CN1176656C - Freeze-drying composition for injection - Google Patents

Abstract

The present invention provides a freeze drying composition of the extract of ginkgo leaves and dipyridamole and a preparing method thereof. The freeze drying composition has better solubility and better stability and is suitable to be used as safe and stable injection.

Description

The injection freeze-dried composition

Technical field

The present invention relates to a kind of freeze-drying medicinal composition, specifically, relate to injection freeze-drying medicinal composition that contains Semen Ginkgo and dipyridamole and preparation method thereof.

Background technology

Modern pharmacological research shows that Semen Ginkgo and effective ingredient thereof have pharmacological action widely, has blood fat reducing, atherosclerosis, improves effect (Zhuo Bin etc., Chinese Pharmaceutical 11 phases of calendar year 2001: 67-69 page or leaf such as microcirculation in heart and brain; Tang Ling etc., China's medical science the 3rd phase of calendar year 2001).Simultaneously, people have also carried out deep research to the coupling of Folium Ginkgo extract and other active substances, and obtained certain progress (for example, woods Jinhua etc., the time precious traditional Chinese medical science traditional Chinese medicines the 9th phase of calendar year 2001; With CN1262103A etc.).Wherein especially it should be noted that the coupling (Zheng Chunhui of Semen Ginkgo and dipyridamole, modern diagnosis and 2002 02 phases of treatment: 72 pages), zoopery shows, Folium Ginkgo extract has slight dilating effect to tremulous pulse, and can reduce erythrocyte aggregation, antiplatelet aggregation, reduce whole blood viscosity, increase erythrocyte deformability, increase cell wall elasticity, thereby improve the perfusion of ischemic tissue.Dipyridamole (dipyridamole) has the effect of definite coronary artery dilator and anticoagulant.Clinical experiment shows that the associating of two medicines can strengthen its dilating coronary blood vessel and anticoagulant, the effect of blood viscosity lowering.

At present, the Folium Ginkgo extract of standard is the Egb761 (DE2117429A) by German Schwabe patent explained hereafter in the world, wherein mainly contain flavone compound and terpene lactone, comprise organic acid, alkyl phenol and alkyl phenolic acid, steroidal compounds and trace element etc. in addition.Big quantity research confirms that even EGb761 is further purified again, its pharmacological effect also can not get improving.Therefore, ginkgo leaf extract preparation mainly adopts the EGb761 standard.Like this, the complicated chemical composition of Folium Ginkgo extract has brought certain difficult problem for the preparation and the quality control of injection preparation, and for example, wherein terpene lactone composition bilobalide (ginkgolide) A, B belong to diterpenes diterpenoids lactones, and itself is difficult to water-soluble; Bilobalide (biobalide) belongs to sesquiterpene lactones, its structure less stable decomposes in aqueous solution easily, is difficult to cyclization again after adding alkali open ring, this is (Xie Peishan, 1999 01 phase of CHINA JOURNAL OF CHINESE MATERIA MEDICA: the 3-5 page or leaf) of the unsettled reason of content in different product; Impurity (the gingkolic acid constituents that sensitization for example, is arranged) level is high excessively.For this reason, formulation specialist has been carried out certain improvement, for example, adds specific solvent (for example CN1298738A) in injection, and bilobalide is made sodium salt (for example CN1315175A) etc.Yet all there are some quality problems in conventional Semen Ginkgo extrac injection in varying degrees, and for example not good, the solvent of stability is to patient's zest with side effect is big, color and luster easily changes etc.In addition, in order to solve the not good shortcoming of light durability, commercially available Ginkgo Leaf Extract and Dipyridamole Injection (little aqueous injection) adopts brown peace bottle to pack, and this is unfavorable for the visual examination control of product quality; In order to solve the shortcoming of principal agent poor solubility, also added about 5% ethanol.

To those skilled in the art, when Semen Ginkgo and dipyridamole coupling, other quality problems of its compound preparation (especially injection preparation) are difficult to especially expect, and also do not find the clearly instruction of relevant solution in the prior art.

Therefore, this area is starved of Semen Ginkgo and dipyridamole made and has good stability and deliquescent compound injection pharmaceutical composition.

Summary of the invention

We have carried out deep research to pharmaceutical technology, and the final employing freeze drying process of finding can address the above problem effectively, and the present invention has promptly been finished in further research on this basis.

An object of the present invention is to provide the ginkgo Damo freeze-drying compositions that contains surfactant.Studies show that the ginkgo Damo freeze-drying preparation that does not contain surfactant is when medicinal diluent (especially water) dilutes, freeze-dried powder is insoluble substantially.The inventor is surprised to find, in Semen Ginkgo and dipyridamole, add surfactant, can make stable freeze-dried products (to call the ginkgo Damo freeze-drying compositions in the following text) through lyophilization, add medicinal aqueous diluent in use, can promote active component dissolving and be reconstructed into settled solution rapidly.In addition, do not contain medicinal organic solvent in the present composition, therefore avoided irritative response.

Being suitable for surfactant of the present invention comprises but is not limited to: the mixed system that tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvinylpyrrolidone, poloxamer (poloxamer) and their are formed.Be preferably polyvinylpyrrolidone, poloxamer or their mixed system.Be understandable that those of ordinary skills can determine suitable kinds of surfactants and consumption thereof by normal experiment, to guarantee obtaining clear solutions after the reconstruction.

Advantageously, also can add medicinal freeze drying excipient in the pharmaceutical composition of the present invention.Preferably, described excipient is selected from mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, xylitol, lactose and their mixture, is preferably mannitol.Randomly, also can add stabilizing agent, for example nicotiamide in the lyophilized formulations of the present invention.

In one embodiment of the invention, the parts by weight of described various compositions, proportioning is as follows: Folium Ginkgo extract 1.0-3.0, dipyridamole 0.18-0.22, surfactant 1-10.

In a preferred embodiment of the invention, the parts by weight of described various compositions, proportioning is as follows: Folium Ginkgo extract 1.0-3.0, dipyridamole 0.18-0.22, surfactant 1-10, stabilizing agent 0-5, freeze-dried excipient 10-20.

Another object of the present invention provides the above-mentioned ginkgo Damo freeze-drying method for compositions of preparation, comprising following steps:

(1) fully stirring splashes into sodium hydroxide solution in the Folium Ginkgo extract down, after waiting to dissolve, adds surfactant, and regulates pH value;

(2) fully stirring splashes into hydrochloric acid in the dipyridamole down, after waiting to dissolve, successively adds stabilizing agent and other surfactants, and regulates pH value;

(3) under agitation, gained drips of solution in the step (2) is added in step (1) the gained solution, add freeze-dried excipient solution then through charcoal treatment, replenish water for injection, again under 50-60 ℃ of condition, add proper amount of active carbon, stirred about 15 minutes, and used 0.8um microporous filter membrane coarse filtration while hot, reuse 0.2um microporous filter membrane fine straining, gained filtrate is replenished an amount of water for injection, and the adjusting pH value, be divided in the cillin bottle every bottle of 2.0ml then, deliver to lyophilization in the freeze drying box, tamponade adds aluminium lid in case.

The last pH value of the Injectable compound preparation that said method makes is 5.0-7.5.

Those skilled in the art can adjust the freeze dried cycle according to the demand of clinical preparation and concrete production equipment.Usually, uniform preparation can be placed the cillin bottle of 5ml to 40ml, pre-freeze temperature-20 ℃ is preferably-40 ℃ to-50 ℃ to-60 ℃, 1 hour to 8 hours pre-freeze time, is preferably 2-4 hour.Freeze temperature-10 ℃ is preferably-15 ℃ to-20 ℃ to-30 ℃, and freeze-drying time 10 hours to 40 hours is preferably 25 hours to 35 hours.The final moisture content of freeze-dried composition generally is lower than 5%, is preferably 1% to 3%.

Ginkgo Damo freeze-drying compositions of the present invention is particularly suitable for using clinically.Before use, can add an amount of aseptic medicinal aqueous diluent (for example, water for injection, normal saline, G/W and other known aqueous carriers), be reconstructed into pharmaceutical solutions for intramuscular injection or intravenous drip (intravenous administration) usefulness.

Following examples are intended to further specify the present invention, scope of the present invention are not limited.

Embodiment 1: preparation contains the lyophilized formulations of surfactant

Prescription:

Folium Ginkgo extract 2.0g

Dipyridamole 0.2g

Mannitol 15g

Poloxamer 3g

Nicotiamide 2.5g

Polyvinylpyrrolidone 2g

Technology:

(1) fully stirring splashes into sodium hydroxide solution in the Folium Ginkgo extract down, after waiting to dissolve, adds poloxamer, regulates pH value to 5.4;

(2) fully stirring splashes into hydrochloric acid in the dipyridamole down, after waiting to dissolve, successively adds nicotiamide, polyvinylpyrrolidone, regulates pH value to 5.7;

(3) under agitation, step (2) gained drips of solution is added in step (1) the gained solution, add the mannitol solution that charcoal treatment is crossed then, replenish water for injection, again under 50-60 ℃ of condition, add proper amount of active carbon, stirred about 15 minutes, and used 0.8 μ m microporous filter membrane coarse filtration while hot, reuse 0.2 μ m microporous filter membrane fine straining, gained filtrate is replenished an amount of water for injection, after being transferred to proper pH value, be divided in the cillin bottle every bottle of 2.0ml, deliver to lyophilization in the freeze drying box, tamponade adds aluminium lid in case.

Reference example 1: preparation does not contain the lyophilized formulations of surfactant

Prepare lyophilized formulations by embodiment 1 prescription and method, but wherein do not contain surfactant, for following comparative experiments.

Comparing embodiment 1

The lyophilized formulations (sample B) that does not contain surfactant prepares lyophilized formulations (sample A) relatively with embodiment 1 prescription and method, adopting water for injection is that diluent is rebuild solution, the settled solution that sample A in jolting is in 5 seconds is, and sample B jolting still can't obtain qualified settled solution more than 5 minutes.The two significant difference.

In addition, under same experimental conditions, also the content to Ginkgo total flavones in lyophilized formulations of the present invention and the injection formulation compares, and the result is as follows:

In stage on-test, Ginkgo total flavones is 4.413mg in the lyophilized formulations, and Ginkgo total flavones is 4.647mg in the injection; Behind 80 ℃, 50 hours of the high temperature, lyophilized formulations is 3.985mg (descending 9.7%), and injection is 3.018mg (descending 35.1%); High light (illumination is 4500LX) is after 50 hours, and lyophilized formulations is 4.194mg (descending 5.0%), and injection is 3.936mg (descending 15.3%).This shows that the stability of lyophilized formulations of the present invention (adopting colourless transparent glass cillin bottle packing) significantly is better than injection solution (adopting brown glass peace bottle packing).

Above result shows: lyophilized formulations of the present invention adds can rebuild rapidly behind the water and obtains supernatant liquid; Under same experimental conditions, the stability of lyophilized formulations significantly is better than injection solution.This fine solubility and stability characteristic have not only guaranteed clinical application safety, the also corresponding effect duration that prolongs the ginkgo bilobate extract compound preparation.

Claims (6)

1, a kind of freeze-drying medicinal composition, comprising the component of following parts by weight, its proportioning is:

Folium Ginkgo extract 1.0-3.0

Dipyridamole 0.18-0.22

Surfactant 1-10.

2, compositions as claimed in claim 1, wherein surfactant is selected from the mixed system of tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvinylpyrrolidone, poloxamer and their compositions.

3, compositions as claimed in claim 1, wherein surfactant is selected from the mixed system of polyvinylpyrrolidone, poloxamer and their compositions.

4, as the compositions of claim 2 or 3, also comprise stabilizing agent and freeze-dried excipient.

5, compositions as claimed in claim 4, comprising the component of following parts by weight, its proportioning is:

Folium Ginkgo extract 1.0-3.0

Dipyridamole 0.18-0.22

Surfactant 1-10

Stabilizing agent 0-5

Freeze-dried excipient 10-20.

6, compositions as claimed in claim 5 is the injection freeze-dried products.