CN105726464B - A kind of slow-releasing gel used preparation method of test article for pharmacological research of Shexiang Baoxin Pills - Google Patents
A kind of slow-releasing gel used preparation method of test article for pharmacological research of Shexiang Baoxin Pills Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, are related to a kind of slow-releasing gel used preparation method of test article for pharmacological research of Shexiang Baoxin Pills.It is slow-releasing gel used that the present invention provides a kind of Shexiang Baoxin Pills, by weight percentage, including following components: Shexiang Baoxin Pills powder 0.1-30%;Gel-type vehicle agent 0.9-30%;Solvent 40-99%.The present invention further provides the slow-releasing gel used preparation method of Shexiang Baoxin Pills and its purposes in the drug that preparation promotes angiogenesis.The present invention furthermore provides the purposes in the drug of the slow-releasing gel used Ex vivo animal model for carrying out Shexiang Baoxin Pills treatment angiogenesis Mechanism Study in preparation of Shexiang Baoxin Pills.The slow-releasing gel used preparation method of test article for pharmacological research of a kind of Shexiang Baoxin Pills provided by the invention, sustained release drug can be stablized, so that drug is played the effect for promoting Therapeutic Angiogenesis to greatest extent, new dosage form is provided for Shexiang Baoxin Pills pharmacological research.
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to a kind of Shexiang Baoxin Pills it is slow-releasing gel used for pharmacological research for examination
Product preparation method, and in particular to it is a kind of for local administration using compound Chinese medicinal preparation Shexiang Baoxin Pills as the sustained-release gel of main ingredient
Agent and preparation method thereof.
Background technique
" Shexiang Baoxin Pills " are the exclusive products of Hehuang Pharmaceutical Co., Ltd., Shanghai, for clinically for treat myocardial infarction,
Anginal compound Chinese medicinal preparation caused by the thoracic obstruction of caused by energy stagnation and blood stasis, myocardial ischemia, the treatment for clinical coronary heart disease are made
Major contribution." Shexiang Baoxin Pills " have carried out a series of modernization of cmm, including material base and effect from after listing
Mechanism study, modern pharmacological research, post-marketing clinical study etc..
" Shexiang Baoxin Pills " prescription is by muscone, ginseng extract, storax, calculus bovis factitius, cortex cinnamomi, the dried venom of toads and borneol
Seven flavor medicine composition.Modern pharmacological research tentatively shows that " Shexiang Baoxin Pills " have coronary artery dilator, protection blood vessel endothelium, promote
Into Therapeutic angiogenesis, inhibit four pharmacological action features outstanding such as vessel wall inflammation.Clinical research shows to take for a long time
" Shexiang Baoxin Pills " can be with serious painstaking effort such as Global Macros blood vessel, the attack times of reduction coronary disease and angina pectoris and myocardial infarctions
It runs affairs the incidence of part.In body the study found that " Shexiang Baoxin Pills " can make experimental myocardial infarction rat myocardial infarction model area bright
It is aobvious to reduce, while promoting the proliferation of microvascular endothelial cells of heart and forming luminal structure, increase myocardial vascular density, and it promotees
Into between angiogenesis function and dosage, there are dose-effect relationships.After " Shexiang Baoxin Pills " medication 6 months, patients with coronary heart disease heart muscle perfusion
Imaging display: myocardial metabolism improves, and ischemic areas is reduced." Shexiang Baoxin Pills " promote the mechanism of angiogenesis that may can promote with it
Keep endothelial cell related to the expression of VEGF with bFGF gene.
Modern studies have found that the Chinese medicine of certain treatment coronary heart disease has the function of certain promotion angiogenesis.Blood vessel is raw
At human body can be helped to establish effective Doppler flow mapping, fundamentally alleviate myocardial ischemia symptom, improve the state of an illness, coronary heart disease,
It is of great significance in treatment, recovery and the prognosis of the ischemic diseases such as ischemic cerebral embolism." Shexiang Baoxin Pills " are preced in treatment
There is extraordinary clinical efficacy, major function is clear, and still " Shexiang Baoxin Pills " promote the drug effect of angiogenesis in terms of heart trouble
Material base and the mechanism of action are not very clear.
There are many Ex vivo animal models of the Therapeutic angiogenesis Mechanism Study of " Shexiang Baoxin Pills ", such as sponge
(sponge) it is implanted into animal model, establishes angiogenesis model caused by inflammation after back of mice is implanted into sponge (sponge).
But sponge (sponge) implantation animal model on, need by be implanted to back of mice sponge (sponge) part to
The effect for giving " Shexiang Baoxin Pills " to study drug to angiogenesis.Currently, " Shexiang Baoxin Pills " clinical application is particle pill,
It is oral, three times a day, it cannot achieve the local administration on the animal model.Therefore this patent develops a kind of delaying for Shexiang Baoxin Pills
Gelling agent is released, carries out the research for the treatment of angiogenesis function on model in animal body for carrying out " Shexiang Baoxin Pills ".
Summary of the invention
Shexiang Baoxin Pills clinical application is particle pill, oral administration.Due to being implanted into animal model at sponge (sponge)
On to verify Shexiang Baoxin Pills for the effect for the angiogenesis being partially formed, if being administered orally if cannot be by medicine
Object transports local organization.In view of the limitation of existing dosage form described above, the purpose of the present invention is to provide a kind of Moschus guarantors
The slow-releasing gel used preparation method of test article for pharmacological research of heart ball, drug is embedded in gel, active medicine is being spread
It under double action with gel auto-degradation, is slowly released inside gel, reduces administration number of times, it is dense to improve topical remedy
Degree, has widened administration route.The still not no report about Shexiang Baoxin Pills sustained-release gel both at home and abroad at present, the invention patent gel
Preparation method simple and stable provides new dosage form for " Shexiang Baoxin Pills " pharmacological research.
In order to achieve the above objects and other related objects, it is slow-releasing gel used to provide a kind of Shexiang Baoxin Pills by the present invention, by weight
Measure percentages, including following components:
Shexiang Baoxin Pills powder 0.1-30%;
Gel-type vehicle agent 0.9-30%;
Solvent 40-99%.
Preferably, the Shexiang Baoxin Pills are slow-releasing gel used, by weight percentage, including following components:
Shexiang Baoxin Pills powder 5-26%;
Gel-type vehicle agent 15-30%;
Solvent 44-75%.
Preferably, the Shexiang Baoxin Pills powder is the commercially available Shexiang Baoxin Pills of Hehuang Pharmaceutical Co., Ltd., Shanghai, through grinding
Solid fines after alms bowl grinding.
Preferably, the gel-type vehicle agent is poly- selected from poly-dl-lactide (DL-PLA), l-lactic acid (PLLA), dextrorotation
One of lactic acid (PDLA), poly(lactide-co-glycolic acid) copolymer (PLGA) or a variety of mixing.The l-lactic acid
(PLLA) and dextrorotation polylactic acid (PDLA) is isomer.
Wherein, No. CAS of poly-dl-lactide (DL-PLA) is 26100-51-6, poly(lactide-co-glycolic acid) copolymer
(PLGA) No. CAS is 26780-50-7, and No. CAS of l-lactic acid (PLLA) is 33135-50-1, dextrorotation polylactic acid
(PDLA) No. CAS is 25038-75-9.
It is highly preferred that the poly-dl-lactide is selected from ester sealing end poly-dl-lactide (OH-DL-PLA-COOR), end hydroxyl
One of base poly-dl-lactide (OH-DL-PLA-OH), carboxyl end group poly-dl-lactide (OH-DL-PLA-COOH) are a variety of
Mixing.
It is highly preferred that the l-lactic acid is left-handed selected from ester sealing end l-lactic acid (OH-PLLA-COOR), terminal hydroxy group
One of polylactic acid (OH-PLLA-OH), carboxyl end group l-lactic acid (OH-PLLA-COOH) or a variety of mixing.
It is highly preferred that the dextrorotation polylactic acid, which is selected from ester, blocks dextrorotation polylactic acid (OH-PDLA-COOR), terminal hydroxy group dextrorotation
One of polylactic acid (OH-PDLA-OH), carboxyl end group dextrorotation polylactic acid (OH-PDLA-COOH) or a variety of mixing.
It is highly preferred that the poly(lactide-co-glycolic acid) copolymer (PLGA), which is selected from ester, blocks poly (lactic acid-glycolic acid)
Copolymer (OH-PLGA-COOR), terminal hydroxy group poly(lactide-co-glycolic acid) copolymer (OH-PLGA-OH), the poly- (lactic acid-of carboxyl end group
Hydroxyacetic acid) one of copolymer (OH-PLGA-COOH) or a variety of mixing.
Ester sealing end polylactic acid in above-mentioned difference polylactic acid refers to that the c-terminus in polylactic acid structure is esterified;Terminal hydroxy group is poly-
Lactic acid, which refers to, free hydroxyl in polylactic acid structure;There is free carboxyl in carboxyl end group polylactic acid.With above-mentioned different structure
Polylactic acid there is no difference in physical property, it is only variant in structure, as gel-type vehicle agent and indistinction.
Preferably, the weight average molecular weight of the gel-type vehicle agent is 3000-10 ten thousand, it is highly preferred that the gel-type vehicle agent
Weight average molecular weight be 6000-2 ten thousand.
Preferably, the solvent is selected from N-Methyl pyrrolidone (N-methyl pyrrolidone), dimethyl sulfoxide
Or one of N-Methyl pyrrolidone (N-methyl pyrrolidone), dimethyl sulfoxide (DMSO) one of (DMSO)
With one of water, ethyl alcohol, acetone, ethyl acetate, chloroform or a variety of mix.
It is highly preferred that the solvent is selected from one of N-Methyl pyrrolidone, dimethyl sulfoxide or N- crassitude
The mixing of one of ketone, dimethyl sulfoxide and water.
Preferably, the weight ratio between the Shexiang Baoxin Pills powder and gel-type vehicle agent is 1:0.1~10.
It is highly preferred that the weight ratio between the Shexiang Baoxin Pills powder and gel-type vehicle agent is 1:1~3.
The present invention further provides a kind of preparation methods that Shexiang Baoxin Pills are slow-releasing gel used, according to the ratio by Shexiang Baoxin Pills
Powder is mixed with gel-type vehicle agent, and solvent is added after vortex oscillation, and ultrasonic extraction is slow-releasing gel used to get Shexiang Baoxin Pills.
The slow-releasing gel used Shexiang Baoxin Pills are transparent semi-solid brown formulations.
Preferably, the Shexiang Baoxin Pills powder is the solid fines by Shexiang Baoxin Pills after mortar grinder.
Preferably, 120 mesh of fineness < of the Shexiang Baoxin Pills powder.
Preferably, the condition of the vortex oscillation are as follows: duration of oscillation: 10-20min;Oscillation rate: 1500-2000rpm;
It vibrates at room temperature.The vortex oscillation is dispersed in Shexiang Baoxin Pills powder particle in gel-type vehicle agent.The room temperature
It is 20-25 DEG C.
Preferably, the condition of the ultrasonic extraction are as follows: extraction time is 5-10 hours;Extracting temperature is 20-30 DEG C;It extracts
Power is 200-300W.It is highly preferred that the condition of the ultrasonic extraction are as follows: extraction time is 5-10 hours;Extracting temperature is 25
℃;Extraction power is 240W.
It is slow-releasing gel used in the drug that preparation promotes angiogenesis that the present invention further provides a kind of Shexiang Baoxin Pills
Purposes.
It is slow-releasing gel used in preparation progress Shexiang Baoxin Pills treatment blood that the present invention furthermore provides a kind of Shexiang Baoxin Pills
Purposes in the drug of the Ex vivo animal model of pipe Research on generation mechanism.
Preferably, the Ex vivo animal model is raw for blood vessel caused by implantation sponge (sponge) in animal body afterwards inflammation
At model.
As described above, a kind of slow-releasing gel used test sample preparation side for pharmacological research of Shexiang Baoxin Pills of the invention
Method, the Shexiang Baoxin Pills prepared are slow-releasing gel used, and drug is embedded in gel, can stablize sustained release drug, make medicine
Object can reduce administration number of times within a certain period of time in local tissue sites slow release, improve local drug concentration, widened to
Medicine approach, bioavilability is high, and drug can be made to play the effect for promoting treatment angiogenesis to greatest extent, for animal in vivo
Shexiang Baoxin Pills are carried out on model promotes the research for the treatment of angiogenesis mechanism to provide reliable guarantee.Do not have still both at home and abroad at present
About the report of Shexiang Baoxin Pills sustained-release gel, the invention patent gel process for preparing simple and stable is " Shexiang Baoxin Pills "
Pharmacological research provides new dosage form.
Detailed description of the invention
Fig. 1 is shown as slow-releasing gel used implantation sponge (sponge) in animal body of Shexiang Baoxin Pills of the invention inflammation afterwards
The facilitation schematic diagram that new vessels are generated on caused angiogenesis model.
Fig. 2 is shown as slow-releasing gel used implantation sponge (sponge) in animal body of Shexiang Baoxin Pills of the invention inflammation afterwards
The facilitation schematic diagram that vascular endothelial growth factor VEGF is generated on caused angiogenesis model.
Fig. 3 is shown as slow-releasing gel used implantation sponge (sponge) in animal body of Shexiang Baoxin Pills of the invention inflammation afterwards
The facilitation schematic diagram that vascular endothelial growth factor VEGF mRNA is generated on caused angiogenesis model.
Specific embodiment
The present invention is further explained combined with specific embodiments below, it should be appreciated that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment;It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention;In description of the invention and claims, unless in text
In addition explicitly point out, singular "one", " one " and " this " include plural form.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two ends of each numberical range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, the present invention used in all technologies and
Scientific term is identical as the normally understood meaning of those skilled in the art of the present technique.Except specific method, equipment used in embodiment,
Outside material, grasp and record of the invention according to those skilled in the art to the prior art can also be used and this
Any method, equipment and the material of the similar or equivalent prior art of method described in inventive embodiments, equipment, material come real
The existing present invention.
Unless otherwise stated, disclosed in this invention experimental method, detection method, preparation method be all made of this technology neck
Molecular biology, biochemistry, chromatin Structure and the analysis of domain routine, analytical chemistry, cell culture, recombinant DNA technology and
The routine techniques of related fields.These technologies have perfect explanation in the prior art, and for details, reference can be made to Sambrook etc.
MOLECULAR CLONING:A LABORATORY MANUAL, Second edition, Cold Spring Harbor
Laboratory Press, 1989 and Third edition, 2001;Ausubel etc., CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987 and periodic updates;the
Series METHODS IN ENZYMOLOGY, Academic Press, San Diego;Wolffe, CHROMATIN
STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998;METHODS IN
ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic
Press, San Diego, 1999;With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin
Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc..
Shexiang Baoxin Pills of the present invention are the commercially available Shexiang Baoxin Pills (lot number of Hehuang Pharmaceutical Co., Ltd., Shanghai
150415);Poly-dl-lactide PLA (ester sealing end, terminal hydroxy group, carboxyl end group), l-lactic acid PLLA (ester sealing end, terminal hydroxy group, end
Carboxyl), dextrorotation polylactic acid PDLA (ester sealing end, terminal hydroxy group, carboxyl end group), poly(lactide-co-glycolic acid) copolymer PLGA (ester envelope
End, terminal hydroxy group, carboxyl end group) (Jinan Mount Tai handle of the Big Dipper biology);N-Methyl pyrrolidone (>=99.5%, lark prestige);Dimethyl sulfoxide (>=
99.8%, SIGMA);Ethyl alcohol (>=99.5%, permanent space glass);Acetone (>=99.5%, traditional Chinese medicines);Ethyl acetate (>=99.5%,
Permanent space glass);Chloroform (>=99.5%, An Naiji);Water is self-control pure water.
Embodiment 1
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 45mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Add poly-dl-lactide (PLA) 30mg mixing, at room temperature with
Dimethyl sulfoxide 110mg is added after vortex oscillation makes particle be uniformly dispersed between 15min for the rate of 1750rpm, 25 DEG C, mention
Taking power is to obtain the slow-releasing gel used sample 1# of Shexiang Baoxin Pills ultrasonic extraction 8 hours under 240W.Shexiang Baoxin Pills sustained-release gel
Agent sample 1# is transparent semi-solid brown formulations.In the slow-releasing gel used sample 1# of the Shexiang Baoxin Pills of preparation, percentage by weight
Than meter, Shexiang Baoxin Pills powder is 24.3%, poly-dl-lactide 16.2%, dimethyl sulfoxide 59.5%.
Embodiment 2
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 45mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Add poly-dl-lactide (PLA) 30mg mixing, at room temperature with
N-Methyl pyrrolidone is added after vortex oscillation makes particle be uniformly dispersed between 10-20min in the rate of 1500-2000rpm
102.8mg, 25 DEG C, extract power be 240W under ultrasonic extraction 8 hours, obtain the slow-releasing gel used sample 2# of Shexiang Baoxin Pills.
The slow-releasing gel used sample 2# of Shexiang Baoxin Pills is transparent semi-solid brown formulations.The slow-releasing gel used sample of the Shexiang Baoxin Pills of preparation
In product 2#, by weight percentage, Shexiang Baoxin Pills powder is 25.3%, poly-dl-lactide 16.9%, N- methylpyrrole
Alkanone is 57.8%.
Embodiment 3
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 45mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Add poly-dl-lactide (PLA) 30mg mixing, at room temperature with
The rate of 1500-2000rpm be added after vortex oscillation makes particle be uniformly dispersed between 10-20min dimethyl sulfoxide 55mg and
Water 50mg, 25 DEG C, extract power be 240W under ultrasonic extraction 8 hours, obtain the slow-releasing gel used sample 3# of Shexiang Baoxin Pills.Musk deer
The fragrant slow-releasing gel used sample 3# of heart pill is transparent semi-solid brown formulations.The slow-releasing gel used sample of the Shexiang Baoxin Pills of preparation
In 3#, by weight percentage, Shexiang Baoxin Pills powder be 25.0%, poly-dl-lactide 16.7%, dimethyl sulfoxide and
Water is 58.3%.
Embodiment 4
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 45mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Add poly-dl-lactide (PLA) 30mg mixing, at room temperature with
N-Methyl pyrrolidone is added after vortex oscillation makes particle be uniformly dispersed between 10-20min in the rate of 1500-2000rpm
51.4mg and water 50mg, 25 DEG C, extract power be 240W under ultrasonic extraction 8 hours, obtain Shexiang Baoxin Pills it is slow-releasing gel used
Sample 4#.The slow-releasing gel used sample 4# of Shexiang Baoxin Pills is transparent semi-solid brown formulations.The Shexiang Baoxin Pills of preparation are sustained
In gelling agent sample 4#, by weight percentage, Shexiang Baoxin Pills powder is 25.5%, poly-dl-lactide 17.0%, N-
Methyl pyrrolidone and water are 57.5%.
Embodiment 5
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 30mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Add l-lactic acid (PLLA) 60mg mixing, at room temperature with
Dimethyl sulfoxide 110mg is added after vortex oscillation makes particle be uniformly dispersed between 20min for the rate of 1500rpm, 30 DEG C, mention
Taking power is to obtain the slow-releasing gel used sample 5# of Shexiang Baoxin Pills ultrasonic extraction 5 hours under 300W.Shexiang Baoxin Pills sustained-release gel
Agent sample 5# is transparent semi-solid brown formulations.In the slow-releasing gel used sample 5# of the Shexiang Baoxin Pills of preparation, percentage by weight
Than meter, Shexiang Baoxin Pills powder is 15.0%, l-lactic acid 30.0%, dimethyl sulfoxide 55.0%.
Embodiment 6
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 15mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Add dextrorotation polylactic acid (PDLA) 50mg mixing, at room temperature with
N-Methyl pyrrolidone 102.8mg is added after vortex oscillation makes particle be uniformly dispersed between 10min in the rate of 2000rpm,
20 DEG C, extract power be 200W under ultrasonic extraction 10 hours, obtain the slow-releasing gel used sample 6# of Shexiang Baoxin Pills.Shexiang Baoxin Pills
Slow-releasing gel used sample 6# is transparent semi-solid brown formulations.In the slow-releasing gel used sample 6# of the Shexiang Baoxin Pills of preparation, press
Weight percent meter, Shexiang Baoxin Pills powder are 8.9%, and dextrorotation polylactic acid is 29.8%, N-Methyl pyrrolidone 61.3%.
Embodiment 7
Commercially available Shexiang Baoxin Pills (Hehuang Pharmaceutical Co., Ltd., Shanghai, lot number 150415) 45mg is placed in mortar and is ground into
Fine powder, 120 mesh of fineness < of Shexiang Baoxin Pills powder.Poly(lactide-co-glycolic acid) copolymer (PLGA) 30mg mixing is added,
N-Methyl pyrrolidone is added after vortex oscillation makes particle be uniformly dispersed between 15min with the rate of 1750rpm at room temperature
102.8mg, 25 DEG C, extract power be 240W under ultrasonic extraction 8 hours, obtain the slow-releasing gel used sample 7# of Shexiang Baoxin Pills.
The slow-releasing gel used sample 7# of Shexiang Baoxin Pills is transparent semi-solid brown formulations.The slow-releasing gel used sample of the Shexiang Baoxin Pills of preparation
In product 7#, by weight percentage, Shexiang Baoxin Pills powder is 25.3%, poly(lactide-co-glycolic acid) copolymer 16.9%,
N-Methyl pyrrolidone is 57.8%.
Comparative example 1
Poly-dl-lactide (PLA) 30mg mixing is added, be vortexed between 15min with the rate of 1750rpm vibration at room temperature
Swing after so that particle is uniformly dispersed addition dimethyl sulfoxide 110mg, 25 DEG C, extract under power is 240W ultrasonic extraction 8 hours, obtain
Obtain slow-releasing gel used blank control sample 1*.Slow-releasing gel used blank control sample 1* is transparent semi-solid white preparation.
Embodiment 8
The blank control that will be prepared in the slow-releasing gel used sample 1# of the Shexiang Baoxin Pills prepared in embodiment 1 and comparative example 1
Sample 1* carries out the Ex vivo animal model experiment of the Therapeutic angiogenesis Mechanism Study of Shexiang Baoxin Pills, specific to carry out dynamic
Object is implanted into sponge (sponge), and angiogenesis model caused by inflammation is tested afterwards.
1, experimentation
C57BLK6 mouse (weight 22g ± 3, male) is taken to be divided to two groups, the Blank gel of non-dosing is added in blank control group
Agent, medicine group addition Shexiang Baoxin Pills are slow-releasing gel used, every group of each 15 mouse.It is molten that mouse peritoneal injects 1% yellow Jackets
Mouse is fixed on experimental bench by liquid by mouse anesthesia after anesthesia onset, back upward, using slipemaster by back of mice hair
It takes off, abjection one fritter about 3 × 3cm's goes to hair-fields, cuts off exocuticle after removing hair-fields Iodophor and alcohol disinfecting, uses haemostatic clamp
Inner space is expanded under skin.By corresponding sponge (sponge) and gel preparation implantation in exocuticle and muscle
Between and wound of sewing it up, on wound smear one layer of erythromycin ointment.For first post-operative day per a mouse is observed every other hour, 4 is small
When interior mouse restore normal action, mouse all survives in 24 hours, mouse full recovery normal condition after 3 days.
Observe back of mice implantation sponge (sponge) four week in, different time sections i.e. three day, one week, two weeks,
Internal sponge is taken out in three weeks, surrounding, and spongy tissue is divided into two, and a part is for making paraffin section, and a part is for mentioning
Take RNA.
2, instrument is analyzed
Dewaxing treatment is carried out to the paraffin section for sponge (sponge) production taken out by different time sections, is then used
FITC-Lectin carries out immunofluorescence dyeing, and Lectin is that green fluorescence represents the tiny blood vessels to be formed, soft by Image J
Part calculates fluorescence area, and carries out fluorescence microscope, obtains unit area on different time sections sponge (sponge)
Microvessel density in domain, and discovery is compared to administration group and blank control group: 4 week of animal is implanted in sponge
The nascent blood vessel density of interior Shexiang Baoxin Pills sustained-release gel group is apparently higher than blank control group, and after 2 weeks administration group it is new
Angiogenic area is suitable, shows the facilitation that Shexiang Baoxin Pills sustained-release gel generates new vessels, concrete outcome such as Fig. 1 institute
Show.
Dewaxing treatment is carried out to the paraffin section for sponge (sponge) production taken out by different time sections, then uses blood
Endothelial tube growth factor (VEGF) fluorescence antibody carries out immunofluorescence dyeing, and vascular endothelial growth factor VEGF is red fluorescence,
VEGF is the strongest factor that there are promotion new vessels to generate generally acknowledged at present, and VEGF release, which increases, can promote new vessels
Generation increase.Fluorescence area is calculated by Image J software, is obtained single on different time sections sponge (sponge)
The density of vegf expression in the region of position, and discovery is compared to administration group and blank control group: it is implanted in sponge dynamic
The VEGF of Shexiang Baoxin Pills sustained-release gel group generates density and is apparently higher than blank control group in 4 week of object, and gives after 2 weeks
The VEGF burst size of medicine group is suitable, shows that Shexiang Baoxin Pills sustained-release gel has facilitation, concrete outcome to the release of VEGF
As shown in Figure 2.
The sponge (sponge) taken out by different time sections is shredded, is dissolved by collagenase solution, extracts and raises to sea
Cell in continuous (sponge) tissue, resulting cell extract RNA by Trizol reagent, by reverse transcription acquisition cDNA, then into
Row real time fluorescent quantitative qPCR, analysis vascular endothelial growth factor VEGF mRNA expression.Pass through real time fluorescent quantitative qPCR points
Analysis obtains different time sections and raises the expression quantity to the VEGF mRNA of the cell in sponge (sponge) tissue, and to administration group
Discovery is compared with blank control group: being implanted to Shexiang Baoxin Pills sustained-release gel group in 4 week of animal in sponge
The expression quantity of VEGF mRNA will be apparently higher than blank control group, and at 1 week and 2 weeks the VEGF mRNA of administration group expression quantity
There is the difference of highly significant with blank control group, have statistical significance (P < 0.01) concrete outcome as shown in Figure 3.
So the present invention effectively overcomes various shortcoming in the prior art and has high industrial utilization value.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (5)
1. a kind of Shexiang Baoxin Pills are slow-releasing gel used, by weight percentage, including following components:
Shexiang Baoxin Pills powder 0.1-30%;
Gel-type vehicle agent 0.9-30%;
Solvent 40-99%;
It is total that the gel-type vehicle agent is selected from poly-dl-lactide, l-lactic acid, dextrorotation polylactic acid, poly (lactic acid-glycolic acid)
One of polymers or a variety of mixing;
The solvent is selected from one of N-Methyl pyrrolidone, dimethyl sulfoxide or N-Methyl pyrrolidone, dimethyl sulfoxide
One of with one of water, ethyl alcohol, acetone, ethyl acetate, chloroform or a variety of mix;
Weight ratio between the Shexiang Baoxin Pills powder and gel-type vehicle agent is 1:0.1~10;
The Shexiang Baoxin Pills are slow-releasing gel used to be prepared by following methods, according to the ratio by Shexiang Baoxin Pills powder and gel base
Matter agent mixes, and solvent is added after vortex oscillation, ultrasonic extraction is slow-releasing gel used to get Shexiang Baoxin Pills;
The condition of the vortex oscillation are as follows: duration of oscillation: 10-20min;Oscillation rate: 1500-2000rpm;It shakes at room temperature
It swings;
The condition of the ultrasonic extraction are as follows: extraction time is 5-10 hours;Extracting temperature is 20-30 DEG C;Extraction power is 200-
300W。
2. Shexiang Baoxin Pills according to claim 1 are slow-releasing gel used, which is characterized in that by weight percentage, including
Following components:
Shexiang Baoxin Pills powder 5-26%;
Gel-type vehicle agent 15-30%;
Solvent 44-75%.
3. the slow-releasing gel used preparation method of Shexiang Baoxin Pills according to claim 1 to 2, which is characterized in that by matching
Than mixing Shexiang Baoxin Pills powder with gel-type vehicle agent, solvent is added after vortex oscillation, ultrasonic extraction is to get Shexiang Baoxin Pills
It is slow-releasing gel used;
The condition of the vortex oscillation are as follows: duration of oscillation: 10-20min;Oscillation rate: 1500-2000rpm;It shakes at room temperature
It swings;
The condition of the ultrasonic extraction are as follows: extraction time is 5-10 hours;Extracting temperature is 20-30 DEG C;Extraction power is 200-
300W。
4. Shexiang Baoxin Pills according to claim 1 to 2 are slow-releasing gel used in the drug that preparation promotes angiogenesis
Purposes.
It is controlled in preparation for carrying out Shexiang Baoxin Pills 5. Shexiang Baoxin Pills according to claim 1 to 2 are slow-releasing gel used
Treat the purposes in the drug of the Ex vivo animal model of angiogenesis Mechanism Study.
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