CN105434456B - A kind of chitosan danshen injections and preparation method thereof - Google Patents
A kind of chitosan danshen injections and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
The invention discloses a kind of compound chitosan injection of danshen liquid formulations and preparation method thereof.The compound chitosan injection of danshen liquid formulation is mixed with by medical chitose and danshen injections；Specifically first by medical chitose and danshen injections vortex mixed it is uniform after, appropriate synthesis is added or semi-synthetic polymeric retention aid suspension, water-bath are vibrated to form stable suspension, adds sodium bicarbonate solution, it adjusts between pH to 7.5~7.8 to get to compound chitosan injection of danshen liquid formulation.Said preparation uses in fallopian tubal Interventional Salpingography, can prevent the postoperative adhesion again of fallopian tubal, promote tissue repair, prevent fallopian tubal again adhesion, improve Oviductal Smooth Muscles functions, improve environment and microcirculation in fallopian tubal, adjust acid-base value, improve fertilization success rate, improve uterine pregnancy rate in play a significant role.
Description
Technical field
The invention belongs to gynaecology to intervene pharmaceutical technology field.More particularly, to a kind of compound chitosan danshen injections
Preparation and preparation method thereof.
Background technology
Interventional Salpingography, that is, fallopian tubal Interventional recanalization art, American physician platia in 1985 report that salpingemphraxis is adopted first
With the method for Catheter Interventional Therapy, grinding for Interventional Salpingography treatment Infertility caused by fallopian tube obstruction is hereafter carried out in succession both at home and abroad
Study carefully, this method step：3~7d performs the operation after clean period, and preoperative 0.5h intramuscular injections fenazil 25mg is calm, intramuscular note
Penetrating atropine 0.5mg prevents fallopian tubal spasm；Under Digital Subtraction x line machines perspective, sacculus front end is sent to uterine cervix or son
Uterine cavity injects contrast agent after dilating sacculus, shows uterine cavity form and palace Angle Position, confirms fallopian tube adhesion obstructive position；Through
Foley's tube is sent into seal wire, conduit to Ipsilateral palace angle, and catheter tip is sent at the pull of palace again by seal wire；Microtubular is sent into build
Vertical coaxial pipe system, then the position of salpingemphraxis is opened, achieve preferable clinical efficacy, it has also become treatment fallopian tubal resistance
One of the important method of plug property infertility.
But adhesion or inner membrance afunction, the postoperative rate of adhesion again are up to the easily generation of this method postoperative fallopian tube tube chamber again
20%~50%, it is low to easily lead to pregnancy rate, postoperative uterine pregnancy rate relatively low about 36.84% or so, and fallopian tubal easily occurs
The problem of gestation.It is therefore prevented that it is to improve the important means of patient's pregnancy rate that adhesion again, which occurs, in fallopian tubal intervention, become at this stage
The main direction of studying of Infertility caused by fallopian tube obstruction clinical treatment.
It by means such as sodium hyaluronate, ozone prevents fallopian tubal currently, existing adhesion has their limitation again.State
It is inside and outside to there are some scholars to be had made some progress the problem of preventing fallopian tubal adhesion again after exploring fallopian tubal Interventional Salpingography：
(1) Yan Ying etc. is occluded not high with uterine pregnancy rate again for logical postoperative easy generation fallopian tubal again, using salviamiltiorrhizabung injection row
Fallopian tubal intra-bladder instillation, cooperation Chinese herb decoction opinion are controlled, postoperative 1 year tubal patency rate 91.5%, and pregnancy rate 44.8% is postoperative
2 years uterine pregnancy rates 45.8%, then adhesion rate 12.5%；(2) reports such as Wang Yase, Interventional Salpingography joint danshen injections are controlled
It is 93.61% to treat postoperative 6~12 months tubal patency rates of salpingemphraxis；(3) Hu Wenjun etc. reports O3Joint Radix Salviae Miltiorrhizae is perfused
Blocking rate is 12.9% to injection group again, pregnancy rate 46.8%；(4) yellow to be good for happy be reported in Interventional Salpingography in fallopian tubal
Chitosan is injected, then again from venoclysis danshen injections 20ml, fallopian tube recanalization rate is carried than simple Interventional Salpingography
It is high；(5) our early-stage study is found[6]Recanalization rate 97.9% is intervened using Sodium Hyaluronate group, 3 months after operation fallopian tubal is logical
Water patency rate 88.5%, postoperative 12 months pregnancy rate 41.6%；Chitosan group intervenes recanalization rate 95.7%, the defeated ovum of 3 months after operation
Pipe water flowing patency rate 91.7%, postoperative 12 months pregnancy rate 48.1%.
But there is different problems and defect for the above technology：(1) ozone perfusion fallopian tubal there are the problem of：
During perfusion, the injection rate of ozone is difficult to hold, and the injection of ozone can cause the discomfort of patient, in addition, ozone fills
Note needs the assistance of ozone machine, and general hospital is not equipped with ozone machine；(2) danshen injections row fallopian tubal intra-bladder instillation exists
The problem of：Danshen injections are a kind of water-soluble liquid, and speed of scattering is fast, and action time is short, cannot for a long time keep to fallopian tubal
Effect, and danshen injections prevent tissue adhesion and fungistatic effect not good enough；(3) chitosan injection row fallopian tubal intra-bladder instillation
There are the problem of：Chitosan is thick liquid preparation, and doctor is more difficult when injecting, and often causes patient uncomfortable；Chitosan
The normal Epithelium Cells function of unprotect, and it is not good enough to repair impaired Epithelium Cells；(4) yellow strong happy proposed
Inject chitosan in fallopian tubal, then from the method for venoclysis danshen injections 20ml there are the problem of：This method is chitin
The drug combination of sugar and danshen injections, i.e. chitosan are injected from fallopian tubal, and Radix Salviae Miltiorrhizae passes through venoclysis；First, Radix Salviae Miltiorrhizae whole body
Medication can not reach the effective concentration of fallopian tubal part, greatly reduce the effectiveness of Radix Salviae Miltiorrhizae, secondly, chitosan and pellet in the method
Join individually medication, the increase to curative effect is not especially desirable.
Invention content
The technical problem to be solved by the present invention is to overcome fallopian tubal after existing fallopian tubal Interventional Salpingography adhesion, pregnancy rates again
Low problem, we have developed a kind of new drug solving the adhesion problems again of fallopian tubal after fallopian tubal Interventional Salpingography, i.e., multiple
Square chitosan danshen injections, it can prevent the postoperative adhesion again of fallopian tubal, promote tissue repair, with prevent fallopian tubal again adhesion,
It improves fertilization success rate and improves uterine pregnancy rate；And histocompatbility is good, degradable in vivo, and it is normal with protection
Epithelium Cells repair impaired Epithelium Cells, prevent tissue adhesion, broad-spectrum antibacterial, improve inner partial annular border, promote
Effect into fertilization and advantage.
The object of the present invention is to provide a kind of compound chitosan injection of danshen liquid formulations.
Another object of the present invention is to provide the preparation method of above-mentioned compound chitosan injection of danshen liquid formulation.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：
A kind of compound chitosan injection of danshen liquid formulation, is mixed with by medical chitose and danshen injections.
Its main component is carboxymethyl chitin, danshensu and protocatechualdehyde.
Specifically first by medical chitose and danshen injections vortex mixed it is uniform after, appropriate synthesis or hemizygous is added
At polymeric retention aid suspension, water-bath is vibrated to form stable suspension, adds sodium bicarbonate solution, adjusts pH to 7.5~7.8
Between to get to compound chitosan injection of danshen liquid formulation.
Preferably, the synthesis or semi-synthetic polymeric retention aid suspension are methylcellulose, sodium carboxymethylcellulose, hydroxypropyl
Cellulose or povidone
More specifically, the preparation method of above-mentioned compound chitosan injection of danshen liquid formulation includes the following steps：
S1. according to 1：Medical chitose and danshen injections are placed in same container by 3~6 volume ratio, and vortex 5~
15min makes the two be uniformly mixed；
S2. suitable synthesis or semi-synthetic polymeric retention aid suspension (preferably Methyl cellulose are added into the solution of step S1
Element, sodium carboxymethylcellulose, hydroxypropyl cellulose or povidone), 30~60min is vibrated in 35~40 DEG C of water-baths, is allowed to abundant
Mixing forms stable suspension；
S3. it is added sodium bicarbonate solution into the solution of step S2, adjusts between pH to 7.5~7.8 to get several to compound
Tetrose injection of danshen liquid formulation.
Wherein it is preferred to which the volume ratio of chitosan and danshen injections described in step S1 is 1：5.
Preferably, the time being vortexed described in step S1 is 10min.
Preferably, the addition of synthesis or semi-synthetic polymeric retention aid suspension described in step S2 is 0.05~0.2ml.
It is highly preferred that the addition of synthesis or semi-synthetic polymeric retention aid suspension described in step S2 is 0.1ml.
Preferably, polymeric retention aid suspension described in step S2 is methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose
Or povidone.
Preferably, the condition that water-bath described in step S2 is vibrated is that 40~50min is vibrated in 37~38 DEG C of water-baths.
It is highly preferred that the condition that water-bath described in step S2 is vibrated, which is 38 DEG C of water-baths, vibrates 45min.
Preferably, the concentration of sodium bicarbonate solution described in step S3 is 3~6%, the addition of the sodium bicarbonate solution
Account for 0.5~2v/v% of total solution.
It is highly preferred that the concentration of sodium bicarbonate solution described in step S3 is 5%, the addition of the sodium bicarbonate solution accounts for
The 1v/v% of total solution.
Preferably, between adjusting pH to 7.6~7.7 described in step S3.
The compound chitosan injection of danshen liquid formulation being prepared according to above-mentioned preparation method, also should be in the protection of the present invention
Within the scope of.
In addition, above-mentioned compound chitosan injection of danshen liquid formulation is after preparing fallopian tubal Interventional Salpingography in terms of drug used
Application, also all within protection scope of the present invention.
Further, the drug is that adhesion, pregnancy rate are low again for fallopian tubal after referring to prevent fallopian tubal Interventional Salpingography
The drug of problem.
Further, the drug is to refer to prevent the postoperative adhesion again of fallopian tubal, promote tissue repair, improve fallopian tubal
Microcirculation and adjust acid-base value drug.
The present invention propose in Interventional Salpingography using a kind of postoperative adhesion again of preventions fallopian tubal, promotion tissue repair,
Improve the microcirculation of fallopian tubal and adjust the new drug of acid-base value, i.e. compound chitosan injection of danshen liquid formulation, the medicine is defeated in prevention
Oviduct again be fertilized in success rate, raising uterine pregnancy rate and play a significant role by adhesion, raising.
In actual clinical application, the application method of the compound chitosan injection of danshen liquid formulation is：Row fallopian tubal is situated between
While entering to lead to again art, the drug is injected in fallopian tubal.Dosage is 10~15ml, preferably 12ml.
The present invention to the stability of compound chitosan injection of danshen liquid formulation, with the effect of Epithelium Cells, antibacterial
Effect, acid-base value etc. are studied.And Randomized controlled clinical study is used, 4 groups are randomly divided into, with the defeated ovum of coaxial pipe row
Pipe Interventional Salpingography, A groups only inject liquid of loosening and make anti-inflammatory treatment, B groups：Injection, which is loosened after liquid makees anti-inflammatory treatment, reinjects chitosan
Prevent fallopian tubal adhesion again.C groups:Danshen injections are reinjected after liquid is loosened in injection.D groups:Then noted again after liquid is loosened in injection
Enter compound chitosan danshen injections.Patency rate is observed in the postoperative 12nd month row Salpingography of patient, follow-up is become pregnant in 1 year
Rate, the effect of obstructive fallopian tube recanalization post-operation adhesion is prevented by studying compound chitosan injection of danshen liquid formulation, and analysis makes
With the clinical efficacy and value of compound chitosan injection of danshen liquid formulation, one is provided effectively for Infertility caused by fallopian tube obstruction
Therapy improves fallopian tube recanalization, improves the effect of uterine pregnancy rate.
The pharmacological action of compound chitosan injection of danshen liquid formulation of the present invention is as follows：
(1) normal Epithelium Cells are protected：Blood flow can be increased, improve inflammatory fallopian tubal endothelium hypoxic-ischemic feelings
Condition inhibits oxygen free radical injury excessive, protects Epithelium Cells；
(2) it repairs and is damaged Epithelium Cells：Chitosan promotes epithelial cell endothelial growth, inhibits fibroblast life
It is long, promote the reparation of tissue physiology's property；Radix Salviae Miltiorrhizae has the function of adrenergic α receptor agonist；It can promote the fallopian tubal of damage
The recovery of epithelial cell reparation and cilium；
(3) tissue adhesion is prevented：Chitosan prevents adhesion by lubrication and biological barrier effect；The defeated ovum of compound Danshen Root
Pipe perfusion liquid can dispel the rotten logical stasis of blood, and removal causes the rheuminess object of salpingemphraxis, promotes tissue repair, prevent adhesion again；
Fallopian tubal inflammatory mucomembranous epithelial cell can be made to fall off, just assist in removing necrosis, the epithelial tissue of inflammation promotes tissue to give birth to again
It is long to repair, reach dredging oviduct, prevents adhesion.Radix Salviae Miltiorrhizae plays defeated ovum of loosening by anti-fibrosis, inhibition collagen synthesis
The effect of pipe adhesion；
(4) there is broad-spectrum antibacterial effect：The negative electricity of the positive charge of institute's band and microbial cell film institute band in chitin glycan molecule
Lotus interacts, and can form a film in phage surface, prevent the entrance of nutriment, and the cell membrane that may pass through damage enters bacterium
Inside inhibits the growth of bacterium by inhibiting DNA to be changed into RNA, upsets the synthesis and metabolism of bacterium, generates antibacterial action.
Radix Salviae Miltiorrhizae has inhibiting effect to gold-coloured staphylococci, Bacillus tuberculosis, Escherichia coli, proteus, shigella flexneri etc.；
(5) compound chitosan injection of danshen liquid formulation, through efficient liquid phase detection relative amount variation, main component chitosan
And it is stable that both Radix Salviae Miltiorrhizaes, which are sufficiently mixed,；Due to chitosan high-molecular compound complexity space structure can to Radix Salviae Miltiorrhizae effectively at
Divide and play carrier function, chitosan can be generally more than 3 weeks or more in local residence, have permeability to nutriment, can play slow
The effect of On The Drug Release effective component in red sage；
The compound preparation that (6) two kinds of drugs are prepared after being sufficiently mixed, due to the work of the slow release Radix Salviae Miltiorrhizae of chitosan
With the regular contractile function of Oviductal Smooth Muscles can be improved；
(7) environment and microcirculation in fallopian tubal can be improved；
(8) acid-base value of fallopian tubal is adjusted in the application of this preparation, promotes ovum and sperm successful fertilization to play
Effect；
(9) processing technology of this preparation use, the best stabilization for making chitosan danshen injections with when auxiliary material application
The effect of property further enhances, chitosan danshen injections significantly improves；
(10) fungistatic effect of this preparation further enhances；
(11) this preparation protects to greatest extent while the Epithelium Cells and inflammatory tissue of removal necrosis
The form and function of normal Epithelium Cells.
In addition, for convenience the understanding of the present invention, inventor want it is emphasised that：For in the prior art, Huang Jianyi
Deng the scheme of the chitosan and danshen injections drug combination that are proposed, i.e., chitosan is injected in fallopian tubal, then defeated from vein
The method of note danshen injections 20ml has the following problems：(1) drug combination be not truly obtain a kind of compound
Chitosan injection of danshen liquid formulation, only first chitosan is injected from fallopian tubal, then Radix Salviae Miltiorrhizae is not played pellet by venoclysis
Join the effect of injection local application, also without embodying the effect of injecting fallopian tubal after two kinds of drugs are sufficiently mixed；(2) Radix Salviae Miltiorrhizae is complete
Body medication can not reach the effective concentration of fallopian tubal part, greatly reduce the effectiveness of Radix Salviae Miltiorrhizae；(3) the method is not applied to several
The space structure of tetrose high-molecular compound complexity can play carrier function to effective component in red sage, can not slow release Radix Salviae Miltiorrhizae have
Imitate ingredient；(4) topical application is protecting normal uterine tubal epithelium in fallopian tubal after the method does not embody two kinds of drug mixing
Cell is repaired be damaged Epithelium Cells, prevent tissue adhesion, have the function of broad-spectrum antibacterial effect etc. and can play complementation
And synergistic effect；(5) the method also improves the regular contraction work of Oviductal Smooth Muscles without embodying after two kinds of drugs are sufficiently mixed
It can, improve environment and microcirculation in fallopian tubal, adjust acid-base value, promote the effect of ovum and sperm successful fertilization.
The invention has the advantages that：
Development of the present invention provides a kind of new compound chitosan injection of danshen liquid formulation, can be applied to fallopian tubal intervention again
Logical postoperative can prevent after fallopian tubal Interventional Salpingography the fallopian tubal low problem of adhesion, pregnancy rate again, prevent fallopian tubal
Postoperative adhesion again promotes tissue repair, improves the microcirculation of fallopian tubal and have a significant effect in terms of adjusting acid-base value；The medicine
Object also has the advantages that following notable：
(1) nontoxic, no antigen, histocompatbility is good, degradable in vivo, can be injected by Interventional Salpingography, and agent
Amount is controllable, easy to operate；
(2) mobility will not lead to patient's between danshen injections and chitosan injection because of injections difficult
It is uncomfortable；And stable components, since the space structure of chitosan high-molecular compound complexity can play effective component in red sage load
Body acts on, and chitosan can be generally more than 3 weeks or more in local residence, have permeability to nutriment, can play in fallopian tubal
The effect of slow release effective component in red sage；
(3) both chitosan and Radix Salviae Miltiorrhizae can play complementation and synergistic effect；Have simultaneously on the normal fallopian tubal of protection
Chrotoplast repairs impaired Epithelium Cells, prevents tissue adhesion, has the effects that broad-spectrum antibacterial.
(4) it after two kinds of drugs in compound preparation are sufficiently mixed, due to the effect of the slow release Radix Salviae Miltiorrhizae of chitosan, can carry
The regular contractile function of high Oviductal Smooth Muscles；
(5) after two kinds of drugs in compound preparation are sufficiently mixed, environment and microcirculation in fallopian tubal can be improved；It is adjustable defeated
The acid-base value of oviduct, to play the role of promoting ovum and sperm successful fertilization；
(6) this preparation uses preparation process best matches when auxiliary material application so that chitosan danshen injections it is steady
Qualitative to further enhance, the effect of compound chitosan injection of danshen liquid formulation, significantly improves；The fungistatic effect of this preparation is further
Enhancing；This preparation protects normal defeated to greatest extent while the Epithelium Cells and inflammatory tissue of removal necrosis
The form and function of oviduct epithelial cell.
(7) effect of danshen injections local application can be played, injection fallopian tubal after two kinds of drugs are sufficiently mixed is embodied
Curative effect；Again, two kinds of active ingredients of this preparation are protecting the impaired uterine tubal epithelium of normal Epithelium Cells, reparation thin
Born of the same parents prevent tissue adhesion, can functionally play complementation and synergistic effect with broad-spectrum antibacterial effect etc..
(8) compound chitosan injection of danshen liquid formulation can be additionally used in the positions such as the natural tube chamber of human body, abdominal cavity, can be used for preventing
Only adhesion caused by various operations promotes regeneration and reparation, reduces local inflammation, and recovery organization function has a wide range of application,
Foreground is good.
Description of the drawings
Fig. 1 is the chromatogram of carboxymethyl chitin, danshensu and protocatechualdehyde in compound chitosan injection of danshen liquid formulation；
In figure, A Detection wavelengths 210nm, B Detection wavelength 280nm；1 is carboxymethyl chitin, and 2 be Sodium Danshensu, and 3 be protocatechualdehyde.
Fig. 2 is compound chitosan injection of danshen liquid formulation to rabbit fallopian tubal irritation pathological section figure, A feminine genders group, B blank
Group, C administration groups.
Fig. 3 is the Technology Roadmap that the clinical application research of compound chitosan injection of danshen liquid formulation is tested.
Specific implementation mode
It is further illustrated the present invention below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present invention
It limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus routinely try for the art
Agent, method and apparatus.
Unless stated otherwise, agents useful for same and material of the present invention are purchased in market.
Embodiment 1 prepares compound chitosan injection of danshen liquid formulation
Preparation method is as follows：
S1. pipette precision is used to measure medical chitose 2ml and danshen injections 10ml, according to 1:The ratio of 5 (v/v),
It is placed in same 10ml teat glass, in the 10min that is vortexed on automatic vortice, the two is made to be uniformly mixed；
S2. appropriate polymeric retention aid suspension (methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose or poly- dimension is added
Ketone), 45min is vibrated in 38 DEG C of water-baths, is allowed to mix well, forms stable suspension；
S3. a concentration of 5% sodium bicarbonate solution is added into the solution of step S2, between adjusting pH to 7.5~7.8,
Obtain compound chitosan injection of danshen liquid formulation；The addition of a concentration of 5% sodium bicarbonate solution is that solution is overall
Long-pending 1%.
Embodiment 2 prepares compound chitosan injection of danshen liquid formulation
Preparation method is as follows：
S1. pipette precision is used to measure medical chitose 2ml and danshen injections 6ml, according to 1:The ratio of 3 (v/v), sets
In same 10ml teat glass, in the 5min that is vortexed on automatic vortice, the two is made to be uniformly mixed；
S2. appropriate polymeric retention aid suspension sodium carboxymethylcellulose is added, vibrates 60min in 35 DEG C of water-baths, is allowed to fully mixed
It is even, form stable suspension；
S3. a concentration of 5% sodium bicarbonate solution is added into the solution of step S2, between adjusting pH to 7.6~7.7,
Obtain compound chitosan injection of danshen liquid formulation；The addition of a concentration of 5% sodium bicarbonate solution is that solution is overall
Long-pending 1%.
Embodiment 3 prepares compound chitosan injection of danshen liquid formulation
Preparation method is as follows：
S1. pipette precision is used to measure medical chitose 2ml and danshen injections 12ml, according to 1:The ratio of 6 (v/v),
It is placed in same 10ml teat glass, in the 15min that is vortexed on automatic vortice, the two is made to be uniformly mixed；
S2. appropriate polymeric retention aid suspension hydroxypropyl cellulose is added, vibrates 30minmin in 40 DEG C of water-baths, is allowed to fully mixed
It is even, form stable suspension；
S3. a concentration of 5% sodium bicarbonate solution is added into the solution of step S2, between adjusting pH to 7.5~7.8,
Obtain compound chitosan injection of danshen liquid formulation；The addition of a concentration of 5% sodium bicarbonate solution is that solution is overall
Long-pending 1%.
Embodiment 4 prepares compound chitosan injection of danshen liquid formulation
Preparation method is as follows：
S1. pipette precision is used to measure medical chitose 2ml and danshen injections 10ml, according to 1:The ratio of 5 (v/v),
It is placed in same 10ml teat glass, in the 10min that is vortexed on automatic vortice, the two is made to be uniformly mixed；
S2. appropriate polymeric retention aid suspension povidone is added, vibrates 40min in 40 DEG C of water-baths, is allowed to mix well, is formed steady
Fixed suspension；
S3. a concentration of 5% sodium bicarbonate solution is added into the solution of step S2, between adjusting pH to 7.5~7.8,
Obtain compound chitosan injection of danshen liquid formulation；The addition of a concentration of 5% sodium bicarbonate solution is that solution is overall
Long-pending 1%.
The stability study of 5 compound chitosan injection of danshen liquid formulation of embodiment
Using high performance liquid chromatography, compound chitosan injection of danshen liquid formulation and medical chitose and injection of danshen are measured
Before liquid mixing, the changes of contents that is placed at room temperature for after 0min and 10min.
1, instrument and material
(1) instrument：Japanese Shimadzu DGU-20A5 high performance liquid chromatographs (LC-20AT pumps, SIL-20A autosamplers,
SPD-20A UV detector, CTO-20A column ovens, LCsolution work stations).
(2) preparation：Danshen injections (Wu Liang Ye Group, Yibin Pharmaceutical Co., Ltd., Yibin,Sichuan, batch number
12080311)；Medical chitose (Qisheng Biopreparations Co., Ltd., Shanghai, batch number：120578-01)；
(3) standard items：Sodium Danshensu (Chinese pharmaceutical biological product inspection institute, lot number：110855-200809)；Former catechu
Aldehyde (National Institute for Food and Drugs Control, lot number 110810-201007, content 98.2%)
2, method
(1) chromatographic condition：Chromatographic column：Inertsil C18 columns (4.6 × 250mm, 5 μm)；Flow velocity：1.0mL·min-1；
Double Detection wavelengths：210nm and 280nm；Sample size：10μL；Mobile phase：1% phosphoric acid (A), methanol (B) gradient elution, are shown in Table 1.
1 gradient elution time-program(me) of table
(2) it after danshen injections (5mL) plus ultra-pure water (1mL) mix, is sampled in 0min, 10min, 30min, dilutes 2 times,
Individually into liquid phase, chromatogram is recorded, determines its main component danshensu and protocatechualdehyde appearance time, peak area.
(3) it after medical chitose (1mL) and ultra-pure water (5mL) mix, is sampled in 0min, 10min, 30min, dilutes 2 times,
Individually into liquid phase, chromatogram is recorded, determines its main component carboxymethyl chitin appearance time, peak area.
(4) compound chitosan injection of danshen liquid formulation (medical chitose 1mL with danshen injections 5mL), in 0min,
10min, 30min are sampled, and dilute 2 times, into liquid phase, are recorded chromatogram, are determined various main component appearance times, peak area.
3, result
(1) chromatogram as shown in Figure 1, the carboxymethyl chitin, danshensu and protocatechualdehyde in test sample retention time
Respectively 2.5min, 8.8min and 14.5min.
(2) precision
The danshen injections, medical chitose and compound chitosan injection of danshen liquid formulation for being placed at room temperature for 10min are each
Sample average measures 5 times, and precision such as the following table 2 meets the requirements.
2 precision result of table
(3) main component relative peak area is as shown in table 3
3 main component relative peak area ratio (n=3) of table
(3) the above results the results are shown in Table 4 after statistical analysis (t inspections).As it can be seen that not statistically significant between each group.Table
0min and 10 minute before and after bright mixing, there was no significant difference for the content of each main component.It is stable that the two, which is blended in 10min,.
4 Contents of Main Components of table changes results of statistical analysis (t inspections)
4, conclusion
In conclusion the compound chitosan danshen injections system that the present invention is prepared using medical chitose with danshen injections
Agent, through efficient liquid phase detection relative amount variation, the results showed that no significant difference, i.e. both chitosan danshen injections
Ingredient the present invention prepare before and after be it is stable, i.e., the present invention prepared by compound chitosan injection of danshen liquid formulation in,
Main component does not change, and drug has good stability.
The evaluation experimental that 6 compound chitosan injection of danshen liquid formulation of embodiment influences the postoperative mucous membrane of new zealand rabbit fallopian tubal
1, material
Animal：Healthy qualification regular grade new zealand rabbit, female, 1.8~2.2kg of weight are tested by Traditional Chinese Medicine University Of Guangzhou
Animal center provides.Up-to-standard credit number：Scxk (Guangdong) 2008-0020, it was demonstrated that number：0104918；Use licensing
Number：Syxk (Guangdong) 2008-0085.
2, method
(1) selection 1.8~2.2kg healthy adult level-ones new zealand female rabbit 6 is aseptically, illumination, temperature, wet
The constant raising of degree.Experimental rabbit is randomly divided into 3 groups, including experimental group 3, every bilateral salpingo gives injection, and empty
White control group 2, every bilateral give isometric physiological saline and negative control group 1, do not give any processing.
(2) preoperative first intramuscular injection gentamicin prevents infection.Anesthesia presses weight 2.0mLkg with 20% chloraldurate-1
Intraperitoneal injection, observation respiratory rate are down to 10-15 times/min, and loss of eyelash reflex is that anesthesia is satisfied with.Animal is fixed on operation
On platform, abdomen depilation, skin routine disinfection cuts off stomach wall and peritonaeum, exposure uterus, fallopian tubal and ovary, Yu Shuan along ventrimeson
5.0mL danshen injections, suturing them after administration are squeezed into the nearly uterus side of oviductus lateralis with syringe.Same treatment blank
Control group changes danshen injections into physiological saline.Negative control group does not make any processing.Put to death 6 rabbits afterwards for 24 hours, dissection takes
Go out oviduct tissue to be fixed with 10% formalin, carries out histopathologic examination.
3, the results are shown in Figure 2.
The injection has a certain impact to tunica mucosa tubae uterinae, and impaired mucomembranous epithelial cell is made to fall off to some extent, and
With the neutrophil leucocyte being dispersed in.Blank control group and negative control group show that tunica mucosa tubae uterinae is normal complete, in apparent
Property granulocyte exudation.
4, conclusion：Compound chitosan injection of danshen liquid formulation can dispel the rotten logical stasis of blood, and removal causes the inflammatory of salpingemphraxis
Secretion promotes tissue repair, prevents adhesion again, can make impaired Mucous Epithelium of Fallopian Tube cell detachment, just assist in removing bad
Extremely, the epithelial tissue of inflammation promotes tissue re-growth reparation, reaches dredging oviduct, prevent adhesion and other effects.Radix Salviae Miltiorrhizae passes through
Anti-fibrosis inhibits collagen synthesis to play the role of fallopian tube adhesion of loosening.
The Clinical application evaluation of 7 compound chitosan injection of danshen liquid formulation of embodiment
The technology path of research experiment is as shown in Figure 3.
1, key instrument and material：
Equipment is GE companies OEC9600C arm X-ray machines.The fallopian tube recanalization dual balloon catheter of COOK companies of U.S. production,
5.5F " J " types conduit, 3.0F microtubulars, 0.18in micro-wires, 0.035in seal wires.
Key agents are medical chitose (Qisheng Biopreparations Co., Ltd., Shanghai, batch numbers 12080311)；Radix Salviae Miltiorrhizae
Injection (Wu Liang Ye Group, Yibin Pharmaceutical Co., Ltd., Yibin,Sichuan, batch number：120578-01).Other drugs
Including non-ionic contrast medium --- Ioversol, gentamicin, chymotrypsin, lidocaine, dexamethasone.
2, step：
(1) it selects unilateral or bilateral interstitial tubal and isthmus to block patient by Salpingography, is randomly divided into A
Group, B groups, C groups, D groups, each 100.
(2) treatment is led in intervention again：3-7d performs the operation after clean period, the towns preoperative 0.5h intramuscular injections fenazil 25mg
Quiet, intramuscular injection atropine 0.5mg prevents fallopian tubal spasm.Under Digital Subtraction x line machines perspective, sacculus front end is sent to uterus
Neck or uterine cavity inject contrast agent after dilating sacculus, show uterine cavity form and palace Angle Position, confirm fallopian tube adhesion obstruction
Position.It is sent into seal wire, conduit to Ipsilateral palace angle through foley's tube, catheter tip is sent at the pull of palace again by seal wire.It is sent into
Microtubular establishes coaxial pipe system, then opens the position of salpingemphraxis.
After injection contrast agent confirmation is led to successfully again, using Randomized controlled clinical study, 4 groups are randomly divided into, A groups：Through conduit
Injection conventional liquid of loosening (gentamicin 80000U, chymotrypsin 1000U, 2% lidocaine 10ml, the dexamethasone per side
The mixed liquor of 10mg) make anti-inflammatory treatment.B groups：After through conduit, per side, the conventional liquid of loosening of injection makees anti-inflammatory treatment, reinject medical
Chitosan 2ml prevents fallopian tubal adhesion again.C groups：Danshen injections 10ml is reinjected after injecting liquid of loosening；D groups：Inject liquid of loosening
After reinject compound chitosan injection of danshen liquid formulation (wherein medical chitose 2ml, danshen injections 10m, proportioning 1:5 compounds
Intermixture).
Art finishes tube drawing.Postoperative infection prevention takes the circumstances into consideration to give analgesic, physical therapy and anti symptom treatment, continues the infertile training of gynaecology
Systematic treating.
3, observation index：
Preoperative observation index：Sex hormone, leukorrhea routine, Visual quality, laparoscope and hysteroscope, hysterosalpingography etc.
Inspection result；
Observation index in art：Uterine cavity form, the position of salpingemphraxis, the recanalization rate of interventional treatment salpingemphraxis；
Clinical follow index：Hydrotubation patency rate at 3 months, postoperative 12 months pregnancy rate are (in vitro fertilization to remove
Outside), the pregnancy rate of follow-up patient, ectopic pregnancy rate, pregnant interval time and other complication situations.It becomes pregnant at postoperative 12 months still ends
Row Salpingography, understand tubal patency rate.
4, effect criterion：
(1) radiography：
1. unobstructed：Two oviductus lateralis whole process are shown when radiography, there is more contrast agent disperse in pelvic cavity；
2. blocking：In fallopian tubal, distal end do not develop or have partial development, without contrast agent disperse pelvic cavity；
3. logical and unsmooth：Contrast agent discharge fallopian tubal enters pelvic cavity, and fallopian tubal is shown, but form thickness is irregular, radiography
Agent part enters pelvic cavity and disperse is uneven.
(2) hydrotubation efficacy determination：
1. unobstructed：3 months after operation row water flowing is treated, and smoothly injects 20ml physiological saline non-resistances, and pressure maintains 60~
80mm Hg (1mm Hg=0.133kPa) hereinafter, or start slightly resistance, subsequent resistance disappears, no liquid reflux, patient also without
Sense of discomfort；
2. blocking：Inadequate saline injection 5ml, which feels, resistance, and pressure gauge shows that pressure persistently rises without seeing below
Drop, patient have inferior belly gas pain sense, stopping to inject rear liquid and be back in syringe again；
3. logical and unsmooth：Injecting fluid has resistance, but pressurized injection can promote again, illustrate have slight adhesion to be divided
From the patient feels have abdominal pain.
5, result
(1) the results are shown in Table 5 for fallopian tube recanalization Success Rate Analysis after Interventional Salpingography.
Fallopian tube recanalization Success Rate Analysis after 5 Interventional Salpingography of table
Note：Lead to success rate=postoperative unobstructed item number/original again and blocks item number × 100%.
As shown in table 5, result of study shows that 400 patients share 800, fallopian tubal, and original obstruction totally 692 is postoperative aobvious
Show that success rate difference is led in control group, chitosan group, Radix Salviae Miltiorrhizae group and the intervention of compound chitosan injection of danshen liquid formulation group fallopian tubal again
For 94.1% (159/169), 97.1% (170/175), 96.5% (166/172) and 98.2% (173/176), four groups of fallopian tubals
Lead to success rate no significant difference (P again>0.05), compound chitosan injection of danshen liquid formulation group is micro- is higher than other each groups.
(2) 3 months after operation hydrotubation patency rate analysis result is as shown in table 6.
63 months after operation hydrotubation patency rate of table is analyzed
Note：Patency rate=postoperative unobstructed item number/original blocks item number × 100%.
As shown in table 6,3 months after operation hydrotubation patency rate：3 months after operation hydrotubation patency rate statistical result
It has been shown that, the patency rate (90.9%, 160/176) of compound chitosan injection of danshen liquid formulation group be significantly higher than control group (73.9%,
125/169), the statistically significant (P of difference<0.05)；, and it is also apparently higher than chitosan group and Radix Salviae Miltiorrhizae group simultaneously.
(3) it is as shown in table 7 to lead to postoperative 12 months tubal patencies rate analysis result again.
Table 7 leads to postoperative 12 months tubal patency rates analysis again
Note：Patency rate=postoperative unobstructed item number/original blocks item number × 100%.
As shown in table 7, then lead to postoperative 12 months tubal patencies rate compound chitosan injection of danshen liquid formulation group
(85.2%, 150/176) patency rate is apparently higher than control group (39%, 66/169), the statistically significant (P of difference<0.05), and
Also it is apparently higher than chitosan group and Radix Salviae Miltiorrhizae group simultaneously.
(4) it is as shown in table 8 to lead to pregnancy rate analysis result in postoperative 12 months again.
Pregnancy rate is analyzed in table 8 postoperative 12 months
Note：Pregnancy rate=gestation number/sum × 100%
As shown in table 8, pregnancy rate compound chitosan injection of danshen liquid formulation group (54%, 54/100) is aobvious in postoperative 12 months
It writes and is higher than control group (14%, 14/100), difference has statistical significance (P<0.05)；And it is also apparently higher than chitosan group simultaneously
With Radix Salviae Miltiorrhizae group.
(5) complication
400 patients have 322 postoperative to have a small amount of colporrhagia and abdominal pain, general l~3d voluntarily to alleviate.Compound is not found
Chitosan injection of danshen liquid formulation group has the adverse reactions such as allergy.Patient occurs in compound chitosan injection of danshen liquid formulation group art
The complication such as pain are rare, and postoperative untoward reaction is less than other three groups.
6, conclusion
Find out from the clinical application test result of this research, compound chitosan injection of danshen liquid formulation is in Interventional Salpingography
Application improve the recanalization rate (98.2%) of Interventional Salpingography really.Leading to postoperative 12 months tubal patency rates, compound again
Chitosan injection of danshen liquid formulation group (85.2%) is significantly higher than control group (39%, 66/169), the statistically significant (P of difference<
0.05), and it is apparently higher than chitosan combination Radix Salviae Miltiorrhizae group.Pregnancy rate compound chitosan injection of danshen liquid formulation group in postoperative 12 months
(54%) it is significantly higher than control group (14%), the also statistically significant (P of difference<0.05), and it is apparently higher than chitosan combination pellet
Ginseng group.
These results illustrate that compound chitosan injection of danshen liquid formulation leads to postoperative 12 months tubal patency rates again to improving
And pregnancy rate plays an important role in postoperative 12 months.Practice have shown that compound chitosan injection of danshen two active ingredients of liquid formulation are several
Compatibility between tetrose and Radix Salviae Miltiorrhizae is good, can play synergistic effect.The few intercurrent disease of patient during use, doctor can grasp
The property made higher improves patency rate, raising uterine pregnancy rate after fallopian tubal interventional procedure, is suitble to widely popularize.
The medicament slow release Journal of Sex Research of 8 compound chitosan injection of danshen liquid formulation of embodiment
1, the present invention has done relevant research to the controlled drug release of compound chitosan injection of danshen liquid formulation, as a result table
Bright, using chitosan as carrier, being formed by chitosan Radix Salviae Miltiorrhizae topical remedy system (DDS), there is preferably internal, external sustained release to make
With being a kind of long sustained release that has that initial stage drug release amount is big, effective concentration is held time, carrier chitosan is in vivo by lysozyme
It slowly degrades and absorbs.
2, in addition, drug study, which shows that Radix Salviae Miltiorrhizae is sustainable, discharges into tissue, in initial 24 hours, about 16%
Danshensu releases, sustainable 3 weeks of concentration or more.
To sum up result of study, when showing row Salpingostomy in conjunction with clinical effectiveness, using the compound chitosan of the present invention
Danshen injections, the incidence for occurring fallopian tube adhesion again obviously lower, and further illustrate the drug by slow releasing function,
Extend the time that the medicine keeps effective concentration.
The research that 9 compound chitosan injection of danshen liquid formulation of embodiment influences smart ovum and rate of fertilization
It is shown by test, the pH value of compound chitosan injection of danshen liquid formulation of the invention is 7.8 or so, basicly stable
7.8.
Fallopian tubal prefecundation pH value be 7.1~7.3, capacitation but need to pH be 7.5~7.8 in the environment of, and
The use of the compound chitosan injection of danshen liquid formulation of the present invention can adjust the acid-base value of fallopian tubal, stronger steady by the medicine
Persistent qualitative and in fallopian tubal is adjusted the acid-base balance of tube chamber, is conducive to the activity of sperm and ovum, greatly increases
The success rate of fertilization.
The research of 10 compound chitosan injection of danshen liquid formulation bacteriostasis of embodiment
1, by scraps of paper diffusion drug sensitive test (KB methods) the study found that the compound chitosan injection of danshen liquid formulation of the present invention
Larger to the inhibition zone diameter of the main pathogenic bacteria Escherichia coli of salpingitis, about 10~12mm, the duration is long.
2, the compound chitosan injection of danshen liquid formulation of the studies have shown that present invention is also to proteus, shigella flexneri
Gold-coloured staphylococci etc. has inhibiting effect.
In addition, the rule that the compound chitosan injection of danshen liquid formulation of the present invention can also improve Oviductal Smooth Muscles is shunk
Function.Components in Salvia miltiorrhiza in the compound chitosan injection of danshen liquid formulation plays the role of adrenergic α receptor agonist, Radix Salviae Miltiorrhizae
Also have and increase the effect of pelvic cavity local blood flow, so Oviductal Smooth Muscles rule contractile function can be promoted, due to compound chitosan
The effect of the slow release Radix Salviae Miltiorrhizae of chitosan in injection of danshen liquid formulation, hence it is evident that improve the regular contraction work of Oviductal Smooth Muscles
Energy.
It is confirmed according to pharmacological research, microcirculation and the histotrophic nutrition of pelvic cavity part can be improved using blood-activating and stasis-removing, adjusted
Anabolism, to promote tissue repair.Components in Salvia miltiorrhiza in the compound chitosan injection of danshen liquid formulation of the present invention has on kidney
The effect of parathyrine energy α receptor stimulating agents, can be such that the erythrocyte membrane fluidity caused by inflammation increases, improve the deformation energy of red blood cell
Power can improve inflammatory fallopian tubal endothelium hypoxic-ischemic situation.
Claims (8)
1. a kind of compound medical chitose injection of danshen liquid formulation, which is characterized in that the medical chitose danshen injections system
Agent main component is carboxymethyl chitin, danshensu and protocatechualdehyde, is prepared by the following method：
S1. according to 1：Medical chitose and danshen injections are placed in same container by 3~6 volume ratio, and vortex 5~
15min makes the two be uniformly mixed；
S2. the synthesis of 0.05~0.2ml or semi-synthetic polymeric retention aid suspension are added into the solution of step S1, in 35~40 DEG C of water
Bath 30~60min of oscillation, is allowed to mix well, forms stable suspension；
S3. it is added sodium bicarbonate solution, adjusts between pH to 7.5~7.8 to get to compound medical chitose danshen injections system
Agent.
2. the preparation method of compound medical chitose injection of danshen liquid formulation according to claim 1, which is characterized in that
S1 are according to 1：Medical chitose and danshen injections are placed in same container by 3~6 volume ratio, and vortex 5~
15min makes the two be uniformly mixed；
The synthesis of the .2ml of 0 .05~0 or semi-synthetic polymeric retention aid suspension are added into the solution of step S1 by S2, in 35~40
30~60min is vibrated in DEG C water-bath, is allowed to mix well, forms stable suspension；
Sodium bicarbonate solution is added in S3, adjust pH between the .8 of 7 .5~7 to get to compound medical chitose injection of danshen
Liquid formulation.
3. preparation method according to claim 2, which is characterized in that medical chitose and danshen injections described in step S1
Volume ratio be 1：5.
4. preparation method according to claim 2, which is characterized in that the time being vortexed described in step S1 is 10min.
5. preparation method according to claim 2, which is characterized in that synthesis or semi-synthetic macromolecule suspending described in step S2
Agent is methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose or povidone.
6. preparation method according to claim 2, which is characterized in that the condition that water-bath described in step S2 is vibrated is 37~38
40~50min is vibrated in DEG C water-bath.
7. preparation method according to claim 2, which is characterized in that the concentration of sodium bicarbonate solution described in step S3 is 3
~6%, the addition of the sodium bicarbonate solution accounts for 0 .5 of total solution~2v/v%.
8. compound medical chitose injection of danshen liquid formulation described in claim 1 prevents defeated after preparing fallopian tubal Interventional Salpingography
The oviduct application in adhesion drug again.
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| CN2812967Y (en) * | 2005-07-28 | 2006-09-06 | 广东药学院附属第一医院 | Air bag catheter for salpingographic rethrough |
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| Title |
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| 丹参注射液介入再通治疗输卵管阻塞性***的量效关系初步研究;梁伟华等;《中药新药与临床药理》;20100731;第21卷(第4期);第443-445页 * |
| 医用几丁糖凝胶预防输卵管复通后的粘连;聂桂香;《中国组织工程研究与临床康复》;20110716;第15卷(第29期);第5413-5416页 * |
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