CN109602699A - The injection of children's forsythin phillygenol and its derivative - Google Patents
The injection of children's forsythin phillygenol and its derivative Download PDFInfo
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- CN109602699A CN109602699A CN201910034372.9A CN201910034372A CN109602699A CN 109602699 A CN109602699 A CN 109602699A CN 201910034372 A CN201910034372 A CN 201910034372A CN 109602699 A CN109602699 A CN 109602699A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- A61K9/08—Solutions
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The present invention provides forsythin/phillygenol and its injections of derivative, are particularly suitable for pediatric pharmaceuticals.The invention also includes the dehydration preparation of the injection and preparation method and application etc..
Description
Technical field
The invention belongs to pharmaceutical technology fields, include forsythin and phillygenol the present invention relates to one kind more precisely
Or injection of Fructus Forsythiae glycoside derivates and preparation method thereof etc., the injection are particularly suitable for children.
Technical background
The present inventor is dedicated to the research of Chinese medical extract, accidentally and it is surprisingly found that, forsythin and less Fructus Forsythiae
Rouge element forms Pharmaceutical composition, has synergy, especially synergistic medicinal effects at a variety of medicinal aspects.For example, Chinese
Patent application CN105362283A discloses a kind of forsythin/phillygenol composition and its application in antiviral；China
Patent application CN105796861A discloses a kind of forsythin/phillygenol composition and its application in raising immunity；
Chinese patent application CN106063788A discloses a kind of forsythin/phillygenol composition and its answering in treatment vomiting
With；Chinese patent application CN106063789A discloses a kind of forsythin/phillygenol composition and its in treatment lymph nodule
Application in core disease；Chinese patent application CN106063790A discloses a kind of forsythin/phillygenol composition and its anti-
Application in aging；Chinese patent application CN106063791A discloses a kind of forsythin/phillygenol composition and its anti-
Application in inflammation；Chinese patent application CN106063792A discloses a kind of forsythin/phillygenol composition and its slow
Solve the application in pain；Chinese patent application CN106063793A disclose a kind of forsythin/phillygenol composition and its
Treat the application in bacterium infection；Chinese patent application CN106063794A discloses a kind of forsythin/phillygenol composition
And its preventing and treating the application in hepatic injury；Chinese patent application CN106063795A discloses a kind of forsythin/Fructus Forsythiae
Rouge promotor composition and its application in prevention and treatment hyperlipemia；Chinese patent application CN106063796A discloses one kind
Forsythin/phillygenol composition and its application in detumescence；Chinese patent application CN106063797A discloses a kind of company
Stick up glycosides/phillygenol composition and its application in anti-oxidant；Chinese patent application CN106176786A discloses a kind of company
It sticks up glycosides/phillygenol composition and its is preventing and treating the application in obesity；Chinese patent application CN106176788A is disclosed
A kind of forsythin/phillygenol composition and its application in treatment urinary tract infections；Chinese patent application
CN108066350A discloses a kind of forsythin/phillygenol composition and its answering in anti-prevention and treatment senile dementia
With.
However, above-mentioned forsythin/although the prompt of phillygenol composition can be configured to injection to be administered, due to
For the solubility of phillygenol in water less than 20 μ g/g, the solubility of forsythin is not also high, so these patent applications only disclose
The formula of oral preparation, does not develop injection agent prescription, and oral preparation basically comprises cyclodextrin and its derivative,
Especially beta-cyclodextrin and its derivative.
In addition, the present inventor is investigated the derivative of forsythin and phillygenol.For example, Chinese patent application
CN104650108A discloses a kind of phillygenol sulfuric ester, and the phenolic hydroxyl group Sulfation on phillygenol can be formed
Corresponding sodium salt, sylvite, ammonium salt or other salt, for antiviral；Chinese patent application CN104945452A discloses a kind of company
Stick up rouge element glucuronic acid derivative, including 33- hydroxyl-phillygenol glucuronide, 9- hydroxyl-phillygenol glucose
Aldehydic acid glycosides and 33,34- methylene dioxy-phillygenol glucuronide etc. are used for resisiting influenza virus；Chinese patent application
CN106188176A discloses another phillygenol glucuronic acid derivative, including phillygenol glucuronic acid methyl ester,
Sodium salt and sylvite of phillygenol glucuronic acid etc..Said derivative other than phillygenol glucuronic acid methyl ester, by
In introducing acid group, water solubility can be improved to a certain extent at salt.
Currently, pediatric drugs generally follow the principle of " oral just not inject ", therefore research and development are suitable for the injection of children
Demand it is very low, especially forsythin/phillygenol composition can be configured to injection with cyclodextrin and its derivative, so
It is usually not necessary to continue to research and develop new forsythin/phillygenol injection；Further, for improving water-soluble Fructus Forsythiae
Glycosides and phillygenol derivative, more It is not necessary to continue to research and develop new injection.However, the inventors discovered that, injection for
Quick, the dosage of children is accurately administered and is also advantageous；However, it has also been found that, cyclodextrin, especially beta-cyclodextrin meeting
Stronger hemolytic and damaging renal toxicity are caused, even the present inventor preferably goes out sulphur butyl from a large amount of cyclodextrin types
Ether-beta-cyclodextrin still has certain Toxicity of Kidney after long-time service, this develops also incomplete children for renal function and comes
Say it is unfavorable, be at least unfavorable for promoting and applying, so, it is considered herein that there are also research and development be suitable for the new forsythin of children/
Necessity of phillygenol injection.
Pharmaceutic adjuvant in the prior art is many kinds of, and the combination and proportion between variety classes are even more astronomical figure.This hair
Bright people by long-term research and practice, from largely can not in the medical accessory of desired effect it is surprisingly specific auxiliary
There is not hemolytic and renal toxicity, preferred auxiliary material to prepare forsythin/phillygenol injection within the positive common medicine phase in material
Even all do not occur hemolytic and renal toxicity after long-term administration, enhances the safety to pediatric pharmaceuticals, and convenient for cold
It is lyophilized dry and redissolves, enhance the flexibility of dosage form production, more surprisingly, preferably the powder-injection of auxiliaries is even suitable
In needleless powder injection is made.Moreover, the suitability of the dosage form is good, forsythin and phillygenol derivative are also suitable.
In addition, this can be single the present inventors have additionally discovered that phillygenol glucuronic acid derivative has the effect of bringing down a fever
Only oral application can also be configured to injection, be especially suitable for the injection of above-mentioned pediatric pharmaceuticals, widen of the invention answer
Use range.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new forsythin/phillygenol injection, particularly suitable for
Pediatric pharmaceuticals, and be also particularly suitable for flexibly being produced as the injection of different dosage forms.Moreover, the present invention also provides the injections
Preparation method.In addition, the present invention also provides the pharmacy applications of Fructus Forsythiae glycoside derivates.
Specifically, in a first aspect, the present invention provides forsythin/phillygenol injection, it includes forsythin and
Phillygenol also includes the auxiliary material for children's drug administration by injection safety.In addition, first aspect present invention additionally provides forsythin
Derivative composition injection, it includes Fructus Forsythiae glycoside derivates, also include the auxiliary material for children's drug administration by injection safety.
The injection of first aspect present invention may include forsythin and phillygenol is active constituent, preferably only
Active constituent, that is, the injection of first aspect present invention is preferably by forsythin and phillygenol and pharmaceutically acceptable auxiliary
Material composition.
Herein, as without opposite instruction, " forsythin/phillygenol ", " forsythin and phillygenol " and " forsythin with
Phillygenol composition " may be used interchangeably, and refer to the composition being made of forsythin and phillygenol, i.e. forsythin/company
Rouge element is stuck up to measure as a whole.It is preferred that in the injection of first aspect present invention, the weight of forsythin and phillygenol
Than for 2~98:2~98, preferably 80~98:2~20, more preferably 90~98:2~10, such as 90:10 or 98:2.According to this
The research of inventor, which can be applied to a variety of medicinal aspects such as antiviral, and majority produces collaboration
The effect of synergy.
It is active constituent, preferably only activity that the injection of first aspect present invention, which may include Fructus Forsythiae glycoside derivates,
Ingredient, that is, the injection of first aspect present invention is preferably made of Fructus Forsythiae glycoside derivates and pharmaceutically acceptable auxiliary material.
Herein, as without opposite instruction, " Fructus Forsythiae glycoside derivates " and " forsythin and phillygenol derivative " can be mutual
Use is changed, refers to that the present inventor studies the derivative of the forsythin and phillygenol that obtain, including Chinese patent application
The phillygenol of phillygenol sulfuric ester or its salt, Chinese patent application CN104945452A record that CN104650108A is recorded
Glucuronic acid derivative or Chinese patent application CN106188176A phillygenol glucuronic acid derivative or its salt or its
Ester.Preferably, Fructus Forsythiae glycoside derivates include phillygenol sulfuric ester or its salt (such as sodium salt, sylvite or ammonium salt), 33- hydroxyl-company
Stick up rouge element glucuronide, 9- hydroxyl-phillygenol glucuronide, 33,34- methylene dioxy-phillygenol grape
Glycuronide, phillygenol glucuronic acid, phillygenol glucuronate salt (such as sodium salt or sylvite) or phillygenol grape
Glycuronate (e.g., methyl esters).
It is preferred that the injection of first aspect present invention is unit formulation (e.g. a, needle), wherein forsythin and phillygenol contain
Measuring (that is, unit dose) is 5~100mg, preferably 20~50mg, such as 20mg or 50mg；Alternatively, wherein Fructus Forsythiae glycoside derivates contain
Measuring (that is, unit dose) is 5~100mg, preferably 20~50mg, such as 20mg or 50mg.Such unit dose is suitble to children
Application.Herein, children refer to 2 to 12 years old childs or children.For adult, unit dose can increase.
Herein, pharmaceutically acceptable auxiliary material refers to filler, dilute that is substantially nontoxic and not influencing active constituent action
Release agent, solubilizer, pH adjusting agent, osmotic pressure regulator, protective agent, preservative or other pharmaceutical adjuncts.PH adjusting agent includes medicine
Acceptable organic acid, inorganic acid, organic base and/or inorganic base on, in a specific embodiment of the invention, pH adjusting agent
It is hydrochloric acid.Osmotic pressure regulator can be NaCl or glucose.It is preferred that the pH of the injection of the first aspect of the present invention be 6.5~
7.5, more preferably 7.0~7.3.
However, pharmaceutically acceptable auxiliary material is very more, such as common beta-cyclodextrin, however it will cause it is stronger molten
Hemorrhagic and damaging renal toxicity is not appropriate for safely to children's drug administration by injection；PH adjusting agent and osmotic pressure are adjusted also as noted above
Agent, forsythin/phillygenol or Fructus Forsythiae glycoside derivates individually can not be configured to stable injection by them.The prior art does not have
Stable injection can be configured to forsythin/phillygenol or Fructus Forsythiae glycoside derivates and safely infuse to children by providing
Penetrate the auxiliary material of administration.
The injection of first aspect present invention includes the auxiliary material for children's drug administration by injection safety.It is preferred that in the present invention first
In the injection of aspect, the auxiliary material includes L-arginine or sulfobutyl ether-beta-cyclodextrin.These auxiliary materials not only can be by Fructus Forsythiae
Glycosides/phillygenol or Fructus Forsythiae glycoside derivates are configured to stable injection, and are not in hemolytic within the positive common medicine phase
And renal toxicity, for renal function develops children complete not enough, the latter is particularly advantageous.The more preferable accessory package
L-arginine is included, even if forsythin/phillygenol or Fructus Forsythiae glycoside derivates injection long term administration with its preparation, will not go out
Existing hemolytic and renal toxicity, more ensure that the safety to pediatric pharmaceuticals.It is preferred that the injection of first aspect present invention is continuous
Toxicity of Kidney is not generated within medication 7 days, more preferable continuous use does not generate Toxicity of Kidney in 30 days.
Specifically, the injection of first aspect present invention is made of A and B and optional C, and wherein A is forsythin and company
It sticks up rouge element or Fructus Forsythiae glycoside derivates, B is L-arginine or sulfobutyl ether-beta-cyclodextrin, C is water, pH adjusting agent and/or infiltration
Press regulator.For example, the injection of first aspect present invention can be by forsythin and phillygenol and L-arginine and water, salt
Acid and NaCl composition, can also be made of forsythin and phillygenol and sulfobutyl ether-beta-cyclodextrin and NaCl；For another example, originally
The injection of invention first aspect can be made of Fructus Forsythiae glycoside derivates and L-arginine and water, hydrochloric acid and NaCl, can also be with
It is made of Fructus Forsythiae glycoside derivates and sulfobutyl ether-beta-cyclodextrin and NaCl.
It is preferred that in the injection of first aspect present invention, the weight ratio of forsythin and phillygenol and L-arginine is 1:
10~50, more preferably 1:20~30；Alternatively, the weight ratio of Fructus Forsythiae glycoside derivates and L-arginine is 1:10~50, more preferably
For 1:20~30.
It is also preferred that in the injection of first aspect present invention, forsythin and phillygenol and sulfobutyl ether-beta-cyclodextrin
Weight ratio 1:30~150, more preferably 1:60~75；Or Fructus Forsythiae glycoside derivates, the weight with sulfobutyl ether-beta-cyclodextrin
Than 1:30~150, more preferably 1:60~75.
Herein, injection has the common meaning of this field, refers to the general designation of the dosage form for injection.It is preferred that this
The injection of invention first aspect is injection liquor, that is, the injection includes water.The preparation side of the more preferably described injection liquor
Method includes the steps that forsythin and phillygenol are mixed with the auxiliary material；Alternatively, the preparation method of the injection liquor includes connecting
Stick up the step of glycoside derivates are mixed with the auxiliary material.
In the specific embodiment of the present invention, include the following steps:
(1) forsythin and phillygenol for being dissolved in organic solvent are dried under reduced pressure after mixing with auxiliary material soluble in water；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator.
In another embodiment of the invention, include the following steps:
(1) the Fructus Forsythiae glycoside derivates and auxiliary material soluble in water for being dissolved in solvent are dried under reduced pressure after mixing；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator.
It is also preferred that the injection of first aspect present invention is powder-injection, that is, the injection does not include water.It is more preferably described
The preparation method of powder-injection includes the steps that dry above-mentioned injection liquor.Drying can be spray drying, and it is dry to be also possible to freezing
It is dry.In a specific embodiment of the invention, include the following steps:
(4) it is freeze-dried above-mentioned injection liquor.
It is also preferred that the injection of first aspect present invention is needleless powder injection, that is, the injection does not include water, described
Auxiliary material includes L-arginine, and the granular size of the injection is suitble to the injection of needleless powder.The more preferably described needleless powder injection
The preparation method of agent includes the steps that the above-mentioned powder-injection of screening, it may for example comprise sieves above-mentioned powder-injection to granular size between 400
The step of between mesh and 120 mesh, includes the following steps: in a specific embodiment of the invention
(5) above-mentioned powder-injection is soaked, granulation, tabletting simultaneously crush, and then screening collects granular size between 400 mesh and 120
Powder between mesh.
In second aspect, the present invention provides the preparation methods of the injection of first aspect present invention comprising forsythin
The step of being mixed with phillygenol with the auxiliary material for children's drug administration by injection safety；Or comprising Fructus Forsythiae glycoside derivates with it is right
The step of auxiliary material mixing of Yu children drug administration by injection safety.The auxiliary material preferably includes L-arginine or sulfobutyl ether-β-ring paste
Essence.
It is preferred that the preparation method of second aspect of the present invention is to inject the preparation method of liquor comprising forsythin and Fructus Forsythiae rouge
Plain the step of being mixed with the auxiliary material；Or comprising the step of Fructus Forsythiae glycoside derivates are mixed with the auxiliary material.
In the specific embodiment of the present invention, the preparation method of the injection liquor includes the following steps:
(1) forsythin and phillygenol for being dissolved in organic solvent are dried under reduced pressure after mixing with auxiliary material soluble in water；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator.
In another embodiment of the invention, the preparation method of the injection liquor includes the following steps:
(1) the Fructus Forsythiae glycoside derivates and auxiliary material soluble in water for being dissolved in solvent are dried under reduced pressure after mixing；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator.
It is also preferred that the preparation method of second aspect of the present invention is the preparation method of powder-injection comprising dry above-mentioned injection
The step of agent.
In the specific embodiment of the present invention, the preparation method of the powder-injection includes the following steps:
(1) forsythin and phillygenol for being dissolved in organic solvent are dried under reduced pressure after mixing with auxiliary material soluble in water；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator；
(4) the injection liquor that freeze-drying step (3) obtains.
In another embodiment of the invention, the preparation method of the powder-injection includes the following steps:
(1) the Fructus Forsythiae glycoside derivates and auxiliary material soluble in water for being dissolved in solvent are dried under reduced pressure after mixing；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator；
(4) the injection liquor that freeze-drying step (3) obtains.
It is also preferred that the preparation method of second aspect of the present invention is the preparation method of needleless powder injection comprising screening is above-mentioned
The step of powder-injection, and wherein, auxiliary material includes L-arginine.It is preferred that the preparation method of the needleless powder injection includes in screening
State powder-injection to granular size between 400 mesh and 120 mesh the step of.
In the specific embodiment of the present invention, which includes the following steps:
(1) forsythin and phillygenol for being dissolved in organic solvent are dried under reduced pressure after mixing with auxiliary material soluble in water；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator；
(4) the injection liquor that freeze-drying step (3) obtains；
(5) moistening step (4) obtain powder-injection, granulation, tabletting simultaneously crush, then screening collect granular size between
Powder between 400 mesh and 120 mesh.
In another embodiment of the invention, which includes the following steps:
(1) the Fructus Forsythiae glycoside derivates and auxiliary material soluble in water for being dissolved in solvent are dried under reduced pressure after mixing；
(2) desciccate that step (1) obtains is dried under reduced pressure after being dissolved in water；
(3) desciccate that step (2) obtains is dissolved in water, and is optionally added pH adjusting agent and/or osmotic pressure regulator；
(4) the injection liquor that freeze-drying step (3) obtains；
(5) moistening step (4) obtain powder-injection, granulation, tabletting simultaneously crush, then screening collect granular size between
Powder between 400 mesh and 120 mesh.
In the third aspect, the present invention provides Fructus Forsythiae glycoside derivates in preparation for the application in antipyretic drug.At this
Wen Zhong, it is antipyretic and bring down a fever and may be used interchangeably, it refers to the body temperature for reducing fever, is preferably dropped to normal body temperature.Of the invention
In specific embodiment, fever is caused by heterologous antigen (e.g., yeast) injection.
It is preferred that the application of third aspect present invention is application of the Fructus Forsythiae glycoside derivates separately as active constituent, i.e., preferably originally
The invention third aspect provides Fructus Forsythiae glycoside derivates individually in preparation for the application in antipyretic drug.
It is preferred that the Fructus Forsythiae glycoside derivates are 33- hydroxyl-phillygenol glucose in the application of third aspect present invention
Aldehydic acid glycosides, 9- hydroxyl-phillygenol glucuronide or 33,34- methylene dioxy-phillygenol glucuronide.
The beneficial effects of the present invention are, stable forsythin/phillygenol or Fructus Forsythiae glycoside derivates injection are provided,
It is highly-safe, it is especially suitable for the also immature children of renal function；The flexibility of dosage form is high, can be produced and be injected with flexible conversion
The difference injection type such as liquor, powder-injection and needleless powder injection；The suitability of dosage form is good, the Fructus Forsythiae suitable for a variety of ratios
Glycosides/phillygenol and a variety of Fructus Forsythiae glycoside derivates；In addition, the present invention provides Fructus Forsythiae glycoside derivates antipyretic aspect application,
The indication of Fructus Forsythiae glycoside derivates is widened.
In order to make it easy to understand, the present invention will be described in detail by specific embodiment and attached drawing below.It needs
It is emphasized that these descriptions are only exemplary description, and it is not meant to limit the scope of the invention.According to this explanation
The discussion of book, many variations of the invention, change will be apparent from for those skilled in the art.In addition, this hair
It is bright to refer to open source literature, these documents be in order to more clearly describe the present invention, their entire contents be included in herein into
Row reference just looks like that repeated description herein has been excessively for their full text.
Detailed description of the invention
Fig. 1 illustratively shows the photo for the renal tissue slice of renal tubule vacuole occurred.
Fig. 2 illustratively shows the photo of the renal tissue slice of no abnormality seen (including having no renal tubule vacuole).
Specific embodiment
Further illustratively illustrate the present invention by the following examples.As not specified, side used in embodiment
Method is recorded in the technical literature of this field and the authority file of Drug Administration mechanism, and instrument, raw materials and reagents are disclosure
What market was bought.
The composition of 1 Fructus Forsythiae glycoside derivates of embodiment and forsythin and phillygenol, which declines to rabbit caused by yeast to generate heat, tests
Influence
1 test material
1.1 drugs and reagent
Forsythin, white powder, the production of Dalian Fu Sheng natural drug development corporation, Ltd. are examined through two kinds of high performance liquid chromatography
Survey device UV detector and evaporative light scattering detector area normalization method measurement, purity 99.5%, and with China drug
It is 99.5% that its content is demarcated and confirmed to biological products assay forsythin reference substance.
33- hydroxyl-phillygenol glucuronide (Fructus Forsythiae glycoside derivates A), white powder, the raw natural drug of Dalian richness
Development corporation, Ltd.'s production.Through two kinds of detector UV detector of high performance liquid chromatography and evaporative light scattering detector area normalization
The measurement of change method, purity 98.5%.
9- hydroxyl-phillygenol glucuronide (Fructus Forsythiae glycoside derivates B), white powder, the raw natural drug of Dalian richness
Development corporation, Ltd.'s production.Through two kinds of detector UV detector of high performance liquid chromatography and evaporative light scattering detector area normalization
The measurement of change method, purity 99.2%.
33,34- methylene dioxies-phillygenol glucuronide (Fructus Forsythiae glycoside derivates C), white powder, Dalian are rich
Raw natural drug development corporation, Ltd. production.Through two kinds of detector UV detector of high performance liquid chromatography and Evaporative light scattering detector
The measurement of device area normalization method, purity 98.7%.
Yeast, it is commercially available.
Positive control drug: aspirin, the favorable to the people pharmaceutical factory in medicine company Hefei, Nanjing, lot number: 130809
1.2 experimental animal
White Rabbit, 2.5 soil 0.5kg of weight, half male and half female are purchased from Dalian Medical Univ's Experimental Animal Center, up-to-standard
Card number: SCXK (13) 2012-0008.
2 test methods:
The selection of 2.1 dosage
Recommend the maximum possible given low of dosage and sample that 3 forsythin experimental groups are set according to the human body of tested material,
That is forsythin low, middle and high dose groups, dosage are respectively 3,6,12mg/kg；
Fructus Forsythiae glycoside derivates A, B, C are respectively set 3 Fructus Forsythiae glycoside derivates experimental groups, i.e. Fructus Forsythiae glycoside derivates A is low, in,
High dose group, dosage are respectively 3,6,12mg/kg；Fructus Forsythiae glycoside derivates B low, middle and high dose groups, dosage is respectively 3,6,
12mg/kg；Fructus Forsythiae glycoside derivates C low, middle and high dose groups, dosage are respectively 3,6,12mg/kg；
Separately set a blank control group and positive drug control group (aspirin, 250mg/kg).
2.2 groupings and administration
Healthy White Rabbit is taken, 2.5 ± 0.5kg of weight, male and female are infertile, and surveying anus temperature, (thermometer gos deep into 3cm or so, misses twice
Difference is no more than 0.2 DEG C), 36-38 DEG C of 100 rabbit are filtered out, are randomly divided into 20 groups, every group 5, i.e. blank control group, company
Stick up glycosides medicine group (low, in, high three dosage groups), Fructus Forsythiae glycoside derivates A, B, C (low, in, high three dosage groups), positive drug control
Group (aspirin, 250mg/kg/d).
Blank control group: physiological saline (NS) gastric infusion, 1 time a day, successive administration 3 days；Forsythin group, forsythin spread out
The drug of the other gastric infusion corresponding dosage of biological A, B, component C, daily gastric infusion 1 time, successive administration 3 days；Positive drug control
Group: giving aspirin gastric infusion 250mg/kg, 1 time a day, successive administration 3 days.
1 hour after the last administration, 4.5g/kg injection sterilised yeast suspension, and 0 5h after Yu Zhire are subcutaneously pressed in tested rabbit,
Lh, 2h, 4h, 8h survey its anus temperature, and the results are shown in Table 1.
3 experimental results
1 Fructus Forsythiae glycoside derivates of table, Fructus Forsythiae glycoside derivates/phillygenol to rabbit caused by yeast decline fever experiment influence
(x ± s n=5)
By antipyretic experiment it is found that blank control group rabbit body temperature significantly increases, and forsythin, company compared with model control group
It is significant to stick up each drug administration preventing and controlling group antipyretic response of glycoside derivates, middle high dose group have significant difference p < 0.01, each low dose group with
P < 0.05 is compared before this group of pyrogenicity, the P < O.01 compared with model comparison.
2 forsythins of embodiment/phillygenol injects liquor
1 test drug
Forsythin/phillygenol composition A: forsythin (purity 99.5%), white powder, the raw natural drug of Dalian richness are opened
Send out Co., Ltd's production；Phillygenol (purity 99.2%), white powder, Dalian Fu Sheng natural drug development corporation, Ltd. are raw
It produces；The weight ratio of forsythin and phillygenol is 98:2.
Forsythin/phillygenol composition B: forsythin (purity 99.5%), white powder, the raw natural drug of Dalian richness are opened
Send out Co., Ltd's production；Phillygenol (purity 99.2%), white powder, Dalian Fu Sheng natural drug development corporation, Ltd. are raw
It produces；The weight ratio of forsythin and phillygenol is 90:10.
The preparation of 2 forsythins/phillygenol injection liquor
2.1 formulas 1
2g forsythin/phillygenol composition B is taken, has been dissolved with acetonitrile-ethanol mixed liquor (volume ratio 75:25) 200mL
Entirely, spare.Sulfobutyl ether-beta-cyclodextrin 150g is taken, water for injection 350mL is added, is heated to 45 DEG C of dissolutions completely, it is spare.
Keeping temperature is 45 DEG C, and above-mentioned forsythin/phillygenol composition solution is added drop-wise to the speed of 5mL/min
It states in sulfobutyl ether-beta-cyclodextrin solution, is stirred when being added dropwise.Rotary evaporator is splined on after being added dropwise to complete with 0.05MPA's
Vacuum degree and 100 DEG C are dried under reduced pressure, recycling design, and desciccate repeats after adding 200mL water for injection to dissolve with the true of 0.05MPA
Reciprocal of duty cycle and 100 DEG C of rotary evaporations are dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous dissolution, is settled to 200mL, after 0.22um filtration sterilization,
Packing, sealing are prepared into forsythin/phillygenol injection (formula 1) that specification is 2mL:20mg.
2.2 formulas 2
2g forsythin/phillygenol composition A is taken, is dissolved completely with dehydrated alcohol 400mL, it is spare.Take sulfobutyl ether-β-
Cyclodextrin 120g adds water for injection 280mL, is heated to 40 DEG C of dissolutions completely, spare.
Keeping temperature is 40 DEG C, and above-mentioned forsythin/phillygenol composition solution is added drop-wise to the speed of 10mL/min
In above-mentioned sulfobutyl ether-beta-cyclodextrin solution, stirred when being added dropwise.Rotary evaporator is splined on after being added dropwise to complete with 0.05MPA
Vacuum degree and 100 DEG C be dried under reduced pressure, recycling design, desciccate add 80mL water for injection dissolve after repeat with 0.05MPA's
Vacuum degree and 100 DEG C of rotary evaporations are dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous dissolution, is settled to 80mL, after 0.22um filtration sterilization, point
Dress, sealing are prepared into forsythin/phillygenol injection (formula 2) that specification is 2mL:50mg.
2.3 formulas 3
2g forsythin/phillygenol composition B is taken, has been dissolved with acetonitrile-ethanol mixed liquor (volume ratio 70:30) 250mL
Entirely, spare.L-arginine 50g is taken, water for injection 450mL is added, dissolution is completely, spare.
At room temperature, above-mentioned forsythin/phillygenol composition solution is added drop-wise to above-mentioned smart ammonia with the speed of 5mL/min
It in acid solution, is stirred when being added dropwise, continues to stir 15min after being added dropwise to complete.Stirring after the completion of be splined on rotary evaporator with
The vacuum degree of 0.04MPA and 100 DEG C are dried under reduced pressure, recycling design, desciccate repeated after adding 200mL water for injection to dissolve with
The vacuum degree of 0.04MPA and 100 DEG C of rotary evaporations are dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous solution 150mL to dissolve, and adjusts pH to 7.2 with 5N hydrochloric acid solution,
0.9% (w/v) NaCl aqueous solution is added to be settled to 200mL, after 0.22um filtration sterilization, packing, sealing, being prepared into specification is 2mL:
The forsythin of 20mg/phillygenol injection (formula 3).
2.4 formulas 4
2g forsythin/phillygenol composition A is taken, it is spare with acetonitrile-ethanol mixed liquor (volume ratio 75:25) 200mL.
L-arginine 60g is taken, water for injection 340mL is added, is heated to 35 DEG C of dissolutions completely, it is spare.
Keeping temperature is 35 DEG C, and above-mentioned forsythin/phillygenol composition solution is added drop-wise to the speed of 5mL/min
It states in arginine solution, is stirred when being added dropwise, continue to stir 10min after being added dropwise to complete.Rotary evaporation is splined on after the completion of stirring
Device is dried under reduced pressure with the vacuum degree of 0.05MPA and 100 DEG C, recycling design, and desciccate repeats after adding 80mL water for injection to dissolve
It is dry with the vacuum degree of 0.05MPA and 100 DEG C of rotary evaporations.
Final desciccate adds 0.9% (w/v) NaCl aqueous solution 50mL to dissolve, and adjusts pH to 7.2 with 5N hydrochloric acid solution, adds
0.9% (w/v) NaCl aqueous solution is settled to, and after 0.22um filtration sterilization, packing, sealing, being prepared into specification is 2mL:50mg's
Forsythin/phillygenol injection (formula 4).
2.5 formulas 5
2g forsythin/phillygenol composition B is taken, is dissolved completely with acetonitrile 150mL, it is spare.L-arginine 40g is taken, is added
Water for injection 360mL, dissolution are completely, spare.
At room temperature, above-mentioned forsythin/phillygenol composition solution is added drop-wise to above-mentioned smart ammonia with the speed of 5mL/min
In acid solution, stirred when being added dropwise.Rotary evaporator is splined on after being added dropwise to complete to depressurize with the vacuum degree of 0.04MPA and 100 DEG C
Dry, recycling design, desciccate repeats to steam with the vacuum degree of 0.04MPA and 100 DEG C of rotations after adding 200mL water for injection to dissolve
It is dry dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous solution 150mL to dissolve, and adjusts pH to 7.2 with 5N hydrochloric acid solution,
0.9% (w/v) NaCl aqueous solution is added to be settled to 200mL, after 0.22um filtration sterilization, packing, sealing, being prepared into specification is 2mL:
The forsythin of 20mg/phillygenol injection (formula 5).
3 forsythins/phillygenol injection liquor stability study
Under the conditions of the injection liquor prepared referring to above-mentioned formula is placed on 25 DEG C, progress stability study 180 days, as a result
As shown in table 2.
The forsythin of the invention of table 2/phillygenol injection liquor ordinary temperature stability
The result shows that preparation method through the invention, either using sulfobutyl ether-beta-cyclodextrin as auxiliary material, or with
Arginine is auxiliary material, can sufficiently dissolve forsythin/phillygenol composition, substantially without forsythin/phillygenol active matter
The loss of matter, and have good stability, it can be saved steadily in the long term in room temperature level.
3 forsythin derivative injection agent of embodiment
1 test drug
33- hydroxyl-phillygenol glucuronide (derivative A, purity 98.5%), white powder, Dalian Fu Shengtian
Right drug development Co., Ltd production.
9- hydroxyl-phillygenol glucuronide (derivative B, purity 99.2%), white powder, Dalian Fu Shengtian
Right drug development Co., Ltd production.
33,34- methylene dioxies-phillygenol glucuronide (derivative C, purity 98.7%), white powder,
The production of Dalian Fu Sheng natural drug development corporation, Ltd..
Phillygenol sodium sulphate (derivative D), white powder, the production of Dalian Fu Sheng natural drug development corporation, Ltd..Through
Two kinds of detector UV detector of high performance liquid chromatography and the measurement of evaporative light scattering detector area normalization method, purity are
99.9%.
Phillygenol Sodium Glucuronate (derivative E), white powder, Dalian Fu Sheng natural drug development corporation, Ltd. are raw
It produces.It is measured through two kinds of detector UV detector of high performance liquid chromatography and evaporative light scattering detector area normalization method, it is pure
Degree is 99.3%.
Phillygenol glucuronic acid methyl ester (derivative F), white powder, Dalian Fu Sheng natural drug development corporation, Ltd.
Production.It is measured through two kinds of detector UV detector of high performance liquid chromatography and evaporative light scattering detector area normalization method,
Purity is 99.6%.
The preparation of 2 forsythin derivative injection agent
2.1 derivative A formula 1
2g derivative A is taken, is dissolved completely with 50% (volume ratio) ethyl alcohol 200mL, it is spare.Take sulfobutyl ether-beta-cyclodextrin
150g adds water for injection 350mL, is heated to 45 DEG C of dissolutions completely, spare.
Keeping temperature is 45 DEG C, and said derivative solution A is added drop-wise to above-mentioned sulfobutyl ether-β-with the speed of 10mL/min
In cyclodextrin solution, stirred when being added dropwise.Rotary evaporator is splined on after being added dropwise to complete with the vacuum degree of 0.05MPA and 100 DEG C
It is dried under reduced pressure, recycling design, desciccate repeats to revolve with the vacuum degree of 0.05MPA and 100 DEG C after adding 200mL water for injection to dissolve
Turn evaporation drying.
Final desciccate adds 0.9% (w/v) NaCl aqueous dissolution, is settled to 200mL, after 0.22um filtration sterilization,
Packing, sealing are prepared into the derivative A injection (formula A1) that specification is 2mL:20mg.
2.2 derivative A formula 2
2g derivative A is taken, is dissolved completely with 50% (volume ratio) ethyl alcohol 200mL, it is spare.L-arginine 50g is taken, filling is penetrated
With water 450mL, dissolution is complete, spare.
At room temperature, said derivative solution A is added drop-wise in above-mentioned arginine solution with the speed of 10mL/min, side drop
Edged stirring continues to stir 10min after being added dropwise to complete.Rotary evaporator is splined on after the completion of stirring with the vacuum degree of 0.05MPA
Be dried under reduced pressure with 100 DEG C, recycling design, desciccate repeat after adding 200mL water for injection to dissolve with the vacuum degree of 0.05MPA and
100 DEG C of rotary evaporations are dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous solution 150mL to dissolve, and adjusts pH to 7.2 with 5N hydrochloric acid solution,
0.9% (w/v) NaCl aqueous solution is added to be settled to 200mL, after 0.22um filtration sterilization, packing, sealing, being prepared into specification is 2mL:
The derivative A injection (formula A2) of 20mg.
2.3 derivative B formula 1
Referring to the preparation method of said derivative A formula 1, different being only that replaces derivative A with derivative B, makes
It is standby to obtain the derivative B injection (formula B1) that specification is 2mL:20mg.
2.4 derivative B formula 2
Referring to the preparation method of said derivative A formula 2, different being only that replaces derivative A with derivative B, makes
It is standby to obtain the derivative B injection (formula B2) that specification is 2mL:20mg.
2.5 derivative C formula 1
Referring to the preparation method of said derivative A formula 1, different being only that replaces derivative A with derivative C, makes
It is standby to obtain the derivative C injection (formula C1) that specification is 2mL:20mg.
2.6 derivative C formula 2
Referring to the preparation method of said derivative A formula 2, different being only that replaces derivative A with derivative C, makes
It is standby to obtain the derivative C injection (formula C2) that specification is 2mL:20mg.
2.7 derivative D formula 1
Referring to the preparation method of said derivative A formula 1, different being only that replaces derivative A with derivative D, makes
It is standby to obtain the derivative D injection (formula D1) that specification is 2mL:20mg.
2.8 derivative D formula 2
Referring to the preparation method of said derivative A formula 2, different being only that replaces derivative A with derivative D, makes
It is standby to obtain the derivative D injection (formula D2) that specification is 2mL:20mg.
2.9 derivative E formula 1
Referring to the preparation method of said derivative A formula 1, different being only that replaces derivative A with derivative E, makes
It is standby to obtain the derivative E injection (formula E1) that specification is 2mL:20mg.
2.10 derivative E formula 2
Referring to the preparation method of said derivative A formula 2, different being only that replaces derivative A with derivative E, makes
It is standby to obtain the derivative E injection (formula E2) that specification is 2mL:20mg.
2.11 derivative F formula 1
2g derivative F is taken, is dissolved completely with chloroform 200mL, it is spare.Sulfobutyl ether-beta-cyclodextrin 150g is taken, injection is added
Water 350mL is heated to 45 DEG C of dissolutions completely, spare.
Keeping temperature is 45 DEG C, and said derivative F solution is added drop-wise to above-mentioned sulfobutyl ether-β-with the speed of 5mL/min
It in cyclodextrin solution, is stirred when being added dropwise, continues to stir 5min after being added dropwise to complete.Be splined on after being added dropwise to complete rotary evaporator with
The vacuum degree of 0.05MPA and 100 DEG C are dried under reduced pressure, recycling design, desciccate repeated after adding 200mL water for injection to dissolve with
The vacuum degree of 0.05MPA and 100 DEG C of rotary evaporations are dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous dissolution, is settled to 200mL, after 0.22um filtration sterilization,
Packing, sealing are prepared into the derivative F injection (formula F1) that specification is 2mL:20mg.
2.12 derivative F formula 2
2g derivative F is taken, is dissolved completely with chloroform-ethanol mixed liquor (volume ratio 75:25) 200mL, it is spare.Take L- essence ammonia
Sour 50g, adds water for injection 450mL, and dissolution is completely, spare.
At room temperature, said derivative F solution is added drop-wise in above-mentioned arginine solution with the speed of 5mL/min, side drop
Edged stirring continues to stir 15min after being added dropwise to complete.Rotary evaporator is splined on after the completion of stirring with the vacuum degree of 0.05MPA
Be dried under reduced pressure with 100 DEG C, recycling design, desciccate repeat after adding 200mL water for injection to dissolve with the vacuum degree of 0.05MPA and
100 DEG C of rotary evaporations are dry.
Final desciccate adds 0.9% (w/v) NaCl aqueous solution 150mL to dissolve, and adjusts pH to 7.2 with 5N hydrochloric acid solution,
0.9% (w/v) NaCl aqueous solution is added to be settled to 200mL, after 0.22um filtration sterilization, packing, sealing, being prepared into specification is 2mL:
The derivative F injection (formula F2) of 20mg.
The stability study of 3 forsythin derivative injection agent
Under the conditions of the injection liquor prepared referring to above-mentioned formula is placed on 25 DEG C, progress stability study 180 days, as a result
As shown in table 3.
The ordinary temperature stability of the forsythin derivative injection agent of the invention of table 3
The result shows that preparation method through the invention, either using sulfobutyl ether-beta-cyclodextrin as auxiliary material, or with
Arginine is auxiliary material, the forsythin derivative injection agent of preparation, the basic loss without forsythin derivatives active substance, and
And have good stability, it can be saved steadily in the long term in room temperature level.
4 forsythins of embodiment/phillygenol injection liquor safety research
Wistar rat 27 (male, 120~150g of weight) is taken, 9 groups is randomly divided into, every group 3, uses embodiment 2
Formula 1-4 drug administration by injection.It is as follows to be grouped situation；
1 seven days blank control group (intravenous injection physiological saline), formula groups are (in terms of forsythin/phillygenol composition
The injection of 5mg/kg INTRAVENOUS FORMULATION 1, once a day, continuous seven days), formula group in 1 January is (with forsythin/phillygenol
The injection liquor of composition meter 5mg/kg INTRAVENOUS FORMULATION 1, once a day, continuous 30 days), 2 seven days groups of formula (use formula instead
2, remaining with formula 1 seven days groups), formula 2 January groups (use formula 2 instead, remaining with formula 1 January group), formula 3 seven days groups (change
With formula 3, remaining with formula 1 seven days groups), formula 3 January groups (use formula 3 instead, remaining with formula 1 January group), formula 4 seven days
Group (using formula 4 instead, remaining is with 1 seven days groups of formula), formula group in 4 January (using formula 4 instead, remaining is with formula group in 1 January).
Each group mouse weight during administration is ingested normal, and haemolysis appearance is not observed.1 hour after the last administration
Rat (disposing with seven days groups for two in blank control group, another two are disposed with group in January) is put to death, renal tissue, slice dyeing are taken
Microscopy afterwards.Respectively having two rats renal tubule vacuole occur in microscopy discovery, formula group in 1 January and formula group in 2 January, (it is typical
Histotomy it is as shown in Figure 1)；Remaining (including blank control group, formula 1 seven days groups, formula 2 seven days groups, formula 3 seven days groups,
Be formulated 3 January group, formula 4 seven days groups and formula 4 January group all animals) do not note abnormalities (and its typically organize cut
Piece is as shown in Figure 2).
The result shows that injecting liquor in positive common medicine by the forsythin of auxiliary material/phillygenol of sulfobutyl ether-beta-cyclodextrin
Period (usually 3 days, be no more than 7 days) interior good security, but if the long-term continuous medication of excess, will appear certain
Toxicity of Kidney；And inject liquor good security using arginine as the forsythin of auxiliary material/phillygenol, no matter short-period used, also
It is long-term lasting use, does not occur Toxicity of Kidney.
The powder-injection of 5 forsythins of embodiment/phillygenol and its derivative
By the injection liquor and formula A1, A2 of embodiment 3 of the formula 1~5 of embodiment 2, B1, B2, C1, C2, D1, D2,
E1, E2, F1 and F2 are distributed into cillin bottle after filtration sterilization respectively, every bottle of 2ml, and freeze-drying seals, obtains and respectively match
The freeze drying powder injection of side.It when facing administration, is redissolved with water for injection, the freeze drying powder injection being respectively formulated can redissolve in 10 seconds, molten
Liquid clarification, no precipitating.
The needleless powder injection of 6 forsythins of embodiment/phillygenol and its derivative
The freeze drying powder injection of formula A2, B2, C2, D2, E2 and F2 of the formula 3~5 and embodiment 3 of embodiment 2 are also suitable for
It is made needleless powder injection, and the formula 1~2 of embodiment 2 and the freeze-drying with formula A1, B1, C1, D1, E1 and F1 of embodiment 3
Powder-injection is difficult to effectively penetrate epidermis, improper that needleless powder injection is made.
The freeze drying powder injection of the formula 3~5 of Example 2 and formula A2, B2, C2, D2, E2 and F2 of embodiment 3 respectively,
It (can be formed but without water droplet) with the wetting of appropriate water for injection, cross the granulation of 20 meshes, with crushing after tabletting machine, cross 120 mesh
Sieve is collected and collects unsifted powder after 400 meshes by the powder of sieve, obtains the needleless powder injection of each formula.
Full skin removing on the inside of the leg of pork, so that pigskin be made；30g gelatin is taken, distilled water is added and dissolves by heating, is settled to
100mL is placed in square container and solidifies, so that apery skin be made.The needleless powder injection of formula 3~5 is respectively charged into
Powderject powder syringe carries out pressurized jet injection to pigskin and apery skin respectively with the pressure of 4MPa, then distinguishes
The part of different depth on each skin is sampled, HPLC detects forsythin, and the depth capacity for detecting forsythin is as shown in table 4.
The maximum injection depth of the needleless powder injection of the invention of table 4
The result shows that the needleless powder note of formula A2, B2, C2, D2, E2 and F2 of the formula 3~5 and embodiment 3 of embodiment 2
The estimated people's epidermis that about 0.1mm thickness can be penetrated by conveying of agent is penetrated, into dermal capillary, so as to Needleless injection administration
Forsythin/phillygenol and its derivative.
Claims (10)
1. forsythin/phillygenol or Fructus Forsythiae glycoside derivates injection, it includes forsythins and phillygenol, or include Fructus Forsythiae
Glycoside derivates, which is characterized in that it also includes the auxiliary material for children's drug administration by injection safety.
2. injection described in claim 1, wherein forsythin and phillygenol or forsythin derivative content be 5~
100mg, preferably 20~50mg.
3. injection described in claim 1, wherein the auxiliary material includes L-arginine or sulfobutyl ether-beta-cyclodextrin, preferably
It is L-arginine.
4. injection as claimed in claim 3, wherein the weight of forsythin and phillygenol or Fructus Forsythiae glycoside derivates and L-arginine
Amount is than being 1:10~50, preferably 1:20~30；Or, forsythin and phillygenol or Fructus Forsythiae glycoside derivates and sulfobutyl ether-β-
Weight ratio 1:30~150 of cyclodextrin, preferably 1:60~75.
5. injection described in claim 1 does not generate Toxicity of Kidney for continuous use 7 days, do not produce within preferably continuous use 30 days
Raw Toxicity of Kidney.
6. injection described in claim 1, the preparation method for injection liquor, the preferably described injection liquor includes forsythin
The step of being mixed with phillygenol or Fructus Forsythiae glycoside derivates with the auxiliary material.
7. injection described in claim 1 is powder-injection, the preparation method of the preferably described powder-injection includes drying (preferably
Freeze-drying) injection liquor as claimed in claim 6 the step of.
8. injection described in claim 1 is needleless powder injection, the preparation method packet of the preferably described needleless powder injection
Include the step of sieving powder-injection (to granular size between 400 mesh and 120 mesh) as claimed in claim 7.
9. the preparation method of injection described in claim 1 comprising forsythin and phillygenol or Fructus Forsythiae glycoside derivates with
The step of being mixed for the auxiliary material of children's drug administration by injection safety.
10. Fructus Forsythiae glycoside derivates are in preparation for the application in antipyretic drug, the preferably described Fructus Forsythiae glycoside derivates are 33- hydroxyls
Base-phillygenol glucuronide, 9- hydroxyl-phillygenol glucuronide or 33,34- methylene dioxy-Fructus Forsythiae rouge
Plain glucuronide.
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| CN102266285A (en) * | 2010-06-03 | 2011-12-07 | 沈阳双鼎科技有限公司 | Low excitant ibuprofen injection |
| CN104414977A (en) * | 2013-09-09 | 2015-03-18 | 重庆汇智药物研究院有限公司 | Artesunate and L-arginine composition for injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6063383A (en) * | 1999-01-28 | 2000-05-16 | Hsu; Wu-Ching | Pharmaceutical suppository composites for fever and influenza and method of producing the composites |
| CN105362283A (en) * | 2014-08-07 | 2016-03-02 | 富力 | Applications of phillyrin/phillygenin composition in preparation of drugs or health products for relieving or/and treatment of viral diseases |
| CN106063791A (en) * | 2015-04-23 | 2016-11-02 | 富力 | The application in preparing anti-inflammatory drug of the compositions of phillyrin, phillyrin derivant, phillyrin and phillygenol |
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| CN109602699B (en) | 2020-06-09 |
| CN111481563A (en) | 2020-08-04 |
| CN111481563B (en) | 2022-11-15 |
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