CN111481563A - Injection of forsythin and forsythiaside and derivatives thereof for children - Google Patents
Injection of forsythin and forsythiaside and derivatives thereof for children Download PDFInfo
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Abstract
The invention provides an injection of phillyrin/phillygenin and derivatives thereof, which is particularly suitable for children. The invention also comprises a dehydrated preparation of the injection, a preparation method, application and the like.
Description
Prior application
The application is a divisional application of Chinese patent application 201910034372.9 filed on 15/1/2019.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an injection containing forsythin and forsythiaside or a forsythin derivative, a preparation method thereof and the like.
Technical Field
The present inventors have conducted intensive studies on extracts of Chinese herbs and have discovered, occasionally and surprisingly, that a pharmaceutical composition comprising forsythin and less forsythiaside has a synergistic, especially synergistic, pharmaceutical effect in various pharmaceutical aspects. For example, chinese patent application CN105362283A discloses a forsythin/forsythiaside composition and its application in anti-virus; chinese patent application CN105796861A discloses a phillyrin/phillygenin composition and its application in improving immunity; chinese patent application CN106063788A discloses a phillyrin/phillygenin composition and its application in the treatment of emesis; chinese patent application
CN106063789A discloses a phillyrin/phillygenin composition and its application in treating lymph node tuberculosis; chinese patent application CN106063790A discloses a phillyrin/phillygenin composition and its application in anti-aging; chinese patent application CN106063791A discloses a phillyrin/phillygenin composition and its application in anti-inflammation; chinese patent application CN106063792A discloses a phillyrin/phillygenin composition and its application in relieving pain; chinese patent application CN106063793A discloses a phillyrin/phillygenin composition and its application in treating bacterial infection; chinese patent application CN106063794A discloses a phillyrin/phillygenin composition and its application in preventing and treating liver injury; chinese patent application CN106063795A discloses a phillyrin/phillygenin composition and its application in preventing and treating hyperlipidemia; chinese patent application CN106063796A discloses a phillyrin/phillygenin composition and its application in detumescence; chinese patent application CN106063797A discloses a phillyrin/phillygenin composition and its application in antioxidation; chinese patent application CN106176786A discloses a phillyrin/phillygenin composition and its application in preventing and treating obesity; chinese patent application CN106176788A discloses a phillyrin/phillygenin composition and its application in the treatment of urinary tract infection; chinese patent application CN108066350A discloses a phillyrin/phillygenin composition and application thereof in the prevention and treatment of senile dementia.
However, although the forsythin/forsythiaside composition mentioned above suggests that it can be administered as an injection, since forsythiaside has a solubility in water of less than 20 μ g/g and is also not highly soluble, these patent applications only disclose formulations for oral preparations, and no injection formulation has been studied, and the oral preparations substantially contain cyclodextrin and its derivatives, particularly β -cyclodextrin and its derivatives.
In addition, the present inventors have also studied derivatives of forsythin and forsythiaside. For example, chinese patent application CN104650108A discloses a forsythiaside sulfate, which esterifies phenolic hydroxyl group of forsythiaside to form corresponding sodium salt, potassium salt, ammonium salt or other salts for anti-virus; chinese patent application CN104945452A discloses a forsythiaside glucuronide derivative, which comprises 33-hydroxy-forsythiaside glucuronide, 9-hydroxy-forsythiaside glucuronide, 33, 34-methylenedioxy-forsythiaside glucuronide and the like, and is used for resisting influenza virus; chinese patent application CN106188176A discloses another forsythiaside glucuronic acid derivative, which comprises forsythiaside glucuronic acid methyl ester, sodium salt and potassium salt of forsythiaside glucuronic acid, and the like. Besides forsythiaside glucuronic acid methyl ester, the derivative can form salt due to the introduction of acid radicals, and the water solubility is improved to a certain extent.
At present, paediatric drugs generally follow the principle of 'oral administration without injection', so that the requirement for developing a new injection suitable for children is low, and particularly, a phillyrin/phillygenin composition can be prepared into an injection with cyclodextrin and derivatives thereof, so that the development of a new phillyrin/phillygenin injection is generally unnecessary, and further, the development of a new injection is unnecessary for improving the water solubility of the phillyrin and the phillygenin derivatives.
The pharmaceutical excipients in the prior art are various in types, and the combination and the proportion among different types are astronomical numbers. The inventor of the invention has found that specific auxiliary materials are unexpectedly used for preparing the forsythin/forsythin lipid injection from a large amount of medical auxiliary materials with unexpected effects after long-term research and practice, hemolysis and nephrotoxicity do not occur in the normal medication period, and the optimized auxiliary materials do not occur in the hemolysis and nephrotoxicity even after long-term medication, thereby enhancing the safety of children medication, being convenient for freeze drying and redissolution, enhancing the flexibility of dosage form production, and being more unexpected, the powder injection prepared by the optimized auxiliary materials is even suitable for being prepared into needleless powder injection. Moreover, the preparation has good adaptability, and is also suitable for phillyrin and phillygenin derivatives.
In addition, the inventor also finds that the forsythiaside glucuronic acid derivative has the antipyretic effect, can be singly orally taken for application, and can also be prepared into injection, in particular to the injection suitable for the pediatric application, thereby widening the application range of the invention.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel phillyrin/phillyrin injection, which is particularly suitable for children and is particularly suitable for flexible production of injections of different dosage forms. Moreover, the invention also provides a preparation method of the injection. In addition, the invention also provides pharmaceutical application of the forsythin derivative.
In particular, in a first aspect, the invention provides a forsythin/forsythin injection, which comprises forsythin and forsythin, and further comprises auxiliary materials safe for children injection administration. In addition, the invention also provides a forsythin derivative injection, which comprises the forsythin derivative and auxiliary materials safe for children injection.
The injection of the first aspect of the present invention may comprise phillyrin and phillygenin as active ingredients, preferably the only active ingredients, i.e., the injection of the first aspect of the present invention preferably consists of phillyrin and phillygenin and pharmaceutically acceptable excipients.
In this context, unless indicated to the contrary, "forsythin/forsythin", "forsythin and forsythin" and "forsythin and forsythin composition" are used interchangeably and refer to a composition consisting of forsythin and forsythin, i.e. forsythin/forsythin as a whole. Preferably, in the injection of the first aspect of the present invention, the weight ratio of phillyrin to forsythiaside is 2-98: 2-98, preferably 80-98: 2-20, more preferably 90-98: 2-10, such as 90:10 or 98: 2. According to the research of the inventor, the phillyrin/phillygenin can be applied to various medicinal aspects such as antivirus and the like, and most of the phillyrin/phillygenin can produce a synergistic effect.
The injection of the first aspect of the present invention may comprise a forsythin derivative as an active ingredient, preferably the only active ingredient, i.e., the injection of the first aspect of the present invention preferably consists of a forsythin derivative and a pharmaceutically acceptable adjuvant.
In this context, unless indicated to the contrary, "forsythin derivatives" and "forsythin and forsythiaside derivatives" are used interchangeably and refer to the derivatives of forsythin and forsythiaside as obtained by the present inventors, including forsythiaside sulfate or a salt thereof as described in chinese patent application CN104650108A, forsythiaside glucuronic acid derivatives as described in chinese patent application CN104945452A, or forsythiaside glucuronic acid derivatives as described in chinese patent application CN106188176A, or a salt or an ester thereof. Preferably, the forsythin derivative comprises forsythiaside sulfate or a salt thereof (e.g. sodium, potassium or ammonium salt), 33-hydroxy-forsythiaside, 9-hydroxy-forsythiaside, 33, 34-methylenedioxy-forsythiaside, forsythiaside glucuronide, forsythiaside glucuronate (e.g. sodium or potassium salt) or forsythiaside glucuronate (e.g. methyl ester).
Preferably, the injection of the first aspect of the present invention is a unit formulation (e.g., a single needle) having a forsythin and forsythiaside content (i.e., unit dose) of 5 to 100mg, preferably 20 to 50mg, such as 20mg or 50 mg; alternatively, the forsythin derivative content (i.e., unit dose) is 5-100 mg, preferably 20-50 mg, such as 20mg or 50 mg. Such unit doses are suitable for pediatric administration. Herein, a child refers to a young child or child of 2 to 12 years old. For adults, the unit dose may be increased.
Pharmaceutically acceptable excipients in this context mean fillers, diluents, solubilizers, pH regulators, osmo-regulators, protective agents, preservatives or other formulation excipients which are substantially non-toxic and do not influence the onset of action of the active ingredient. The pH adjusting agent includes pharmaceutically acceptable organic acids, inorganic acids, organic bases and/or inorganic bases, and in a specific embodiment of the present invention, the pH adjusting agent is hydrochloric acid. The osmotic pressure regulator may be NaCl or glucose. Preferably, the injection of the first aspect of the present invention has a pH of 6.5 to 7.5, more preferably 7.0 to 7.3.
However, many pharmaceutically acceptable excipients such as β -cyclodextrin, which causes strong hemolytic and injurious nephrotoxicity and is not suitable for safe administration to children, and pH regulators and osmotic pressure regulators, which cannot prepare forsythin/forsythiaside or forsythiaside derivatives alone into stable injections.
The injection of the first aspect of the invention contains an auxiliary material which is safe for children to inject, preferably, in the injection of the first aspect of the invention, the auxiliary material comprises L-arginine or sulfobutyl ether- β -cyclodextrin, the auxiliary material can not only prepare the forsythin/forsythiaside or forsythin derivatives into a stable injection, but also can not generate hemolytic and renal toxicity in a normal administration period, and the latter is particularly beneficial to children with incomplete development of renal function.
Specifically, the injection of the first aspect of the present invention consists of A and B and optionally C, wherein A is forsythin and forsythiaside or is a forsythin derivative, B is L-arginine or sulfobutyl ether- β -cyclodextrin, and C is water, a pH regulator and/or an osmotic pressure regulator.
Preferably, in the injection of the first aspect of the present invention, the weight ratio of forsythin and forsythiaside to L-arginine is 1: 10-50, more preferably 1: 20-30, or the weight ratio of forsythin derivatives to L-arginine is 1: 10-50, more preferably 1: 20-30.
Also preferably, in the injection of the first aspect of the present invention, the weight ratio of phillyrin and forsythiaside to sulfobutyl ether- β -cyclodextrin is 1: 30-150, more preferably 1: 60-75, or the weight ratio of phillyrin derivative to sulfobutyl ether- β -cyclodextrin is 1: 30-150, more preferably 1: 60-75.
In this context, injection has the ordinary meaning in the art, referring to the general term of dosage forms for injection. Preferably the injection according to the first aspect of the invention is an injection, i.e. the injection comprises water. More preferably, the preparation method of the injection comprises the step of mixing phillyrin and phillygenin with the auxiliary materials; or the preparation method of the injection comprises the step of mixing the phillyrin derivative and the auxiliary materials.
In one embodiment of the present invention, the method comprises the following steps:
(1) mixing phillyrin and phillygenin dissolved in organic solvent with adjuvants dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator.
In another embodiment of the present invention, the method comprises the following steps:
(1) mixing phillyrin derivative dissolved in solvent and adjuvant dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator.
It is also preferred that the injectable formulation of the first aspect of the invention is a powder for injection, i.e. the injectable formulation does not comprise water. More preferably, the preparation method of the powder injection comprises the step of drying the injection liquid. The drying may be spray drying or freeze drying. In a specific embodiment of the present invention, the method comprises the following steps:
(4) freeze drying the injection.
More preferably, the method of preparing the needleless powder injection comprises the step of sieving the powder injection, for example, comprises the step of sieving the powder injection to a particle size of between 400 mesh and 120 mesh, and in a specific embodiment of the present invention comprises the steps of:
(5) moistening the powder for injection, granulating, tabletting, pulverizing, and sieving to collect powder with particle size of 400-120 mesh.
In a second aspect, the present invention provides a process for the preparation of an injection according to the first aspect of the invention, comprising the step of mixing phillyrin and phillygenin with excipients safe for pediatric administration by injection, or alternatively, comprising the step of mixing phillyrin derivatives with excipients safe for pediatric administration by injection, said excipients preferably comprising L-arginine or sulfobutyl ether- β -cyclodextrin.
Preferably, the preparation method of the second aspect of the present invention is a preparation method of an injection solution, which comprises a step of mixing phillyrin and phillygenin with the auxiliary materials; or, it comprises the step of mixing the forsythin derivative with the adjuvant.
In one embodiment of the present invention, the method for preparing the injection solution comprises the following steps:
(1) mixing phillyrin and phillygenin dissolved in organic solvent with adjuvants dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator.
In another embodiment of the present invention, the method for preparing the injection solution comprises the steps of:
(1) mixing phillyrin derivative dissolved in solvent and adjuvant dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator.
Also preferably, the production method of the second aspect of the present invention is a production method of a powder injection, which comprises a step of drying the above-mentioned injection liquid.
In one embodiment of the invention, the preparation method of the powder injection comprises the following steps:
(1) mixing phillyrin and phillygenin dissolved in organic solvent with adjuvants dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator;
(4) and (4) freeze-drying the injection obtained in the step (3).
In another embodiment of the present invention, the preparation method of the powder injection comprises the following steps:
(1) mixing phillyrin derivative dissolved in solvent and adjuvant dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator;
(4) and (4) freeze-drying the injection obtained in the step (3).
Also preferably, the preparation method of the second aspect of the present invention is a preparation method of a needleless powder injection, which comprises the step of sieving the powder injection, and wherein the adjuvant comprises L-arginine.
In one embodiment of the present invention, the needleless powder injection comprises the steps of:
(1) mixing phillyrin and phillygenin dissolved in organic solvent with adjuvants dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator;
(4) freeze-drying the injection obtained in the step (3);
(5) wetting the powder injection obtained in the step (4), granulating, tabletting and crushing, and then screening and collecting powder with the particle size between 400 meshes and 120 meshes.
In another embodiment of the present invention, the needleless powder injection comprises the steps of:
(1) mixing phillyrin derivative dissolved in solvent and adjuvant dissolved in water, and drying under reduced pressure;
(2) dissolving the dried product obtained in the step (1) in water, and drying under reduced pressure;
(3) dissolving the dried product obtained in the step (2) in water, and optionally adding a pH regulator and/or an osmotic pressure regulator;
(4) freeze-drying the injection obtained in the step (3);
(5) wetting the powder injection obtained in the step (4), granulating, tabletting and crushing, and then screening and collecting powder with the particle size between 400 meshes and 120 meshes.
In a third aspect, the present invention provides the use of a phillyrin derivative for the manufacture of a medicament for fever relief. Herein, fever reduction and fever reduction are used interchangeably and refer to the reduction of a febrile body temperature, preferably to normothermia. In a particular embodiment of the invention, fever is triggered by injection of a heterologous antigen (e.g., yeast).
Preferably, the third aspect of the present invention is the use of a forsythin derivative alone as an active ingredient, i.e. preferably the third aspect of the present invention provides the use of a forsythin derivative alone in the manufacture of a medicament for use in fever relief.
Preferably in the use according to the third aspect of the invention, the forsythin derivative is 33-hydroxy-forsythiaside glucuronide, 9-hydroxy-forsythiaside or 33, 34-methylenedioxy-forsythiaside glucuronide.
The invention has the advantages that the stable forsythin/forsythiaside or forsythin derivative injection is provided, the safety is high, and the injection is particularly suitable for children with immature renal functions; the preparation has high flexibility, and can be flexibly converted into different injection preparations such as injection liquid, powder injection, non-needle powder injection and the like; the preparation has good adaptability, and is suitable for forsythin/forsythiaside and various forsythin derivatives with various proportions; in addition, the invention provides the application of the forsythin derivative in the aspect of antipyresis, and widens the indication of the forsythin derivative.
For the purpose of facilitating understanding, the present invention will be described in detail below with reference to specific embodiments and the accompanying drawings. It is to be expressly understood that the description is illustrative only and is not intended as a definition of the limits of the invention. Many variations and modifications of the present invention will be apparent to those skilled in the art in light of the teachings of this specification. In addition, the present invention incorporates publications which are intended to more clearly describe the invention, and which are incorporated herein by reference in their entirety as if reproduced in their entirety.
Drawings
FIG. 1 schematically shows a photograph of a section of kidney tissue in which tubular vacuoles have appeared.
Fig. 2 exemplarily shows a photograph of a section of kidney tissue without abnormalities, including without renal tubular vacuoles.
Detailed Description
The invention is further illustrated by the following examples. Unless otherwise specified, the methods used in the examples are described in the technical literature of the art and in the code documents of the drug administration, and the instruments, raw materials and reagents are commercially available.
Example 1 Effect of phillyrin derivatives and composition of phillyrin and phillygenin on experiments on Yeast-induced fever from Rabbit failure
1 test Material
1.1 drugs and reagents
Phillyrin, white powder, produced by DALIANFUSHENG Natural drug development Co., Ltd, and its purity is determined by area normalization method of high performance liquid chromatography two detectors, ultraviolet detector and evaporative light scattering detector
99.5 percent, and the content of the phillyrin is calibrated and confirmed to be 99.5 percent by using a phillyrin reference substance for measuring the content of Chinese medicine biological products.
33-hydroxy-forsythin glucuronide (phillyrin derivative A), white powder, produced by DALIANGSHENG Natural drug development Co. The purity of the product is 98.5% as determined by two detectors of high performance liquid chromatography, namely an ultraviolet detector and an evaporative light scattering detector by an area normalization method.
9-hydroxy-forsythin glucuronide (phillyrin derivative B), white powder, produced by DALIANGSHENG Natural drug development Co. The purity of the product is 99.2% by area normalization of high performance liquid chromatography two detectors, namely an ultraviolet detector and an evaporative light scattering detector.
33, 34-methylenedioxy-forsythin glucuronide (forsythin derivative C), white powder, produced by Dalian natural drug development Co. The purity of the product is 98.7% as determined by two detectors of high performance liquid chromatography, namely an ultraviolet detector and an evaporative light scattering detector by an area normalization method.
Yeast, commercially available.
Positive control drug: aspirin, Jinling pharmaceutical industry Hefei Limin pharmaceutical factory, batch number: 130809
1.2 Experimental animals
White rabbits, weighing 0.5kg of 2.5 g, half male and female, purchased from the experimental animals center of university of Dalian medical science, quality certification number: SCXK (13) 2012-.
2, test method:
2.1 dose selection
Setting 3 phillyrin experimental groups according to the recommended dosage of a human body of a test object and the maximum possible gavage dosage of a sample, namely, the phillyrin low, medium and high dosage groups, wherein the dosages are 3, 6 and 12mg/kg respectively;
phillyrin derivative A, B, C is respectively provided with 3 phillyrin derivative experimental groups, namely, low, medium and high dose groups of phillyrin derivative A, wherein the doses are respectively 3, 6 and 12 mg/kg; the forsythin derivative B is prepared into low, medium and high dose groups, and the doses are respectively 3, 6 and 12 mg/kg; the forsythin derivative C is used in low, medium and high dosage groups, and the dosage is 3, 6 and 12mg/kg respectively;
a blank control group and a positive drug control group (aspirin, 250mg/kg) were also set.
2.2 grouping and administration
Taking healthy white rabbits with the weight of 2.5 plus or minus 0.5kg, carrying out female-male infertility, measuring the anal temperature (the temperature is deep about 3cm, the error of two times does not exceed 0.2 ℃), screening 100 rabbits with the temperature of 36-38 ℃, randomly dividing the rabbits into 20 groups, and dividing each group into 5 groups, namely a blank control group, a phillyrin group (low, medium and high three dose groups), a phillyrin derivative A, B, C (low, medium and high three dose groups) and a positive drug control group (aspirin, 250 mg/kg/d).
Blank control group: the administration is carried out by intragastric administration with Normal Saline (NS) 1 time per day for 3 days; respectively performing intragastric administration on the phillyrin group and the phillyrin derivative A, B, C for 1 time every day for 3 days; the positive drug control group is administered by aspirin gavage for 250mg/kg 1 time per day for 3 days.
1 hour after the last administration, 4.5g/kg of yeast suspension was injected subcutaneously into the rabbits and the anal temperature was measured 05 h, lh, 2h, 4h, 8h after warming up, and the results are shown in Table 1.
3 results of the experiment
TABLE 1 Effect of forsythin derivatives, forsythin derivatives/forsythiaside on the fever from yeast in rabbit failure (x + -s n ═ 5)
According to fever reduction experiments, the body temperature of the rabbit in a blank control group is obviously increased, compared with a model control group, the fever reduction effect of each administration prevention group of phillyrin and phillyrin derivatives is obvious, the obvious difference P of a medium-high dose group is less than 0.01, the P of each low dose group is less than 0.05 compared with the group before causing fever, and the P of each low dose group is less than O.01 compared with the model control group.
Example 2 phillyrin/phillygenin injection
1 test drug
Phillyrin/phillygenin composition a: phillyrin (purity 99.5%), white powder, produced by DALIANFUSHENG Natural drug development Co., Ltd; forsythiaside (purity 99.2%), white powder, produced by great lian fusheng natural drug development limited; the weight ratio of the forsythin to the forsythiaside is 98: 2.
phillyrin/phillygenin composition B: phillyrin (purity 99.5%), white powder, produced by DALIANFUSHENG Natural drug development Co., Ltd; forsythiaside (purity 99.2%), white powder, produced by great lian fusheng natural drug development limited; the weight ratio of the forsythin to the forsythiaside is 90: 10.
2 preparation of phillyrin/phillygenin injection
2.1 formulation 1
Taking 2g of forsythin/forsythiaside composition B, completely dissolving with acetonitrile-ethanol mixed solution (volume ratio is 75: 25)200m L for later use, taking 150g of sulfobutyl ether- β -cyclodextrin, adding water for injection 350m L, heating to 45 ℃ and completely dissolving for later use.
Maintaining the temperature at 45 deg.C, dropwise adding the phillyrin/phillygenin composition solution into the sulfobutyl ether- β -cyclodextrin solution at 5m L/min under stirring, vacuum drying at 100 deg.C and 0.05MPA in a rotary evaporator, recovering solvent, dissolving the dried product with 200m L water for injection, and rotary evaporating at 100 deg.C and 0.05MPA for drying.
Dissolving the final dried product in 0.9% (w/v) NaCl water solution, metering to 200m L, filtering and sterilizing at 0.22um, packaging, sealing, and making into phillyrin/phillyrin injection (formula 1) with specification of 2m L: 20 mg.
2.2 formulation 2
Taking 2g of forsythin/forsythiaside composition A, completely dissolving with anhydrous ethanol 400m L for later use, taking 120g of sulfobutyl ether- β -cyclodextrin, adding water for injection 280m L, and heating to 40 ℃ for complete dissolution for later use.
Maintaining the temperature at 40 deg.C, dropwise adding the phillyrin/phillygenin composition solution into the sulfobutyl ether- β -cyclodextrin solution at a speed of 10m L/min while stirring, drying the dropwise added product in a rotary evaporator under vacuum degree of 0.05MPA and 100 deg.C under reduced pressure, recovering solvent, dissolving the dried product in 80m L water for injection, and repeatedly performing rotary evaporation and drying under vacuum degree of 0.05MPA and 100 deg.C.
Dissolving the final dried product in 0.9% (w/v) NaCl water solution, metering to 80m L, filtering and sterilizing at 0.22um, packaging, sealing, and making into phillyrin/phillyrin injection (formula 2) with specification of 2m L: 50 mg.
2.3 formulation 3
Taking 2g of forsythin/forsythiaside composition B, completely dissolving with an acetonitrile-ethanol mixed solution (volume ratio 70: 30) of 250m L for later use, taking L-arginine of 50g, adding water for injection of 450m L, and completely dissolving for later use.
At room temperature, dripping the forsythin/phillygenin composition solution into the arginine solution at a speed of 5m L/min, stirring while dripping, continuing to stir for 15min after finishing dripping, drying the mixture in a rotary evaporator at a vacuum degree of 0.04MPA and 100 ℃ under reduced pressure after stirring, recovering the solvent, dissolving the dried product in 200m L water for injection, and repeating the rotary evaporation and drying at the vacuum degree of 0.04MPA and 100 ℃.
Dissolving the final dried product with 0.9% (w/v) NaCl water solution 150m L, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl water solution to constant volume of 200m L, filtering and sterilizing at 0.22um, packaging, sealing, and preparing to obtain forsythin/forsythin injecta (formula 3) with specification of 2m L: 20 mg.
2.4 formulation 4
Taking 2g of forsythin/forsythiaside composition A, using acetonitrile-ethanol mixed liquor (volume ratio is 75: 25)200m L for standby, taking L-arginine 60g, adding water for injection 340m L, heating to 35 ℃ and completely dissolving for standby.
Maintaining the temperature at 35 deg.C, dripping the phillyrin/phillygenin composition solution into the arginine solution at 5m L/min while stirring, stirring for 10min, drying in a rotary evaporator under reduced pressure at 0.05MPA and 100 deg.C, recovering solvent, dissolving the dried product with 80m L water for injection, and rotary evaporating at 0.05MPA and 100 deg.C.
Dissolving the final dried product with 0.9% (w/v) NaCl water solution 50m L, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl water solution to constant volume, filtering and sterilizing at 0.22um, packaging, sealing, and preparing into phillyrin/phillyrin injection (formula 4) with specification of 2m L: 50 mg.
2.5 formulation 5
Taking 2g of forsythin/forsythiaside composition B, completely dissolving with acetonitrile 150m L for later use, taking L-arginine 40g, adding water for injection 360m L, and completely dissolving for later use.
Dripping the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5m L/min at room temperature while stirring, drying the sample in a rotary evaporator under the vacuum degree of 0.04MPA and the temperature of 100 ℃ under reduced pressure after dripping, recovering the solvent, dissolving the dried product in 200m L water for injection, and repeatedly drying by rotary evaporation under the vacuum degree of 0.04MPA and the temperature of 100 ℃.
Dissolving the final dried product with 0.9% (w/v) NaCl water solution 150m L, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl water solution to constant volume of 200m L, filtering and sterilizing at 0.22um, packaging, sealing, and preparing into phillyrin/phillyrin injection (formula 5) with specification of 2m L: 20 mg.
3 stability study of forsythin/phillygenin injection
The injection solution prepared according to the above formulation was left at 25 ℃ for 180 days to conduct stability studies, and the results are shown in Table 2.
TABLE 2 Normal temperature stability of forsythin/forsythiaside injection of the present invention
The result shows that the preparation method of the invention can fully dissolve the phillyrin/phillygenin composition by taking sulfobutyl ether- β -cyclodextrin as an auxiliary material or arginine as an auxiliary material, basically has no loss of active substances of the phillyrin/phillygenin, has good stability and can be stably stored for a long time at room temperature level.
EXAMPLE 3 phillyrin derivative injection solution
1 test drug
33-hydroxy-forsythiaside glucuronide (derivative A, purity 98.5%), white powder, produced by Dalian Fusheng Natural drug development Co., Ltd.
9-hydroxy-forsythiaside glucuronide (derivative B, purity 99.2%), white powder, produced by Dalian Fusheng Natural drug development Co., Ltd.
33, 34-methylenedioxy-forsythiaside glucuronide (derivative C, purity 98.7%), white powder, produced by DALIANGHENGFANGSHENG Natural drug development Co.
Sodium forsythiaside sulfate (derivative D), white powder, produced by DALIANGHENGFANGSHENG Natural drug development Co. The purity of the product is 99.9% by area normalization of high performance liquid chromatography two detectors, namely an ultraviolet detector and an evaporative light scattering detector.
Forsythiaside sodium glucuronate (derivative E), white powder, produced by Daliangfeng natural drug development Co. The purity of the product is 99.3% by area normalization of high performance liquid chromatography two detectors, namely an ultraviolet detector and an evaporative light scattering detector.
Forsythiacin glucuronic acid methyl ester (derivative F), white powder, and is produced by Daliangfeng natural medicine development Co. The purity of the product is 99.6% by area normalization of high performance liquid chromatography two detectors, namely an ultraviolet detector and an evaporative light scattering detector.
2 preparation of phillyrin derivative injection
2.1 derivatives A formulation 1
Taking 2g of derivative A, completely dissolving the derivative A by using 50 percent (volume ratio) of ethanol 200m L for later use, taking 150g of sulfobutyl ether- β -cyclodextrin, adding 350m L of water for injection, and heating to 45 ℃ to completely dissolve the derivative A for later use.
Keeping the temperature at 45 ℃, dropwise adding the derivative A solution into the sulfobutyl ether- β -cyclodextrin solution at the speed of 10m L/min while stirring, drying the mixture in a rotary evaporator under the vacuum degree of 0.05MPA and the temperature of 100 ℃ under reduced pressure after dropwise adding, recovering the solvent, dissolving the dried product in water for injection of 200m L, and repeatedly drying the product by rotary evaporation under the vacuum degree of 0.05MPA and the temperature of 100 ℃.
Dissolving the final dried product with 0.9% (w/v) NaCl water solution, metering to 200m L, filtering and sterilizing at 0.22um, packaging, sealing, and making into 2m L: 20mg derivative A injection (formula A1).
2.2 derivatives A formulation 2
2g of the derivative A is completely dissolved by 50 percent (volume ratio) of ethanol 200m L for standby, L g of arginine 50g is completely dissolved by adding water for injection 450m L for standby.
At room temperature, dropwise adding the derivative A solution into the arginine solution at a speed of 10m L/min, stirring while dropwise adding, continuing stirring for 10min after dropwise adding, drying the mixture in a rotary evaporator under a vacuum degree of 0.05MPA and a temperature of 100 ℃ under reduced pressure after stirring, recovering the solvent, dissolving the dried product in 200m L water for injection, and repeatedly drying the product by rotary evaporation under a vacuum degree of 0.05MPA and a temperature of 100 ℃.
Dissolving the final dried product with 0.9% (w/v) NaCl aqueous solution 150m L, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution to reach volume of 200m L, filtering and sterilizing at 0.22um, packaging, sealing, and preparing into 2m L: 20mg derivative A injection (formula A2).
2.3 derivatives B formulation 1
With reference to the above preparation method of derivative A, formulation 1, except that derivative B was used in place of derivative A, an injection of derivative B (formulation B1) was prepared at a specification of 2m L: 20 mg.
2.4 derivatives B formulation 2
With reference to the above preparation process of derivative A, formulation 2, except that derivative B was used in place of derivative A, an injection of derivative B (formulation B2) was prepared at a specification of 2m L: 20 mg.
2.5 derivatives C formulation 1
With reference to the above preparation method of derivative A formulation 1, except that derivative C was used in place of derivative A, an injection of derivative C (formulation C1) was prepared at a specification of 2m L: 20 mg.
2.6 derivatives C formulation 2
With reference to the above preparation method of derivative A, formulation 2, except that derivative C was used in place of derivative A, an injection of derivative C (formulation C2) was prepared at a specification of 2m L: 20 mg.
2.7 derivatives D formulation 1
With reference to the above preparation method of derivative A formulation 1, except that derivative D was used in place of derivative A, an injection of derivative D (formulation D1) was prepared at a specification of 2m L: 20 mg.
2.8 derivatives D formulation 2
With reference to the above preparation method of derivative A, formulation 2, except that derivative D was used in place of derivative A, an injection of derivative D (formulation D2) was prepared at a specification of 2m L: 20 mg.
2.9 derivatives E formulation 1
With reference to the above preparation process of derivative A, formulation 1, except that derivative E was used in place of derivative A, an injection of derivative E (formulation E1) was prepared at a specification of 2m L: 20 mg.
2.10 derivatives E formulation 2
With reference to the above preparation process of derivative A, formulation 2, except that derivative E was used in place of derivative A, an injection of derivative E (formulation E2) was prepared at a specification of 2m L: 20 mg.
2.11 derivatives F formulation 1
Taking 2g of derivative F, completely dissolving the derivative F by using 200m L of chloroform for later use, taking 150g of sulfobutyl ether- β -cyclodextrin, adding 350m L of water for injection, and heating to 45 ℃ to completely dissolve the derivative F for later use.
Keeping the temperature at 45 ℃, dropwise adding the derivative F solution into the sulfobutyl ether- β -cyclodextrin solution at the speed of 5m L/min while stirring, continuously stirring for 5min after dropwise adding, drying the mixture in a rotary evaporator at the vacuum degree of 0.05MPA and the temperature of 100 ℃ under reduced pressure after dropwise adding, recovering the solvent, dissolving the dried product in 200m L injection water, and repeatedly performing rotary evaporation drying at the vacuum degree of 0.05MPA and the temperature of 100 ℃.
Dissolving the final dried product with 0.9% (w/v) NaCl water solution, metering to 200m L, filtering and sterilizing at 0.22um, packaging, sealing, and making into 2m L: 20mg derivative F injection (formula F1).
2.12 derivatives F formulation 2
2g of the derivative F is completely dissolved by chloroform-ethanol mixed solution (volume ratio is 75: 25) of 200m L for later use, L g of arginine is completely dissolved by adding water for injection of 450m L for later use.
At room temperature, dropwise adding the derivative F solution into the arginine solution at a speed of 5m L/min, stirring while dropwise adding, continuing to stir for 15min after dropwise adding, drying the mixture in a rotary evaporator under a vacuum degree of 0.05MPA and a temperature of 100 ℃ under reduced pressure after stirring, recovering the solvent, dissolving the dried product in 200m L water for injection, and repeatedly drying the product by rotary evaporation under a vacuum degree of 0.05MPA and a temperature of 100 ℃.
Dissolving the final dried product with 0.9% (w/v) NaCl aqueous solution 150m L, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution to reach volume of 200m L, filtering and sterilizing at 0.22um, subpackaging, and sealing to obtain derivative F injection (formula F2) with specification of 2m L: 20 mg.
3 stability study of forsythin derivative injection
The injection solution prepared according to the above formulation was left at 25 ℃ for 180 days to conduct stability studies, and the results are shown in Table 3.
TABLE 3 Normal temperature stability of phillyrin derivative injection of the present invention
The result shows that the phillyrin derivative injection prepared by the preparation method of the invention by taking sulfobutyl ether- β -cyclodextrin as an auxiliary material or arginine as an auxiliary material basically has no loss of active substances of the phillyrin derivative, has good stability and can be stably stored for a long time at room temperature level.
Example 4 safety Studies of phillyrin/phillygenin injection
27 Wistar rats (male, body weight 120-150 g) were randomly divided into 9 groups of 3 rats each and administered by injection using formulations 1-4 of example 2. The grouping situation is as follows;
a blank control group (intravenous physiological saline), a formula 1 seven-day group (5 mg/kg intravenous injection of the formula 1 in terms of phillyrin/phillygenin composition, once a day for seven consecutive days), a formula 1 january group (5 mg/kg intravenous injection of the formula 1 in terms of phillyrin/phillygenin composition, once a day for 30 consecutive days), a formula 2 seven-day group (formula 2 is changed, the rest is the same as the formula 1 january group), a formula 2 january group (formula 2 is changed, the rest is the same as the formula 1 january group), formula 3 seven days (formula 3, the rest is the same as formula 1 seven days), formula 3 january (formula 3, the rest is the same as formula 1 january), formula 4 qidays (formula 4, the rest is the same as formula 1 january), and formula 4 january (formula 4, the rest is the same as formula 1 january).
Mice in each group gained normal weight and food intake during the administration period, and no hemolysis was observed. Rats were sacrificed 1 hour after the last dose (two of the blank control groups were treated with the seven day group and the other two were treated with the one month group), kidney tissues were taken, sectioned and stained for microscopic examination. Two rats in each of the formula 1 january and formula 2 january groups were observed to develop tubular vacuoles (representative tissue sections are shown in fig. 1); no abnormalities were found in the rest (all animals including placebo, formula 1 seven day, formula 2 seven day, formula 3 january, formula 4 seven day and formula 4 january) (typical tissue sections are shown in fig. 2).
The results show that the phillyrin/phillygenin injection taking sulfobutyl ether- β -cyclodextrin as an auxiliary material has good safety in a normal medication period (usually 3 days, not more than 7 days), but certain renal toxicity appears if the phillyrin/phillygenin injection taking arginine as an auxiliary material is continuously taken for a long time in an excessive amount, and the phillyrin/phillygenin injection taking arginine as an auxiliary material has good safety, and has no renal toxicity no matter short-term use or long-term continuous use.
Example 5 powder injection of Forsythiaside/Forsythiaside and its derivatives
The injection liquid of the formulas 1 to 5 in example 2 and the formulas A1, A2, B1, B2, C1, C2, D1, D2, E1, E2, F1 and F2 in example 3 are respectively filtered, sterilized and then are subpackaged into penicillin bottles with 2ml of each bottle, and freeze-dried, capped and sealed to obtain the freeze-dried powder injection of each formula. When the injection is administered, the injection is redissolved by water for injection, the freeze-dried powder injection of each formula can be redissolved within 10 seconds, and the solution is clear and has no precipitate.
Example 6 injectable powder-free formulations of phillyrin/phillygenin and its derivatives
The lyophilized powder injections of the formulations A2, B2, C2, D2, E2 and F2 in the examples 3 and 3 are also suitable for preparing a needleless powder injection, while the lyophilized powder injections of the formulations 1 to 2 in the examples 2 and the formulations A1, B1, C1, D1, E1 and F1 in the examples 3 and 3 are difficult to effectively penetrate the epidermis and are not suitable for preparing the needleless powder injection.
Taking the freeze-dried powder injection of the formulas A2, B2, C2, D2, E2 and F2 in the embodiment 2 and the formulas A2, B2, C2, D2, E2 and F2 in the embodiment 3 respectively, wetting the freeze-dried powder injection with a proper amount of water for injection (which can be formed but does not have water drops), sieving the obtained product with a 20-mesh sieve for granulation, tabletting the obtained product with a tabletting machine, crushing the obtained product, sieving the obtained product with a 120-mesh sieve, collecting the sieved powder, sieving the obtained product with a 400-mesh.
Taking 30g of gelatin, adding distilled water, heating and dissolving, fixing the volume to 100m L, placing in a square container, solidifying, and thus obtaining the imitation human skin, respectively filling the needleless powder injection with the formulas 3-5 into a powder injector of Powderiject, respectively carrying out pressurized injection on the pigskin and the imitation human skin under the pressure of 4MPa, then respectively sampling parts with different depths on each skin, detecting phillyrin by using HP L C, and detecting the maximum depth of the phillyrin as shown in Table 4.
TABLE 4 maximum injection depth for needleless powder injections of the present invention
The results show that the powder-free injections of formulations 3-5 of example 2 and formulations a2, B2, C2, D2, E2 and F2 of example 3 are expected to be delivered through approximately 0.1mm thick human epidermis into the dermal capillaries, allowing for the needleless injection administration of phillyrin/forsythiaside and its derivatives.
Claims (10)
1. The forsythin/forsythiaside or forsythin derivative injection comprises forsythin and forsythiaside or comprises a forsythiaside derivative, and is characterized by further comprising auxiliary materials safe for children injection administration.
2. The injection according to claim 1, wherein the forsythin and the forsythiaside or the forsythin derivative are contained in an amount of 5 to 100mg, preferably 20 to 50 mg.
3. The injection of claim 1, wherein the excipient comprises L-arginine or sulfobutyl ether- β -cyclodextrin, preferably L-arginine.
4. The injection according to claim 3, wherein the weight ratio of forsythin and forsythiaside or forsythin derivatives to L-arginine is 1: 10-50, preferably 1: 20-30, or the weight ratio of forsythin and forsythiaside or forsythiaside derivatives to sulfobutyl ether- β -cyclodextrin is 1: 30-150, preferably 1: 60-75.
5. The injection according to claim 1, which does not produce renal toxicity after 7 consecutive days, preferably 30 consecutive days.
6. The injection according to claim 1, which is an injection solution, preferably the injection solution is prepared by a method comprising the step of mixing phillyrin and forsythiaside or a phillyrin derivative with the adjuvant.
7. The injection according to claim 1, which is a powder injection, preferably the method for the preparation of said powder injection comprises the step of drying (preferably freeze-drying) the injection solution according to claim 6.
8. The injection of claim 1, which is a needleless powder injection, preferably the method for preparing the needleless powder injection comprises the step of sieving the powder injection of claim 7 (to a particle size between 400 mesh and 120 mesh).
9. The method for preparing an injection according to claim 1, which comprises the step of mixing phillyrin and forsythiaside or phillyrin derivatives with excipients safe for pediatric injection.
10. Use of a forsythin derivative for the manufacture of a medicament for fever reduction, preferably the forsythin derivative is 33-hydroxy-forsythiaside glucuronide, 9-hydroxy-forsythiaside glucuronide or 33, 34-methylenedioxy-forsythiaside glucuronide.
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Citations (4)
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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 |
| 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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| US6063383A (en) * | 1999-01-28 | 2000-05-16 | Hsu; Wu-Ching | Pharmaceutical suppository composites for fever and influenza and method of producing the composites |
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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 |
| 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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