CN104940221A - Composition for repairing epithelial injury of bladders and urinary tracts - Google Patents
Composition for repairing epithelial injury of bladders and urinary tracts Download PDFInfo
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Abstract
The invention relates to a composition for repairing epithelial injury of bladders and urinary tracts. The composition is composed of two or three components selected from a group including hyaluronic acid, chitosan and chondroitin sulphate. Clinical animal experiments show that the composition for repairing epithelial injury of bladders and urinary tracts disclosed by the invention is capable of obviously repairing epithelial injury of bladders due to protamine sulphate or cyclophosphamide, obviously reducing the bladder epithelial injury range and the injury degree and lightening the inflammatory infiltration degree.
Description
Technical field
The present invention relates to polymeric material field, specifically, relate to a kind of compositions for bladder and urothelial injury repairing and the clinical scope of application thereof.
Background technology
Cystitis is a kind of inflammation occurring in bladder, is one of modal disease of urinary system.Cystitis is mainly divided into acute and chronic two kinds, and wherein chronic cystitis does not obtain cognitive widely due to its pathogenesis, causes the development of its treatment means to be hindered.Chronic cystitis clinical manifestation is interstitial cystitis, glandular cystitis, chemical cystitis, radiocystitis etc., mainly with urgent micturition, frequent micturition, chronic pelvic pain for main manifestations.
The pathogenesis of chronic cystitis is still indefinite at present, but much research thinks that epithelial damage is the main cause causing chronic cystitis, and interstitial cystitis, chemical cystitis, radiocystitis etc. all show the symptom of mucous membrane of urinary bladder damage.
Urothelium is the important barrier of metabolism toxic waste and high osmosis urine in opposing urine.In urothelium resistant function, the glycosaminoglycan layer (GAGs) of its epithelium umbrella cells has played important effect.GAGs layer forms a hydrophilic protective layer to resist the infringement of toxin in urine at urothelium.GAGs mainly comprises hyaluronic acid, chondroitin sulfate, dermatan sulfate, Heparin sulfate proteoglycan etc.Once GAGs layer suffers damage, urothelium is just easy to the infringement being subject to the factor such as potassium ion, infection, antitumor drug, radiation comprised in urine, thus causes a series of inflammatory reactions of bladder.
Bladder inflammation has a strong impact on the quality of life of patient.In chronic cystitis, with interstitial cystitis to patient, especially the impact of female patient is remarkable.Although the sickness rate of interstitial cystitis there is no explicit data at home at present, but there is related data statistics abroad, the sickness rate of such as American Women's interstitial cystitis is 2,30/,100,000, and finds according to previous investigation, and the sickness rate of interstitial cystitis is rising year by year.But because current doctors and patients not general understanding for interstitial cystitis, many patients are diagnosed as other diseases at the initial stage, the treatment time of delay, cause disease to increase the weight of further, cause serious impact to the physiology of patient and psychology.In addition, domestic at present do not have a kind of medical product can removing patient condition completely, and the research and development therefore for chronic cystitis alleviation product seem particularly important.
Similar to cystitis, after urothelial cell sustains damage, when urinating, mucous membrane of urethra internal layer cell is easy to the infringement of the metabolic waste, particularly potassium ion be subject in urine, thus causes pain.Repairing urothelial cell is a kind of effective means alleviating above-mentioned urodynamic.
Hyaluronic acid, chitosan, chondroitin sulfate are natural macromolecule amylose.Hyaluronic acid refers to that by 2-Acetamido-2-deoxy-D-glucose-D-Glucose aldehydic acid be the straight chain polymer polysaccharide that dissacharide units forms.Chitosan is the deacetylation product of natural polysaccharide chitin, is the straight-chain macromolecular compound coupled together by β-Isosorbide-5-Nitrae-glycosidic bond by N-acetyl-D-glucosamine monomer.The sugar chain of chondroitin sulfate is made up of the glucuronic acid replaced and N-acetylgalactosamine disaccharide unit.
There are some researches show that hyaluronic acid, chitosan, chondroitin sulfate all have the effect promoting urothelium injury repairing, such as, disclosed high dose chondroitin sulfate in patent CN1758920A to the curative effect damaging bladder and the urethral disease caused due to GAGs.
In addition, CN201010502271.9 (CN102441007A) discloses a kind of irrigation of bladder liquid of composite parts, is that the chitosan of 0.1-0.8% and normal saline balance liquid form by concentration 0.5-1% hyaluronic acid sodium, concentration.Hyaluronic acid sodium can participate in repairing, and chitosan can antibacterial pain relieving, thus reaches and can participate in original position and to organize and can the object for the treatment of interstitial cystitis of antibacterial pain relieving.
Disclose with the Intravesical instillation agent of chitosan, hyaluronic acid and phosphate buffer composition in CN201310753152.4 (publication number is CN103655601A), wherein hyaluronic acid concentration is 0.01-0.1%, chitosan 0.005-0.2%, but the effective ingredient relative concentration wherein used is lower.
In patent CN200610024263.1 (publication number is CN101028280A), prepare lavage liquor preparation with hyaluronate sodium and water soluble chitose.This lavage liquor preparation for operation combines the biological characteristics of hyaluronate sodium and chitosan, prepares with different proportionings, can be widely used in the operations such as ophthalmology, surgical operation, intraperitoneal chemotherapy, have better clinical effectiveness.This patent is mainly used for using in operation, and play post-operation adhesion preventing effect, wherein the concentration of hyaluronate sodium is 0.01-0.6%, chitosan 0.1-2.0%.
Do not see other proportionings of hyaluronic acid, chitosan and chondroitin sulfate and the effect in cell migration thereof.
Summary of the invention
The object of this invention is to provide a kind of compositions for bladder and urothelial injury repairing.
A kind of compositions for bladder and urothelial injury repairing provided by the invention, it is made up of two or three in following composition: hyaluronic acid, chitosan and chondroitin sulfate.
Concrete, described compositions is made up of two or three in following composition: hyaluronic acid 1-250 part, chitosan 1-800 part or chondroitin sulfate 1-1000 part.
Preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 1-250 part and chitosan 1-800 part.
Further preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 10-50 part and chitosan 80-800 part.
Further preferred, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 20 parts and chitosan 85 parts.
Or as another technical scheme, preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 1-250 part and chondroitin sulfate 1-1000 part.
Further preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 8-100 part and chondroitin sulfate 10-800 part.
Or as another technical scheme, preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: chitosan 1-800 part and chondroitin sulfate 1-1000 part.
Further preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: chitosan 10-800 part and chondroitin sulfate 50-500 part.
Or as another technical scheme, preferably, described compositions is grouped into by three kinds of one-tenth of following weight portion: hyaluronic acid 1-250 part, chitosan 1-800 part and chondroitin sulfate 1-1000 part.
Further preferably, described compositions is made up of three kinds of components Component of following weight portion: hyaluronic acid 8-100 part, chitosan 10-800 part and chondroitin sulfate 50-500 part.
In above-mentioned composition:
Described hyaluronic acid is hyaluronate, is preferably hyaluronate sodium or hyaluronic acid magnesium;
Described chitosan is soluble chitosan, is preferably carboxymethyl chitosan;
Described chondroitin sulfate is chondroitin sulfate salt, is preferably sodium chondroitin sulfate or calcium chondroitin sulfate.
Present invention also offers the preparation containing above-mentioned composition, in described preparation, the proportion of compositions is 0.02-20.5% (w/v).
Described preparation is gel, aqueous solution.
Described preparation is made up of compositions and aqueous carrier.
Wherein aqueous carrier is sterile liquid, preferred water for injection, normal saline and phosphate buffer, described phosphate buffer sodium chloride-containing, sodium hydrogen phosphate and sodium dihydrogen phosphate.
The reparation that the present invention also provides above-mentioned composition or formulation application to damage in bladder and urothelial.Bladder and urothelial damage are GAGs-shortage property disease, be preferably interstitial cystitis, painful bladder syndrome, chemical cystitis or radiocystitis, the disorder of bladder that clinical manifestation is is symptom with frequent micturition, urgent micturition, chronic bladder pain, the urodynamic that urothelial is damaged and caused.
Compositions provided by the invention and preparation thereof have the following advantages:
1, described bladder and urothelial injury repairing compositions, have good physicochemical property.Its main technical requirements is in table 1.
Table 1 bladder and urothelial injury repairing compositions main technical requirements
| Project | Technical requirement |
| Light transmittance | 660nm place light transmittance >=99.0% |
| PH value | The pH value of solution should be 6.0 ~ 8.0 |
| Protein content | ≤ 0.1% (mass fraction) |
| Content of beary metal | ≤10μg/g |
| Residual ethanol | ≤400μg/g |
| Bacterial endotoxin is limited the quantity | ≤0.5EU/mg |
| Aseptic | Should be aseptic |
| Uv absorption | OD value≤1.0,280nm place; OD value≤1.0,260nm place |
2, the bladder that the present invention relates to and urothelial injury repairing compositions also have reliable biological safety and effectiveness.According to GB 16886 series standard, the cytotoxicity of the compositions that the inventive method is produced is 1 grade, stimulates, hereditary-less toxicity without sensitization and Intradermal, and good with blood compatibility.
3, preclinical animal studies shows, the bladder that the present invention relates to and urothelial injury repairing compositions obviously can repair the urothelium damage caused by protamine sulfate or cyclophosphamide model, remarkable minimizing urothelium damage range and the extent of damage, reduce inflammation infiltration degree.
Detailed description of the invention
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Described w/v is g:mL.
Embodiment 1: for the compositions of bladder and urothelial injury repairing
1, active component content: hyaluronic acid 0.2%, chitosan 0.85%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) by hyaluronic acid dissolves in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.4% (w/v), for subsequent use;
(3) chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 1.7% (w/v), for subsequent use;
(4) solution of step (2) (3) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(5) the sterilized 0.22 μm of filter membrane of composition solution step (4) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains the bladder containing hyaluronic acid and chitosan two kinds of components and urothelial injury repairing compositions.
Embodiment 2: for the compositions of bladder and urothelial injury repairing
1, active component content: hyaluronic acid 0.01%, chitosan 8%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) by hyaluronic acid dissolves in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.02% (w/v), for subsequent use;
(3) chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 16% (w/v), for subsequent use;
(4) solution of step (2) (3) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(5) the sterilized 0.22 μm of filter membrane of composition solution step (4) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains the bladder containing hyaluronic acid and chitosan two kinds of components and urothelial injury repairing compositions.
Embodiment 3: for the compositions of bladder and urothelial injury repairing
1, active component content: hyaluronic acid 2.5%, chitosan 0.01%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) by hyaluronic acid dissolves in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 5% (w/v), for subsequent use;
(3) chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.02% (w/v), for subsequent use;
(4) solution of step (2) (3) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(5) the sterilized 0.22 μm of filter membrane of composition solution step (4) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains the bladder containing hyaluronic acid and chitosan two kinds of components and urothelial injury repairing compositions.
Embodiment 4: for the compositions of bladder and urothelial injury repairing
1, active component content: hyaluronic acid 0.08%, chondroitin sulfate 4%.
2, preparation method
(1) by hyaluronic acid dissolves in physiological saline solution, be mixed with the solution that concentration is 0.16% (w/v), for subsequent use;
(2) chondroitin sulfate is dissolved in physiological saline solution, is mixed with the solution that concentration is 8% (w/v), for subsequent use;
(3) solution of step (1) (2) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(4) the sterilized 0.22 μm of filter membrane of composition solution step (3) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains the bladder containing hyaluronic acid and chondroitin sulfate two kinds of components and urothelial injury repairing compositions.
Embodiment 5: for the compositions of bladder and urothelial injury repairing
1, active component content: hyaluronic acid 0.01%, chondroitin sulfate 10%.
2, preparation method
(1) by hyaluronic acid dissolves in physiological saline solution, be mixed with the solution that concentration is 0.02% (w/v), for subsequent use;
(2) chondroitin sulfate is dissolved in physiological saline solution, is mixed with the solution that concentration is 20% (w/v), for subsequent use;
(3) solution of step (1) (2) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(4) the sterilized 0.22 μm of filter membrane of composition solution step (3) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains the bladder containing hyaluronic acid and chondroitin sulfate two kinds of components and urothelial injury repairing compositions.
Embodiment 6: for the compositions of bladder and urothelial injury repairing
1, active component content: hyaluronic acid 2.5%, chondroitin sulfate 0.01%.
2, preparation method
(1) by hyaluronic acid dissolves in physiological saline solution, be mixed with the solution that concentration is 5% (w/v), for subsequent use;
(2) chondroitin sulfate is dissolved in physiological saline solution, is mixed with the solution that concentration is 0.02% (w/v), for subsequent use;
(3) solution of step (1) (2) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(4) the sterilized 0.22 μm of filter membrane of composition solution step (3) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains the bladder containing hyaluronic acid and chondroitin sulfate two kinds of components and urothelial injury repairing compositions.
Embodiment 7: for the compositions of bladder and urothelial injury repairing
1, active component content: chitosan 1%, chondroitin sulfate 3%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) water-soluble chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 2% (w/v), for subsequent use;
(3) chondroitin sulfate is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 6% (w/v), for subsequent use;
(4) solution of step (2) (3) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(5) composition solution that step (4) obtains is carried out being positioned in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 15min under 0.11MPa condition, obtain the bladder containing chitosan and chondroitin sulfate two kinds of components and urothelial injury repairing compositions.
Embodiment 8: for the compositions of bladder and urothelial injury repairing
1, active component content: chitosan 0.01%, chondroitin sulfate 10%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) water-soluble chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.02% (w/v), for subsequent use;
(3) chondroitin sulfate is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 20% (w/v), for subsequent use;
(4) solution of step (2) (3) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(5) composition solution that step (4) obtains is carried out being positioned in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 15min under 0.11MPa condition, obtain the bladder containing chitosan and chondroitin sulfate two kinds of components and urothelial injury repairing compositions.
Embodiment 9: for the compositions of bladder and urothelial injury repairing
1, active component content: chitosan 8%, chondroitin sulfate 0.01%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) water-soluble chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 16% (w/v), for subsequent use;
(3) chondroitin sulfate is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.02% (w/v), for subsequent use;
(4) solution of step (2) (3) is mixed according to volume ratio 1:1, and fully stirring makes its mix homogeneously.
(5) composition solution that step (4) obtains is carried out being positioned in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 15min under 0.11MPa condition, obtain the bladder containing chitosan and chondroitin sulfate two kinds of components and urothelial injury repairing compositions.
Embodiment 10 is for the compositions of bladder and urothelial injury repairing and preparation thereof
1, active component content: chitosan 0.01%, chondroitin sulfate 5%, hyaluronic acid 0.5%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) water-soluble chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.03% (w/v), for subsequent use;
(3) chondroitin sulfate is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 15% (w/v), for subsequent use;
(4) by hyaluronic acid dissolves in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 1.5% (w/v).
(5) solution of step (2) (3) (4) is mixed according to volume ratio 1:1:1, and fully stirring makes its mix homogeneously.
(6) the sterilized 0.22 μm of filter membrane of composition solution step (5) obtained under high pressure carries out aseptic filtration.Solution after filtration carries out fill, obtains bladder containing chitosan, chondroitin sulfate and hyaluronic acid three kinds of components and urothelial hinders remediation composition capable.
Embodiment 11: for the compositions of bladder and urothelial injury repairing
1, active component content: chitosan 4%, chondroitin sulfate 5%, hyaluronic acid 0.01%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) under hundred grades of clean environments, water-soluble chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 12% (w/v), for subsequent use;
(3) under hundred grades of clean environments, chondroitin sulfate is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 15% (w/v), for subsequent use;
(4) under hundred grades of clean environments, by hyaluronic acid dissolves in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.03% (w/v).
(5) solution of step (2) (3) (4) is mixed according to volume ratio 1:1:1, and fully stirring makes its mix homogeneously.
(6) composition solution that step (5) obtains aseptically is carried out fill, obtain bladder containing chitosan, chondroitin sulfate and hyaluronic acid three kinds of components and urothelial hinders remediation composition capable.
Embodiment 12: for the compositions of bladder and urothelial injury repairing
1, active component content: chitosan 4%, chondroitin sulfate 0.01%, hyaluronic acid 0.5%.
2, preparation method
(1) phosphate buffer of the sodium dihydrogen phosphate of preparation containing the sodium chloride of 0.85% (w/v), the sodium hydrogen phosphate and 0.02% (w/v) of 0.22% (w/v), and be placed in high-pressure steam sterilizing pan, at 121 DEG C, sterilizing 30min under 0.11MPa condition, both sterile phosphate buffer was obtained, for subsequent use;
(2) water-soluble chitosan is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 12% (w/v), for subsequent use;
(3) under hundred grades of clean environments, chondroitin sulfate is dissolved in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 0.03% (w/v), for subsequent use;
(4) under hundred grades of clean environments, by hyaluronic acid dissolves in step 1) in the sterile phosphate buffer that obtains, be mixed with the solution that concentration is 1.5% (w/v), for subsequent use;
(5) solution of step (2) (3) (4) is mixed according to volume ratio 1:1:1, and fully stirring makes its mix homogeneously.
(6) after the composition solution that step (5) obtains being carried out fill, at 121 DEG C, sterilizing 15min under 0.11MPa condition, obtain bladder containing chitosan, chondroitin sulfate and hyaluronic acid three kinds of components and urothelial hinders remediation composition capable.
Experimental example 1: physicochemical property detects
1, detect the compositions that embodiment 1-12 provides, concrete detection method is:
Light transmittance: measure according to the method for " the People's Republic of China's pharmacopeia " annex IV A.
PH value: the method specified according to the Pharmacopoeia of the People's Republic of China two annex VI H measures.
Protein content: adopt Ku Masi light blue method to measure.
Content of beary metal: measure according to the Pharmacopoeia of the People's Republic of China two annex VIII H first methods.
Residual ethanol: adopt headspace gas chromatography that ethanol is separated with other components, with flame ionization ditector detection, and compared with the chromatographic peak ethanol chromatographic peak obtained and embodiment 1-5 obtained, calculates Residual ethanol.
Bacterial endotoxin is limited the quantity: measure according to the Pharmacopoeia of the People's Republic of China (version in 2010) two methods that annex XI E specifies
Aseptic: to measure according to the Pharmacopoeia of the People's Republic of China (version in 2010) two methods that annex XI H specifies
Uv absorption: the compositions that Example provides take normal saline as blank, measures according to the method for the Pharmacopoeia of the People's Republic of China (version in 2010) two annex IV A
2, testing result: in Table 2-1,2-2
Table 2-1 embodiment 1-6 testing result
Table 2-2 embodiment 7-12 testing result
The display of table 2-1,2-2 result, embodiment 1-12 has good physicochemical property.Specifically, light transmittance and the normal saline of embodiment are close, and ultraviolet absorption value meets its technical requirement, and demonstrating bladder prepared by embodiment and urothelial, to hinder remediation composition capable solubility property good, and impurity content is low.Neutral pH value and lower albumen, heavy metal and Residual ethanol, what demonstrate that bladder prepared by embodiment and urothelial hinder remediation composition capable causes the probability of immunologic rejection or stimulation lower, is applicable to human body and uses.In addition, aseptic and lower Bacterial endotoxin limit, demonstrate bladder and urothelial and hinder remediation composition capable and can not cause in application process and infect phenomenon and heat source response.
Experimental example 2: on the impact of the urothelium damage caused by protamine sulfate
1, laboratory animal: Adult female SD rat, Mus 6-8 in age week, body weight 180-260 gram,
2, experiment grouping: 50 rats are divided into 5 groups at random, are respectively contrast 1 group, contrast 2 groups, hyaluronic acid group, chitosan group and embodiment 1-3 group.Wherein often organize sample and pour into 1ml at every turn.
Contrast 1 group: give the sterile phosphate buffer that embodiment 1 provides;
Contrast 2 groups: 0.05% hyaluronic acid prepared with reference to patent CN201310753152.4 (CN103655601A) embodiment and 0.05% chitosan solution, solvent for the embodiment of the present invention 1 provide phosphate buffer;
Hyaluronic acid group, chitosan group: give the solution containing 0.2% hyaluronic acid, 0.8% chitosan respectively, solvent is the sterile phosphate buffer that embodiment 1 provides;
Embodiment 1-3 group: the compositions giving embodiment 1-3 respectively.
3, experimental technique:
Urothelium injured animal model is built by irrigation of bladder 50mg/ml protamine sulfate.
After model is successfully established, pour into according to grouping respectively, and retain 30 minutes.Continous pouring 5 days.
After rat is put to death, by HE dyeing tissues observed inflammatory infiltration situation and monocyte count, and carry out mast cell counts by Toluidine blue staining.
4, experimental result: in table 3
Mononuclear cell, Amount of Mast Cells that table 3. zoopery is respectively organized
| Monocyte count | Mast cell counts | |
| Contrast 1 group | 20.4±3.5 | 11.3±1.2 |
| Hyaluronic acid group | 7.0±1.5 | 3.4±1.0 |
| Chitosan group | 12.2±2.4 | 6.7±1.4 |
| Contrast 2 groups | 5.4±1.7 | 3.2±1.2 |
| Embodiment 1 group | 4.2±1.2 | 2.5±0.5 |
| Embodiment 2 groups | 3.5±0.9 | 2.3±1.1 |
| Embodiment 3 groups | 4.9±1.3 | 2.5±1.4 |
Table 3 result shows: contrast 1 group of urothelium and show edema and hyperemia, urothelium fibrous tissue increases, and hyperplasia is obvious, and inflammatory cell infiltration is serious.Contrast 2 groups, hyaluronic acid, the edema of rat bladder tissue of chitosan group and embodiment 1-3 group and redness degree comparatively light, and the compositions, repairs effect of embodiment 1-3 is better than the repairing effect of hyaluronic acid, chitosan and contrast 2 groups.In embodiment 1-3, the repairing effect of embodiment 2 is relatively better.Data statistics shows, the amount of mononuclear cells of embodiment 2 with contrast, cellophane acid group and chitosan group have significant difference (P<0.05), there was no significant difference (P>0.05) between embodiment 1-3 group.
Experimental example 3: on the impact of the urothelium damage caused by cyclophosphamide
1, laboratory animal: Adult female SD rat, Mus 6-8 in age week, body weight 180-260 gram,
2, experiment grouping: 40 rats are divided into 4 groups at random, are respectively matched group, hyaluronic acid group, chondroitin sulfate group and embodiment 4-6 group, wherein often organizes sample and pours into 1ml at every turn.
Matched group: give physiological saline solution.
Hyaluronic acid group, chondroitin sulfate group: give the solution containing 0.08% hyaluronic acid, 4% chondroitin sulfate respectively, its solvent is physiological saline solution;
Embodiment 4-6 group: give compositions prepared by embodiment 4-6.
3, experimental technique:
By intraperitoneal injection of cyclophosphamide, injected dose is that 200mg/kg (cyclophosphamide consumption/rat weight) builds urothelium injured animal model.
After model is successfully established, pour into according to grouping respectively, and retain 30 minutes.Continous pouring 5 days.
After rat is put to death, by HE dyeing tissues observed inflammatory infiltration situation and single disease cell counting.
4, experimental result: in table 4
Mononuclear cell, Amount of Mast Cells that table 4. zoopery is respectively organized
| Monocyte count | |
| Matched group | 50.4±3.5 |
| Hyaluronic acid group | 27.8±1.3 |
| Chondroitin sulfate group | 21.9±1.0 |
| Embodiment 4 groups | 15.2±0.8 |
| Embodiment 5 groups | 17.7±1.1 |
| Embodiment 6 groups | 13.4±0.9 |
Table 4 result shows: matched group urothelium shows edema and hyperemia, and urothelium fibrous tissue increases, and hyperplasia is obvious, and inflammatory cell infiltration is serious.The edema of the rat bladder tissue of hyaluronic acid, chondroitin sulfate group and embodiment 4-6 group and redness degree are comparatively light, and the compositions, repairs effect of embodiment 4-6 is better than repairing effect when hyaluronic acid and chondroitin sulfate are used alone.In embodiment 4-6, minimum with the mononuclear cell number of embodiment 6, inflammatory reaction is the lightest, and repairing effect is best.Data statistics shows, there were significant differences (P<0.05) for the amount of mononuclear cells of embodiment 4-6 group and matched group, hyaluronic acid group and chondroitin sulfate group, there was no significant difference (P>0.05) between embodiment 4-6 group.
Experimental example 4: on the impact of the urothelium damage caused by protamine sulfate
1, laboratory animal: Adult female SD rat, Mus 6-8 in age week, body weight 180-260 gram,
2, experiment grouping: 40 rats are divided into 4 groups at random, are respectively matched group, chitosan group, chondroitin sulfate group and embodiment 7-9 group.Wherein often organize sample and pour into 1ml at every turn.
Matched group: give phosphate buffer.
Chitosan group, chondroitin sulfate group: give respectively containing 1% chitosan, 3% chondroitin sulfate solution, solvent is the phosphate buffer of embodiment 7.
Embodiment 7-9 group: give compositions prepared by embodiment 7-9.
3, experimental technique:
Urothelium injured animal model is built by irrigation of bladder 100mg/ml protamine sulfate.
After model is successfully established, pour into according to grouping respectively, and retain 30 minutes.Continous pouring 5 days.
After rat is put to death, by HE dyeing tissues observed inflammatory infiltration situation and monocyte count, and carry out mast cell counts by Toluidine blue staining.
4, experimental result: in table 5
Mononuclear cell, Amount of Mast Cells that table 5 zoopery is respectively organized
| Monocyte count | Mast cell counts | |
| Matched group | 30.4±3.5 | 17.3±1.2 |
| Chitosan group | 19.9±2.3 | 8.6±2.9 |
| Chondroitin sulfate group | 12.7±1.0 | 5.3±1.0 |
| Embodiment 7 groups | 7.2±0.8 | 2.5±0.3 |
| Embodiment 8 groups | 8.5±1.7 | 3.4±1.1 |
| Embodiment 9 groups | 9.7±0.6 | 3.9±0.4 |
Table 5 result shows: matched group urothelium shows edema and hyperemia, and urothelium fibrous tissue increases, and hyperplasia is obvious, and inflammatory cell infiltration is serious.The edema of the rat bladder tissue of chitosan group, chondroitin sulfate group and embodiment 7-9 group and redness degree are comparatively light, and the compositions, repairs effect of embodiment 7-9 is better than other 3 groups.Embodiment 7-9 tri-groups contrast, the repairing effect of embodiment 7 is best.Data statistics shows, the mononuclear cell of embodiment 7-9 group and Amount of Mast Cells and other three groups have significant difference (P<0.05), there was no significant difference (P>0.05) between embodiment 7-9 group.
Experimental example 5: on the impact of the urothelium damage caused by protamine sulfate
1, laboratory animal: Adult female SD rat, Mus 6-8 in age week, body weight 180-260 gram,
2, experiment grouping: 50 rats are divided into 5 groups at random, are respectively matched group, chitosan group, hyaluronic acid group, chondroitin sulfate group and embodiment 10-12 group.Wherein often organize sample and pour into 1ml at every turn.
Matched group: give phosphate buffer.
Chitosan group, hyaluronic acid group, chondroitin sulfate group: give the solution containing 0.1% chitosan, 0.5% hyaluronic acid and 0.01% chondroitin sulfate respectively, solvent is the phosphate buffer of embodiment 12.
Embodiment 10-12 group: give compositions prepared by embodiment 10-12.
3, experimental technique:
Urothelium injured animal model is built by irrigation of bladder 50mg/ml protamine sulfate.
After model is successfully established, pour into according to grouping respectively, and retain 30 minutes.Continous pouring 5 days.
After rat is put to death, by HE dyeing tissues observed inflammatory infiltration situation and single disease cell counting, and carry out mast cell counts by Toluidine blue staining.
4, experimental result: in table 6
Mononuclear cell, Amount of Mast Cells that table 6. zoopery is respectively organized
| Monocyte count | Mast cell counts | |
| Matched group | 20.4±3.5 | 11.3±1.2 |
| Chitosan group | 16.7±2.5 | 8.2±2.3 |
| Hyaluronic acid group | 8.3±1.3 | 4.3±1.1 |
| Chondroitin sulfate group | 8.0±1.5 | 5.0±1.9 |
| Embodiment 10 groups | 4.4±0.7 | 2.1±1.1 |
| Embodiment 11 groups | 5.6±1.2 | 2.9±0.3 |
| Embodiment 12 groups | 3..0±0.5 | 1.7±0.4 |
Table 6 result shows: matched group urothelium shows edema and hyperemia, and urothelium fibrous tissue increases, and hyperplasia is obvious, and inflammatory cell infiltration is serious.The edema degree of the rat bladder tissue of chitosan, hyaluronic acid, chondroitin sulfate group and embodiment 10-12 group is lighter, and the compositions, repairs effect of embodiment 10-12 is better than other experimental grouies, in embodiment 10-12, best with the effect of the urothelium injury repairing of embodiment 12.Data statistics shows, the mononuclear cell that embodiment is 12 groups and Amount of Mast Cells and matched group, chitosan group, hyaluronic acid group and chondroitin sulfate group have significant difference (P<0.05), do not have significant difference (P>0.05) between embodiment 10-12 group.
Although above with general explanation, detailed description of the invention and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1., for a compositions for bladder and urothelial injury repairing, it is characterized in that, it is made up of two or three in following composition: hyaluronic acid, chitosan and chondroitin sulfate.
2. compositions according to claim 1, is characterized in that, described compositions is made up of two or three in following composition: hyaluronic acid 1-250 part, chitosan 1-800 part or chondroitin sulfate 1-1000 part.
3. compositions according to claim 2, is characterized in that, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 1-250 part and chitosan 1-800 part;
Preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 10-50 part and chitosan 80-800 part;
Further preferably, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 20 parts and chitosan 85 parts.
4. compositions according to claim 2, is characterized in that, described compositions is grouped into by two kinds of one-tenth of following weight portion: hyaluronic acid 1-250 part and chondroitin sulfate 1-1000 part;
Preferably, described compositions is grouped into by following two kinds of one-tenth: hyaluronic acid 8-100 part and chondroitin sulfate 10-800 part.
5. compositions according to claim 2, is characterized in that, described compositions is grouped into by two kinds of one-tenth of following weight portion: chitosan 1-800 part and chondroitin sulfate 1-1000 part;
Preferably, described compositions is grouped into by following two kinds of one-tenth: chitosan 10-800 part and chondroitin sulfate 50-500 part.
6. compositions according to claim 2, is characterized in that, described compositions is grouped into by three kinds of one-tenth of following weight portion: hyaluronic acid 1-250 part, chitosan 1-800 part and chondroitin sulfate 1-1000 part.
7. compositions according to claim 6, is characterized in that, described compositions is grouped into by three kinds of one-tenth of following weight portion: hyaluronic acid 8-100 part, chitosan 10-800 part and chondroitin sulfate 50-500 part.
8. the compositions according to any one of claim 1-7, is characterized in that, described hyaluronic acid is hyaluronate, is preferably hyaluronate sodium or hyaluronic acid magnesium;
Described chitosan is soluble chitosan, is preferably carboxymethyl chitosan;
Described chondroitin sulfate is chondroitin sulfate salt, is preferably sodium chondroitin sulfate or calcium chondroitin sulfate.
9., containing the preparation of compositions described in any one of claim 1-8, it is characterized in that, in described preparation, the proportion of compositions is 0.02-20.5%.
10. the compositions that provides of any one of claim 1-8 or formulation application according to claim 9 are in the reparation of bladder and urothelial damage, described bladder and urothelial damage are GAGs-shortage property disease, be preferably interstitial cystitis, painful bladder syndrome, chemical cystitis or radiocystitis.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101287473A (en) * | 2005-10-12 | 2008-10-15 | 生化学工业株式会社 | Agent for applying to mucosa and method for production thereof |
| CN102441007A (en) * | 2010-10-11 | 2012-05-09 | 上海景峰制药有限公司 | Bladder perfusate containing composite components |
| CN103655601A (en) * | 2013-12-31 | 2014-03-26 | 上海建华精细生物制品有限公司 | Combination used for bladder irrigation |
| CN104220078A (en) * | 2012-03-30 | 2014-12-17 | 菲迪亚医药公司 | Pharmaceutical formulations comprising chondroitin sulfate and hyaluronic acid derivatives |
| CN105982912A (en) * | 2015-03-02 | 2016-10-05 | 黄绣川 | Pharmaceutical composition containing sodium hyaluronate and chondroitin sulfate |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101287473A (en) * | 2005-10-12 | 2008-10-15 | 生化学工业株式会社 | Agent for applying to mucosa and method for production thereof |
| CN102441007A (en) * | 2010-10-11 | 2012-05-09 | 上海景峰制药有限公司 | Bladder perfusate containing composite components |
| CN104220078A (en) * | 2012-03-30 | 2014-12-17 | 菲迪亚医药公司 | Pharmaceutical formulations comprising chondroitin sulfate and hyaluronic acid derivatives |
| CN103655601A (en) * | 2013-12-31 | 2014-03-26 | 上海建华精细生物制品有限公司 | Combination used for bladder irrigation |
| CN105982912A (en) * | 2015-03-02 | 2016-10-05 | 黄绣川 | Pharmaceutical composition containing sodium hyaluronate and chondroitin sulfate |
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Application publication date: 20150930 |