CN111481563B - Injection of forsythin and forsythiaside and derivatives thereof for children - Google Patents

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

Injection of forsythin and forsythiaside and derivatives thereof for children

Prior application

The application is a divisional application of Chinese patent application 201910034372.9, applied 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/forsythin composition and its application in antivirus; chinese patent application CN105796861A discloses a phillyrin/phillygenin composition and application thereof in improving immunity; chinese patent application CN106063788A discloses a phillyrin/phillygenin composition and its application in treating emesis; in the application of the Chinese patent,

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 application thereof 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; in the application of the Chinese patent,

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 formulations have been developed, 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 on forsythiaside to form corresponding sodium salt, potassium salt, ammonium salt or other salts for antiviral use; 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 degree.

At present, pediatric medicines generally follow the principle of 'oral administration without injection', so the requirement for developing injections suitable for children is low, and particularly, the forsythin/phillygenin composition can be prepared into injections with cyclodextrin and derivatives thereof, so that the development of new forsythin/phillygenin injections is not always needed; furthermore, for phillyrin and phillygenin derivatives with improved water solubility, it is not necessary to continue to develop new injections. However, the present inventors have found that injections are also advantageous for rapid, accurate dosing in infants; however, the invention also finds that cyclodextrin, especially beta-cyclodextrin, causes stronger hemolytic and injurious nephrotoxicity, even though sulfobutyl ether-beta-cyclodextrin is preferably selected from a large number of cyclodextrin types by the inventor, the sulfobutyl ether-beta-cyclodextrin still has certain nephrotoxicity after long-term use, which is unfavorable for children with incomplete development of renal function and at least not beneficial to popularization and application, so the invention considers that the invention also needs to develop a novel phillyrin/phillyrin injection suitable for children.

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" may be 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 to 98, preferably 80 to 98:2 to 20, more preferably 90 to 98:2 to 10, such as 90. 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 forsythin derivatives" may be used interchangeably and refer to derivatives of forsythin and forsythin obtained by the present inventors, including forsythin sulfate or salts thereof as described in chinese patent application CN104650108a, forsythin glucuronic acid derivatives as described in chinese patent application CN104945452A, or forsythin glucuronic acid derivatives as described in chinese patent application CN106188176A, or salts or esters 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 invention is a unit formulation (e.g. a needle) in which the forsythin and forsythin content (i.e. unit dose) is from 5 to 100mg, preferably from 20 to 50mg, such as 20mg or 50mg; alternatively, the forsythin derivative content (i.e. unit dose) is from 5 to 100mg, preferably from 20 to 50mg, such as 20mg or 50mg. 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 invention, the pH adjusting agent is hydrochloric acid. The osmotic pressure regulator may be NaCl or glucose. Preferably, the injection according to the first aspect of the present invention has a pH of from 6.5 to 7.5, more preferably from 7.0 to 7.3.

However, there are many pharmaceutically acceptable excipients, such as commonly used β -cyclodextrin, which however causes strong hemolytic and damaging nephrotoxicity and is not suitable for safe administration to children by injection; as the pH regulator and the osmotic pressure regulator, the forsythin/forsythin or forsythin derivatives cannot be prepared into stable injections by themselves. The prior art does not provide auxiliary materials which can not only prepare the forsythin/forsythiaside or forsythin derivatives into stable injections, but also can be safely injected and administered to children.

The injection of the first aspect of the present invention contains excipients that are safe for pediatric administration by injection. Preferably, in the injection according to the first aspect of the present invention, the excipient comprises L-arginine or sulfobutyl ether- β -cyclodextrin. These adjuvants can not only make forsythin/forsythiaside or forsythin derivatives into stable injection, but also do not produce hemolytic and nephrotoxic in normal administration period, and the latter is especially beneficial for children with incomplete development of renal function. More preferably, the auxiliary material comprises L-arginine, and the forsythin/forsythiaside or forsythin derivative injection prepared by the auxiliary material does not have hemolytic property and nephrotoxicity even if being taken for a long time, thereby ensuring the safety of the children. Preferably, the injectable formulation of the first aspect of the invention does not produce renal toxicity upon continuous administration for 7 days, more preferably it does not produce renal toxicity upon continuous administration for 30 days.

Specifically, the injection of the first aspect of the present invention is composed 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 adjuster and/or an osmotic pressure adjuster. For example, the injection of the first aspect of the present invention may be composed of forsythin, forsythiaside and L-arginine, as well as water, hydrochloric acid and NaCl, or may be composed of forsythin, forsythiaside, sulfobutyl ether- β -cyclodextrin and NaCl; for another example, the injection of the first aspect of the present invention may be composed of phillyrin derivative and L-arginine, as well as water, hydrochloric acid and NaCl, or may be composed of phillyrin derivative and sulfobutyl ether- β -cyclodextrin and NaCl.

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 to 50, more preferably 1:20 to 30 percent; or the weight ratio of the phillyrin derivative to the L-arginine is 1:10 to 50, more preferably 1:20 to 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 to 150, more preferably 1:60 to 75 percent; or the weight ratio of the phillyrin derivative to the sulfobutyl ether-beta-cyclodextrin is 1:30 to 150, more preferably 1:60 to 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.

It is also preferred that the injectant of the first aspect of the present invention is a powder injection without needles, i.e., the injectant does not include water, the excipient comprises L-arginine, and the injectant has a particle size suitable for powder injection without needles. More preferably, the preparation method of the needleless powder injection comprises the step of sieving the powder injection, for example, the step of sieving the powder injection to the particle size between 400 meshes and 120 meshes, and in the specific embodiment of the invention, the method comprises the following steps:

(5) Moistening the above powder for injection, granulating, tabletting, and pulverizing, and sieving to collect powder with particle size of 400-120 meshes.

In a second aspect, the present invention provides a method for preparing the injection of the first aspect of the present invention, which comprises the steps of mixing phillyrin and phillygenin with excipients safe for pediatric injection administration; or, it comprises the step of mixing the forsythin derivative with an adjuvant safe for pediatric injection administration. The auxiliary material preferably comprises L-arginine or sulfobutyl ether-beta-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.

It is also preferable that 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) The forsythin derivative dissolved in the solvent and the auxiliary material dissolved in the water are evenly mixed and then dried 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. Preferably, the preparation method of the needleless powder injection comprises the step of sieving the powder injection to ensure that the particle size is between 400 meshes and 120 meshes.

In one embodiment of the invention, the needleless 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) 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 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 induced 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 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, lian Fusheng, a natural drug, produced by the company Limited, is purified by the area normalization method of two detectors, ultraviolet detector and evaporative light scattering detector, of high performance liquid chromatography,

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, big Lian Fusheng, produced by natural drug development Limited. 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, big Lian Fusheng produced by natural drug development Limited. 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 (phillyrin derivative C), white powder, large Lian Fusheng produced by natural drug development Limited. 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) 2012-0008.

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;

the phillyrin derivatives A, B, C are respectively provided with 3 phillyrin derivative experimental groups, namely, phillyrin derivative A low, medium and high dosage groups, the dosages are respectively 3, 6 and 12mg/kg; the forsythin derivative B is prepared into low, medium and high dose groups, and the doses are respectively 3, 6 and 12mg/kg; the phillyrin derivative C is selected from low, medium and high dose groups, and the dose is 3, 6 and 12mg/kg respectively;

a blank control group and a positive drug control group (aspirin, 250 mg/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 thermometer 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 medicine group (low, medium and high three dose groups), a phillyrin derivative A, B, C (low, medium and high three dose groups) and a positive medicine control group (aspirin, 250 mg/kg/d).

Blank control group: the administration is carried out by intragastric administration of Normal Saline (NS) 1 time per day for 3 days; the phillyrin group and the phillyrin derivative A, B, C group are respectively administered with corresponding doses through intragastric administration for 1 time every day and for 3 days continuously; 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 test rabbits, and the anal temperature was measured at 0 h, lh,2h,4h,8h after reaching the heat, and the results are shown in Table 1.

3 results of the experiment

TABLE 1 Effect of forsythin derivatives, forsythin derivatives/forsythiaside on Yeast induced rabbit fever due to failure test (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 Forsythiaside/Forsythiaside injection

1 test drug

Phillyrin/phillygenin composition a: phillyrin (purity 99.5%), white powder, da Lian Fusheng, produced by Natural drug development, inc.; forsythiaside (purity 99.2%), white powder, lian Fusheng, produced by 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, da Lian Fusheng, produced by Natural drug development, inc.; forsythiaside (purity 99.2%), white powder, lian Fusheng, produced by 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, and completely dissolving the composition B with 200mL of acetonitrile-ethanol mixed solution (volume ratio is 75. 150g of sulfobutyl ether-beta-cyclodextrin is taken, 350mL of water for injection is added, and the mixture is heated to 45 ℃ to be completely dissolved for later use.

Keeping the temperature at 45 ℃, dropwise adding the phillyrin/phillygenin composition solution into the sulfobutyl ether-beta-cyclodextrin solution at the speed of 5mL/min, and stirring while dropwise adding. After the completion of the dropwise addition, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

And finally, adding 0.9% (w/v) NaCl aqueous solution into the dried product for dissolving, fixing the volume to 200mL, filtering and sterilizing 0.22um, subpackaging and sealing to prepare the solution with the specification of 2mL:20mg forsythin/forsythin injection (formula 1).

2.2 formulation 2

Taking 2g of forsythin/forsythiaside composition A, and completely dissolving with 400mL of absolute ethanol for later use. Taking 120g of sulfobutyl ether-beta-cyclodextrin, adding 280mL of water for injection, and heating to 40 ℃ to completely dissolve for later use.

Keeping the temperature at 40 ℃, dropwise adding the phillyrin/phillygenin composition solution into the sulfobutyl ether-beta-cyclodextrin solution at the speed of 10mL/min, and stirring while dropwise adding. After the completion of the dropwise addition, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 80mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

And finally, adding 0.9% (w/v) NaCl aqueous solution into the dried product for dissolving, fixing the volume to 80mL, filtering and sterilizing by 0.22um, subpackaging and sealing to obtain the product with the specification of 2mL:50mg forsythin/forsythin injection (formula 2).

2.3 formulation 3

Taking 2g of forsythin/forsythiaside composition B, and completely dissolving the composition B with 250mL of acetonitrile-ethanol mixed solution (volume ratio of 70. 50g of L-arginine is taken and added with 450mL of water for injection to be completely dissolved for later use.

Dripping the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min at room temperature while stirring, and continuing to stir for 15min after the dripping is finished. After stirring, the sample was dried in a rotary evaporator under a vacuum of 0.04MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.04MPA at 100 ℃.

Dissolving the final dry product in 150mL of 0.9% (w/v) NaCl aqueous solution, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution to a constant volume of 200mL, filtering and sterilizing at 0.22um, packaging, sealing, and preparing to obtain a solution with the specification of 2mL:20mg forsythin/forsythin injection (formula 3).

2.4 formulation 4

Taking 2g of forsythin/forsythiaside composition A, and using 200mL of acetonitrile-ethanol mixed solution (volume ratio is 75. 60g of L-arginine is taken, 340mL of water for injection is added, and the mixture is heated to 35 ℃ to be completely dissolved for later use.

Maintaining the temperature at 35 deg.C, adding phillyrin/phillygenin composition solution into the arginine solution at 5mL/min, stirring while adding dropwise, and stirring for 10min. After stirring, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 80mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

And (3) adding 50mL of 0.9% (w/v) NaCl aqueous solution into the final dried product for dissolving, adjusting the pH to 7.2 by using a 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution for constant volume till the volume is constant, filtering and sterilizing at 0.22um, subpackaging and sealing to obtain a solution with the specification of 2mL:50mg forsythin/forsythin injection (formula 4).

2.5 formulation 5

Taking 2g of forsythin/forsythiaside composition B, and completely dissolving with 150mL of acetonitrile for later use. And (3) taking 40g of L-arginine, and adding 360mL of injection water to completely dissolve the L-arginine for later use.

At room temperature, the forsythin/forsythiaside composition solution is dripped into the arginine solution at the speed of 5mL/min, and stirring is carried out while dripping. After the completion of the dropwise addition, the sample was dried in a rotary evaporator under a vacuum of 0.04MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.04MPA at 100 ℃.

Dissolving the final dried product in 150mL of 0.9% (w/v) NaCl aqueous solution, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution to a constant volume of 200mL, filtering and sterilizing with 0.22um, packaging, sealing, and preparing to obtain the final product with the specification of 2mL:20mg forsythin/forsythin injection (formula 5).

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 can fully dissolve the phillyrin/phillygenin composition by taking sulfobutyl ether-beta-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 at room temperature level for a long time.

EXAMPLE 3 phillyrin derivative injection solution

1 test drug

33-hydroxy-forsythiaside glucuronide (derivative A, purity 98.5%), white powder, da Lian Fusheng, produced by Natural drug development Co., ltd.

9-hydroxy-forsythiaside glucuronide (derivative B, purity 99.2%), white powder, da Lian Fusheng, produced by Natural drug development Co., ltd.

33 34-methylenedioxy-forsythiaside (derivative C, purity 98.7%), white powder, da Lian Fusheng, produced by natural drug development, inc.

Sodium forsythiaside sulfate (derivative D), white powder, da Lian Fusheng, produced by Natural drug development, inc. 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, da Lian Fusheng, produced by Natural drug development, inc. 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, da Lian Fusheng, produced by Natural drug development, inc. 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

2g of derivative A was completely dissolved in 200mL of 50% (volume ratio) ethanol and was used. 150g of sulfobutyl ether-beta-cyclodextrin is taken, 350mL of water for injection is added, and the mixture is heated to 45 ℃ to be completely dissolved for later use.

Keeping the temperature at 45 ℃, dropwise adding the derivative A solution into the sulfobutyl ether-beta-cyclodextrin solution at the speed of 10mL/min, and stirring while dropwise adding. After the completion of the dropwise addition, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

And finally, adding 0.9% (w/v) NaCl aqueous solution into the dried product for dissolving, fixing the volume to 200mL, filtering and sterilizing 0.22um, subpackaging and sealing to obtain the product with the specification of 2mL:20mg of derivative A was injected (formulation A1).

2.2 derivatives A formulation 2

2g of derivative A was completely dissolved in 200mL of 50% (volume ratio) ethanol and was used. 50g of L-arginine is taken and added with 450mL of water for injection to be completely dissolved for later use.

At room temperature, the derivative A solution was added dropwise to the arginine solution at a rate of 10mL/min, followed by stirring, and after completion of the dropwise addition, stirring was continued for 10min. After stirring, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

Dissolving the final dried product in 150mL of 0.9% (w/v) NaCl aqueous solution, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution to a constant volume of 200mL, filtering and sterilizing with 0.22um, packaging, sealing, and preparing to obtain the final product with the specification of 2mL:20mg of derivative A was injected (formulation A2).

2.3 derivatives B formulation 1

Referring to the above preparation of derivative a, formulation 1, except that derivative B was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative B injection (formulation B1).

2.4 derivatives B formulation 2

Referring to the above preparation of derivative a, formulation 2, except that derivative B was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative B injection (formulation B2).

2.5 derivatives C formulation 1

Referring to the above preparation of derivative a, formulation 1, except that derivative C was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative C injection (formulation C1).

2.6 derivatives C formulation 2

Referring to the above preparation of derivative a, formulation 2, except that derivative C was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative C injection (formulation C2).

2.7 derivatives D formulation 1

Referring to the above preparation of derivative a, formulation 1, except that derivative D was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative D was injected (formulation D1).

2.8 derivatives D formulation 2

Referring to the above preparation of derivative a, formulation 2, except that derivative D was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative D injection (formulation D2).

2.9 derivatives E formulation 1

Referring to the above preparation of derivative a, formulation 1, except that derivative E was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative E injection (formulation E1).

2.10 derivatives E formulation 2

Referring to the above preparation of derivative a, formulation 2, except that derivative E was used instead of derivative a, a 2mL specification was prepared: 20mg of derivative E injection (formulation E2).

2.11 derivatives F formulation 1

2g of derivative F was taken and dissolved completely in 200mL of chloroform for further use. 150g of sulfobutyl ether-beta-cyclodextrin is taken, 350mL of water for injection is added, and the mixture is heated to 45 ℃ to be completely dissolved for later use.

Keeping the temperature at 45 ℃, dropwise adding the derivative F solution into the sulfobutyl ether-beta-cyclodextrin solution at the speed of 5mL/min while stirring, and continuously stirring for 5min after dropwise adding. After the completion of the dropwise addition, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

And finally, adding 0.9% (w/v) NaCl aqueous solution into the dried product for dissolving, fixing the volume to 200mL, filtering and sterilizing 0.22um, subpackaging and sealing to prepare the solution with the specification of 2mL:20mg of derivative F injection (formulation F1).

2.12 derivatives F formulation 2

2g of derivative F was completely dissolved in 200mL of a chloroform-ethanol mixture (volume ratio: 75. Taking 50g of L-arginine, adding 450mL of water for injection, and completely dissolving for later use.

At room temperature, the derivative F solution was added dropwise to the arginine solution at a rate of 5mL/min, followed by stirring, and after completion of the dropwise addition, stirring was continued for 15min. After stirring, the sample was dried in a rotary evaporator under a vacuum of 0.05MPA at 100 ℃ under reduced pressure, the solvent was recovered, and the dried product was dissolved in 200mL of water for injection and then dried by rotary evaporation under a vacuum of 0.05MPA at 100 ℃.

Dissolving the final dried product in 150mL of 0.9% (w/v) NaCl aqueous solution, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% (w/v) NaCl aqueous solution to a constant volume of 200mL, filtering and sterilizing with 0.22um, packaging, sealing, and preparing to obtain the final product with the specification of 2mL:20mg of derivative F injection (formulation F2).

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-beta-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 and administered by injection using formulations 1-4 of example 2. The grouping situation is as follows;

a blank control group (intravenous 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 qiday group), a formula 2 january group (formula 2 is changed, the rest is the same as the formula 1 january group), a formula 3 january group (formula 3 is changed, the rest is the same as the formula 1 qiday group), a formula 3 january group (formula 3 is changed, the rest is the same as the formula 1 january group), a formula 4 january group (formula 4 is changed, the rest is the same as the formula 1 qiday group), and a formula 4 january group (formula 4 is changed, the rest is the same as the formula 1 january group).

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 result shows that the phillyrin/phillygenin injection liquid taking sulfobutyl ether-beta-cyclodextrin as an auxiliary material has good safety in a normal medication period (usually 3 days, not more than 7 days), but if the phillyrin/phillygenin injection liquid is continuously taken for a long time in an excessive amount, certain renal toxicity occurs; the forsythin/forsythiaside injection liquid taking arginine as an auxiliary material has good safety, and no renal toxicity occurs no matter the forsythin/forsythiaside injection liquid is used for a short time or is used for a long time continuously.

Example 5 powder injection of phillyrin/phillygenin and its derivatives

The injection liquid of the formulas 1 to 5 in the embodiment 2 and the formulas A1, A2, B1, B2, C1, C2, D1, D2, E1, E2, F1 and F2 in the embodiment 3 are respectively filtered, sterilized, subpackaged in penicillin bottles with 2ml of each bottle, freeze-dried, capped and sealed to prepare 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 formulations 3 to 5 of example 2 and formulations A2, B2, C2, D2, E2 and F2 of example 3 are also suitable for preparing a needleless powder injection, whereas the lyophilized powder injections of formulations 1 to 2 of example 2 and formulations A1, B1, C1, D1, E1 and F1 of example 3 are difficult to effectively penetrate the epidermis and are not suitable for preparing a needleless powder injection.

Taking the freeze-dried powder injection of the formulas 3-5 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 has no water drop), sieving the wet powder injection with a 20-mesh sieve for granulation, tabletting the granules by a tabletting machine, crushing the granules, sieving the granules with a 120-mesh sieve, collecting the powder which passes through the sieve, sieving the granules with a 400-mesh sieve, and collecting the powder which does not pass through the sieve, thereby preparing the needleless powder injection of each formula.

Peeling the whole skin of the inner side of the pig leg to obtain pig skin; and (3) adding 30g of gelatin into distilled water, heating to dissolve, fixing the volume to 100mL, and placing in a square container for solidification to obtain the imitation human skin. The needleless powder injection with the formulas 3-5 are respectively filled into a powder injector of the powder injector, respectively carrying out pressurized injection on the pigskin and the imitation human skin under the pressure of 4MPa, then, different depths of each skin were sampled, and phillyrin was detected by HPLC, and the maximum depths of phillyrin were as shown in Table 4.

TABLE 4 maximum depth of injection for needleless powder injections of the present invention

The results show that the powder injection without needle of formulations 3 to 5 of example 2 and formulations A2, B2, C2, D2, E2 and F2 of example 3 are expected to be delivered through human epidermis about 0.1mm thick into dermal capillaries, thereby allowing the needleless injection administration of phillyrin/phillygenin and its derivatives.

Claims (6)

1. The forsythin/forsythiaside needle-free powder injection comprises forsythin and forsythiaside, and also comprises auxiliary materials safe for children injection, and is prepared by the method comprising the following steps:

taking 2g of forsythin/forsythiaside composition B, wherein the forsythin/forsythiaside composition B consists of forsythin and forsythiaside, and the weight ratio of the forsythiaside to the forsythiaside is 90:10, mixing the raw materials in a volume ratio of 70: 250mL of 30 acetonitrile-ethanol mixed solution is completely dissolved for later use; taking 50g of L-arginine, adding 450mL of water for injection, and completely dissolving for later use;

dripping the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min at room temperature while stirring, and continuing to stir for 15min after dripping; after stirring, loading the sample into a rotary evaporator, drying under reduced pressure at the vacuum degree of 0.04MPA and the temperature of 100 ℃, recovering the solvent, adding 200mL of water for injection into the dried product, dissolving, and repeatedly performing rotary evaporation drying at the vacuum degree of 0.04MPA and the temperature of 100 ℃;

dissolving the final dried product with 0.9% w/v NaCl aqueous solution 150mL, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% w/v NaCl aqueous solution to constant volume of 200mL, filtering with 0.22um for sterilization, packaging into penicillin bottles with 2mL each, freeze drying, capping and sealing to obtain lyophilized powder for injection;

wetting the freeze-dried powder injection with a proper amount of water for injection, sieving with a 20-mesh sieve for granulation, tabletting with a tabletting machine, then crushing, sieving with a 120-mesh sieve, collecting powder passing through the sieve, sieving with a 400-mesh sieve, collecting powder not passing through the sieve, and thus obtaining the needleless powder injection.

2. A method of preparing a needleless powder injection as in claim 1 which comprises the steps of:

taking 2g of forsythin/forsythiaside composition B, wherein the forsythin/forsythiaside composition B consists of forsythin and forsythiaside, and the weight ratio of the forsythiaside to the forsythiaside is 90:10, mixing the components in a volume ratio of 70: 250mL of 30 acetonitrile-ethanol mixed solution is completely dissolved for later use; taking 50g of L-arginine, adding 450mL of water for injection, and completely dissolving for later use;

dripping the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min at room temperature while stirring, and continuing to stir for 15min after dripping; after stirring, loading the sample into a rotary evaporator, drying under reduced pressure at the vacuum degree of 0.04MPA and the temperature of 100 ℃, recovering the solvent, adding 200mL of water for injection into the dried product, dissolving, and repeatedly drying by rotary evaporation at the vacuum degree of 0.04MPA and the temperature of 100 ℃;

dissolving the final dried product with 0.9% w/v NaCl aqueous solution 150mL, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% w/v NaCl aqueous solution to constant volume of 200mL, filtering with 0.22um for sterilization, packaging into penicillin bottles with 2mL each, freeze drying, capping and sealing to obtain lyophilized powder for injection;

wetting the freeze-dried powder injection with a proper amount of water for injection, sieving with a 20-mesh sieve for granulation, tabletting with a tabletting machine, then crushing, sieving with a 120-mesh sieve, collecting powder passing through the sieve, sieving with a 400-mesh sieve, collecting powder not passing through the sieve, and thus obtaining the needleless powder injection.

3. The forsythin/forsythiaside needleless powder injection comprises forsythin and forsythiaside, and also comprises auxiliary materials safe for children injection administration, and is prepared by the method comprising the following steps:

taking 2g of forsythin/forsythiaside composition A, wherein the forsythin/forsythiaside composition A consists of forsythin and forsythiaside, and the weight ratio of the forsythiaside to the forsythiaside is 98:2, mixing the components in a volume ratio of 75: dissolving 200mL of 25 acetonitrile-ethanol mixed solution completely for later use; taking 60g of L-arginine, adding 340mL of water for injection, heating to 35 ℃ and completely dissolving for later use;

keeping the temperature at 35 ℃, dropwise adding the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min, stirring while dropwise adding, and continuously stirring for 10min after dropwise adding; after stirring, loading the sample into a rotary evaporator, drying under reduced pressure at the vacuum degree of 0.05MPA and the temperature of 100 ℃, recovering the solvent, adding 80mL of injection water into the dried product, dissolving, and repeatedly drying by rotary evaporation at the vacuum degree of 0.05MPA and the temperature of 100 ℃;

dissolving the final dried product in 50mL of 0.9 w/v NaCl aqueous solution, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9 w/v NaCl aqueous solution to constant volume, filtering and sterilizing at 0.22um, packaging into penicillin bottles with 2mL each, freeze drying, capping and sealing to obtain lyophilized powder for injection;

wetting the freeze-dried powder injection with a proper amount of water for injection, sieving with a 20-mesh sieve for granulation, tabletting with a tabletting machine, crushing, sieving with a 120-mesh sieve, collecting the powder which passes through the sieve, sieving with a 400-mesh sieve, and collecting the powder which is not sieved, thereby preparing the needleless powder injection.

4. A method of preparing the needleless powder injection of claim 3 comprising the steps of:

taking 2g of forsythin/forsythiaside composition A, wherein the forsythin/forsythiaside composition A consists of forsythin and forsythiaside, and the weight ratio of the forsythiaside to the forsythiaside is 98:2, mixing the components in a volume ratio of 75: completely dissolving 200mL of 25 acetonitrile-ethanol mixed solution for later use; taking 60g of L-arginine, adding 340mL of water for injection, heating to 35 ℃ and completely dissolving for later use;

keeping the temperature at 35 ℃, dropwise adding the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min, stirring while dropwise adding, and continuously stirring for 10min after dropwise adding; after stirring, loading the sample into a rotary evaporator, drying under reduced pressure at the vacuum degree of 0.05MPA and the temperature of 100 ℃, recovering the solvent, adding 80mL of water for injection into the dried product, dissolving, and repeatedly performing rotary evaporation drying at the vacuum degree of 0.05MPA and the temperature of 100 ℃;

dissolving the final dried product in 50mL of 0.9 w/v NaCl aqueous solution, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9 w/v NaCl aqueous solution to constant volume, filtering and sterilizing at 0.22um, packaging into penicillin bottles with 2mL each, freeze drying, capping and sealing to obtain lyophilized powder for injection;

wetting the freeze-dried powder injection with a proper amount of water for injection, sieving with a 20-mesh sieve for granulation, tabletting with a tabletting machine, crushing, sieving with a 120-mesh sieve, collecting the powder which passes through the sieve, sieving with a 400-mesh sieve, and collecting the powder which is not sieved, thereby preparing the needleless powder injection.

5. The forsythin/forsythiaside needleless powder injection comprises forsythin and forsythiaside, and also comprises auxiliary materials safe for children injection administration, and is prepared by the method comprising the following steps:

taking 2g of forsythin/forsythiaside composition B, wherein the forsythin/forsythiaside composition B consists of forsythin and forsythiaside, and the weight ratio of the forsythiaside to the forsythiaside is 90:10, completely dissolving the mixture by using 150mL of acetonitrile for later use; taking 40g of L-arginine, adding 360mL of water for injection, and completely dissolving for later use;

dripping the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min at room temperature while stirring; after the dropwise addition is finished, loading the sample into a rotary evaporator, drying under reduced pressure at the vacuum degree of 0.04MPA and the temperature of 100 ℃, recovering the solvent, adding 200mL of injection water into the dried product, dissolving, and then repeatedly drying by rotary evaporation at the vacuum degree of 0.04MPA and the temperature of 100 ℃;

dissolving the final dried product with 0.9% w/v NaCl aqueous solution 150mL, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% w/v NaCl aqueous solution to constant volume of 200mL, filtering with 0.22um for sterilization, packaging into penicillin bottles with 2mL each, freeze drying, capping and sealing to obtain lyophilized powder for injection;

wetting the freeze-dried powder injection with a proper amount of water for injection, sieving with a 20-mesh sieve for granulation, tabletting with a tabletting machine, crushing, sieving with a 120-mesh sieve, collecting the powder which passes through the sieve, sieving with a 400-mesh sieve, and collecting the powder which is not sieved, thereby preparing the needleless powder injection.

6. A process for preparing the needleless powder injection of claim 5 which comprises the steps of:

taking 2g of forsythin/forsythiaside composition B, wherein the forsythin/forsythiaside composition B consists of forsythin and forsythiaside, and the weight ratio of the forsythiaside to the forsythiaside is 90:10, completely dissolving the mixture by using 150mL of acetonitrile for later use; taking 40g of L-arginine, adding 360mL of water for injection, and completely dissolving for later use;

dripping the phillyrin/phillygenin composition solution into the arginine solution at the speed of 5mL/min at room temperature while stirring; after the dropwise addition is finished, the sample is loaded on a rotary evaporator and dried under the vacuum degree of 0.04MPA and the temperature of 100 ℃ under reduced pressure, the solvent is recovered, and the dried product is dissolved by adding 200mL of water for injection and then is dried by rotary evaporation under the vacuum degree of 0.04MPA and the temperature of 100 ℃ repeatedly;

dissolving the final dried product with 0.9% w/v NaCl aqueous solution 150mL, adjusting pH to 7.2 with 5N hydrochloric acid solution, adding 0.9% w/v NaCl aqueous solution to constant volume of 200mL, filtering with 0.22um for sterilization, packaging into penicillin bottles with 2mL each, freeze drying, capping and sealing to obtain lyophilized powder for injection;

wetting the freeze-dried powder injection with a proper amount of water for injection, sieving with a 20-mesh sieve for granulation, tabletting with a tabletting machine, crushing, sieving with a 120-mesh sieve, collecting the powder which passes through the sieve, sieving with a 400-mesh sieve, and collecting the powder which is not sieved, thereby preparing the needleless powder injection.

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