follows:
Anemoside B4 is dissolved in water for injection, is stirred to dissolve, the freeze-dried excipient is added according to quality proportioning, stirs
It mixes, adjusts pH to 6.0~8.5, the active carbon of the intermediate quality of liquid medicine 0.05%~0.1%, heating stirring at 100 DEG C is added
10~20min is cooled to room temperature, and the concentration that water for injection is added to anemoside B4 is 0.5%~5%, 0.22 μm of micropore
Membrane filtration is to get the intermediate medical fluid；
As a further preferred embodiment, it is furthermore preferred that the preparation steps of the intermediate medical fluid, concrete operations are as follows:
Anemoside B4 is dissolved in water for injection, is stirred to dissolve, the freeze-dried excipient is added according to quality proportioning, stirs
It mixes, adjusts pH to 6.5~8.0, the active carbon of the intermediate quality of liquid medicine 0.05% is added, heating stirring 10 at 100 DEG C~
20min is cooled to room temperature, and the concentration that water for injection is added to anemoside B4 is 2%~3%；0.22 μm of miillpore filter mistake
Filter is to get the intermediate medical fluid.
8. preparation method according to claim 7, which is characterized in that the freeze-drying step include pre-freeze, distillation and
Parsing-desiccation；Pre-freezing temperature is -30 DEG C~-15 DEG C；The vacuum pressure of sublimation stage and parsing drying stage is 0.5~10Pa；
Sublimation temperature is -10 DEG C~0 DEG C；Parsing-desiccation temperature is 25 DEG C~30 DEG C；
It is furthermore preferred that the vacuum pressure of sublimation stage and parsing drying stage is 5~10Pa；
It is furthermore preferred that sublimation temperature is -10 DEG C.
9. preparation method according to claim 8, which is characterized in that the freeze-drying step, concrete operations are as follows:
Intermediate medical fluid is dispensed, is transferred in freezing equipment, with 3.0 DEG C~5.0 DEG C/min or 1.0 DEG C~1.5 DEG C/min's
Rate is cooled to -30 DEG C~-15 DEG C, and temperature is kept to freeze 8~10 hours；It is subsequently placed in closed container, vacuum pressure 0.5
Under~10Pa, it is at the uniform velocity warming up to -10 DEG C~0 DEG C with the rate of 25 DEG C~30 DEG C/3h, 8~10h is kept the temperature, keeps the vacuum constant,
25 DEG C~30 DEG C are warming up to the rate of 1.0 DEG C~1.5 DEG C/min, keeps the temperature 4~6h；
Preferably, the freeze-drying step, concrete operations are as follows:
Intermediate medical fluid is dispensed, is transferred in freezing equipment, with 3.0 DEG C~5.0 DEG C/min or 1.0 DEG C~1.5 DEG C/min
Rate be cooled to -30 DEG C~-20 DEG C, keep temperature to freeze 8 hours；It is subsequently placed in closed container, vacuum pressure 5~
Under 10Pa, be at the uniform velocity warming up to -10 DEG C with the rate of 25 DEG C~30 DEG C/3h, keep the temperature 8h, keep the vacuum constant, with 1.0 DEG C~
The rate of 1.5 DEG C/min is warming up to 25 DEG C~30 DEG C, keeps the temperature 4h.
10. a kind of anemoside B4 freeze drying powder injection, is prepared by preparation method described in any one of claim 7 to 9
It arrives.
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| CN111956655A (en) * | 2020-08-19 | 2020-11-20 | 广西馨海药业科技有限公司 | Application of pulsatilla saponin B4 in preparation of medicine for treating chronic obstructive pulmonary disease |
| CN112315934A (en) * | 2020-10-27 | 2021-02-05 | 广西馨海药业科技有限公司 | Preparation process of pulsatilla chinensis saponin B4 enteric-coated tablet |
| CN113499326A (en) * | 2021-08-02 | 2021-10-15 | 广西馨海药业科技有限公司 | Pulsatillae saponin B4 atomization inhalation preparation and application |
| US11253471B2 (en) | 2018-01-08 | 2022-02-22 | Qi Liu | Rectal mucosal administration preparation of Pulsatilla chinensis saponin B4 and preparation method therefor |
| US11793822B2 (en) | 2018-01-31 | 2023-10-24 | Sichuan Inlu Weite Pharmaceutical Technology Co., Ltd. | Uses of Pulsatilla Chinensis extract in preparing drug for treating viral and/or bacterial diseases |
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