CN113925959B - Recombinant human collagen composition and application thereof - Google Patents
Recombinant human collagen composition and application thereof Download PDFInfo
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- CN113925959B CN113925959B CN202111391132.8A CN202111391132A CN113925959B CN 113925959 B CN113925959 B CN 113925959B CN 202111391132 A CN202111391132 A CN 202111391132A CN 113925959 B CN113925959 B CN 113925959B
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- recombinant human
- human collagen
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention provides a recombinant human collagen composition and application thereof, belonging to the technical field of pharmaceutical compositions; in the invention, the recombinant human collagen composition is prepared based on recombinant human collagen, sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, polyhexamethylene biguanide hydrochloride and water injection water; the recombinant human collagen composition can be used for preparing medicines for treating interstitial cystitis and related diseases; the recombinant human collagen composition has no hepatotoxicity and nephrotoxicity, and has low cost and better effect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical compositions, and particularly relates to a recombinant human collagen composition and application thereof.
Background
Bladder pain syndrome/interstitial cystitis (bladder pain syndrome/interstitial cystitis, BPS/IC) is a chronic, non-bacterial inflammatory disease of unknown cause. The clinical symptoms are mainly manifested by frequent urination, urgent urination and pain in the suprapubic area after bladder filling, and relief after urination. There is no unified conclusion on the cause, pathogenesis, pathophysiology, treatment, etc. of interstitial cystitis. Currently, the glycosaminoglycan layer defect theory (GAGs) is mainly considered as the cause of interstitial cystitis, i.e., the existence of a complete glycosaminoglycan layer in the normal bladder epithelium, and has the effects of permeation resistance and mucosal barrier. In patients with interstitial cystitis, the GAG layer of the mucous membrane layer is reduced, which leads to the change of the permeability of the epithelium, and urine toxic substances permeate the mucous membrane layer, so that the patients can produce symptoms such as pain, frequent urination and the like.
At present, the substitute layers of the GAG layer are endless, including sodium hyaluronate, sodium pentose polysulfate, heparin, chondroitin sulfate and the like, which are used for treating the IC through bladder perfusion, the medicines are mainly components of the bladder mucosa GAG layer, and the medicines can quickly form a barrier on the surface of the bladder mucosa to replace the damaged GAG layer. However, the currently marketed drugs for bladder injection have disadvantages. For example, bladder injection drugs containing DMSO as a main ingredient are prone to cause chemical cystitis, scleral pigmentation, and liver and kidney toxicity, and garlic odor in whole body, and may aggravate frequent urination symptoms of patients at the early stage of treatment; heparin with anticoagulation cannot be used for patients with severe symptoms because the heparin can not be reserved for too long time in the bladder, and blood vessels can be broken due to excessive urine holding, so that heparin combined with lidocaine alkalization cannot be used for patients with severe symptoms, and sodium hyaluronate has the defect of high price. Thus, there is a need for a bladder injection drug to ameliorate interstitial cystitis.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a recombinant human collagen composition and application thereof. In the invention, a recombinant human collagen composition is prepared based on recombinant human type 3 collagen, sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, polyhexamethylene biguanide hydrochloride and water injection; the recombinant human collagen composition can be used for preparing medicines for treating interstitial cystitis and related diseases; the recombinant human collagen composition has no hepatotoxicity and nephrotoxicity, and has low cost and better effect.
The invention firstly provides a recombinant human collagen composition, which comprises recombinant human collagen, sodium chloride, disodium hydrogen phosphate monohydrate, sodium dihydrogen phosphate, polyhexamethylene biguanide hydrochloride and water for injection.
Further, in the recombinant human collagen composition, each 1L of water for injection contains 10g of recombinant human collagen, 7.0-9.0g of sodium chloride, 1.5-2.0g of sodium dihydrogen phosphate, 0.1-1.0g of disodium hydrogen phosphate and 0.01-0.1g of polyhexamethylene biguanide hydrochloride.
Preferably, the recombinant human collagen composition contains 10g of recombinant human collagen, 8.5g of sodium chloride, 1.7g of sodium dihydrogen phosphate, 0.5g of disodium hydrogen phosphate and 0.03g of polyhexamethylene biguanide hydrochloride in each 1L of water for injection.
Further, the recombinant human collagen is recombinant human type 3 collagen; the recombinant human-derived type 3 collagen has the total length of 474 amino acids, wherein 1-229 and 233-461 are identical human III type collagen fragments, EFT connection is arranged between the two human III type collagen fragments, and the human III type collagen fragments of 233-461 are modified by DHHHHHHTGLARF, and the amino acid sequence is shown as SEQ ID NO. 1.
The invention also provides a preparation method of the recombinant human collagen composition, which specifically comprises the following steps:
adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate into water for injection, stirring and mixing uniformly, then adding recombinant human collagen, and stirring until the recombinant human collagen is completely dissolved; then adding polyhexamethylene biguanide hydrochloride solution into the mixture, stirring the mixture uniformly, adjusting the pH value, filtering the mixture, filling the mixture, and sealing the mixture.
Further, each 1L of water for injection contains 10g of recombinant human collagen, 7.0-9.0g of sodium chloride, 1.5-2.0g of sodium dihydrogen phosphate, 0.1-1.0g of disodium hydrogen phosphate and 0.01-0.1g of polyhexamethylene biguanide hydrochloride.
Preferably, each 1L of water for injection contains 10g of recombinant human collagen, 8.5g of sodium chloride, 1.7g of sodium dihydrogen phosphate, 0.5g of disodium hydrogen phosphate and 0.03g of polyhexamethylene biguanide hydrochloride.
Further, the pH value is adjusted by 8.5% sodium hydroxide solution, and the pH value is adjusted to 7.3-7.4.
Further, the filtering operation is as follows: the filtrate was filtered using a 0.45 μm filter and then the filtrate was filtered using a 0.22 μm filter.
The invention also provides application of the recombinant human collagen composition in preparing medicines for treating or preventing interstitial cystitis or related diseases.
Compared with the prior art, the invention has the beneficial effects that:
at present, antibiotics and hyaluronic acid medicines are generally used for perfusion treatment, but the antibiotics and hyaluronic acid medicines are expensive and are easy to generate hepatorenal toxicity. Animal-derived collagen can bring about immune rejection reaction, traditional collagen has poor water solubility, low bioactivity, low absorptivity and poor adhesion to cells, so that higher concentration participation is needed when the composition is used, the recombinant human collagen composition has higher efficiency, and only 1% concentration of recombinant human collagen is needed to exert the optimal curative effect, so that the structure of submucosal collagen fiber stripes is recovered, and collagen fibers are orderly arranged. The recombinant human collagen composition is not a chemical drug, does not cause chemical cystitis and the like caused by chemical substances, has no hepatotoxicity and nephrotoxicity, has no garlic odor, and has better social adaptability for patients.
In the invention, a more reasonable interstitial cystitis model is constructed, and the recombinant human collagen has therapeutic and reparative significance for cystitis through experimental demonstration for the first time. Meanwhile, the bladder sample and pathological section after treatment indicate that the bladder after treatment is soft, and the type III collagen content is rich and is quite opposite to bladder fibrosis caused by repeated inflammation. In addition, compared with the possible immune rejection reaction of animal-derived collagen in the prior art, the invention adopts fully humanized collagen, and the mouse experiment shows that the animal-derived collagen has no immune rejection risk.
The combination of the invention contains PHMB antibacterial components, and can be applied to interstitial cystitis caused by the deficiency of a glycosaminoglycan layer and also used for inflammation caused by bacterial infection. Cytotoxicity experiments in the invention prove that the recombinant human collagen composition has low toxicity. In addition, compared with the anticoagulation effect of heparin, the recombinant human collagen composition disclosed by the invention is easy to cause bladder hemorrhage, can be used for a long time, is not easy to cause hemorrhage, and has better bioavailability.
Drawings
FIG. 1 is a modeling pattern diagram of interstitial cystitis.
FIG. 2 is a graph comparing the urine color of the bladder of rats in the PBS control group, the IC model group, the IC+COL experimental group, and the IC+HA positive group.
FIG. 3 is a graph of HE staining of bladder tissue in PBS control group (A), IC model group (B), IC+COL experimental group (C), IC+HA positive group (D).
FIG. 4 shows the mast cell count in PBS control group (A), IC model group (B), IC+COL test group (C), IC+HA positive group (D).
Fig. 5 is a diagram showing arrangement of urinary bladder submucosa collagen fibers in the PBS control group (a), the IC model group (B), the ic+col experimental group (C), the ic+ha positive group (D), and the right side of A, B, C, D is an enlarged diagram in the left black frame.
FIG. 6 is a graph showing the results of immunohistochemical staining in PBS control group (A), IC model group (B), IC+COL test group (C), IC+HA positive group (D).
FIG. 7 is a graph showing cytotoxicity of recombinant human collagen at various concentrations.
Detailed Description
The invention will be further described with reference to the drawings and the specific embodiments, but the scope of the invention is not limited thereto.
Example 1:
the formula of the recombinant human collagen composition comprises: specification of: 50ml:0.5g, 1% strength
Recombinant human type 3 collagen: 10 (g)
Sodium chloride: 8.5 (g)
Sodium dihydrogen phosphate dihydrate: 1.7 (g)
Disodium hydrogen phosphate dodecahydrate: 0.5 (g)
Polyhexamethylene biguanide hydrochloride (PHMB): 0.03 (g)
Water for injection: 1000mL (split charging 20 bottles)
The preparation process comprises the following steps:
weighing 80% volume of water for injection into a liquid preparation tank, weighing the prescription amount of sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate, adding into the water, stirring for 15 minutes to completely dissolve, adding the prescription amount of recombinant human-derived type 3 collagen, and stirring for 15 minutes to completely dissolve the mixed solution.
Polyhexamethylene biguanide hydrochloride is prepared into mother solution (0.3%) with 100 times concentration, and the mother solution is added into the mixed solution in proportion to determine the pH, and then 8.5% sodium hydroxide solution is used for adjusting the pH to 7.3-7.4. Then, the water is added to a constant volume to full volume, the mixture is filtered by a 0.45 mu m filter membrane, and the filtrate is filtered by a 0.22 mu m filter membrane. Packaging the filtrate (50 ml/bottle), and sealing.
Example 2:
the formula of the recombinant human collagen composition comprises: specification of: 50mL:0.5g, 1% strength
Recombinant human type 3 collagen: 10 (g)
Sodium chloride: 7 (g)
Sodium dihydrogen phosphate dihydrate: 1.5 (g)
Disodium hydrogen phosphate dodecahydrate: 0.1 (g)
Polyhexamethylene biguanide hydrochloride (PHMB): 0.01 (g)
Water for injection: 1000mL (split charging 20 bottle)
The preparation process comprises the following steps:
weighing 80% volume of water for injection into a liquid preparation tank, weighing the prescription amount of sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate, adding into the water, stirring for 15 minutes to completely dissolve, adding the prescription amount of recombinant human-derived type 3 collagen, and stirring for 15 minutes to completely dissolve the mixed solution.
Polyhexamethylene biguanide hydrochloride is prepared into mother solution (0.3%) with 100 times concentration, and the mother solution is added into the mixed solution in proportion to determine the pH, and then 8.5% sodium hydroxide solution is used for adjusting the pH to 7.3-7.4. Then, the water is added to a constant volume to full volume, the mixture is filtered by a 0.45 mu m filter membrane, and the filtrate is filtered by a 0.22 mu m filter membrane. Packaging the filtrate (50 ml/bottle), and sealing.
Example 3:
the formula of the recombinant human collagen composition comprises: specification of: 50mL:0.5g, 1% strength
Recombinant human type 3 collagen: 10 (g)
Sodium chloride: 9 (g)
Sodium dihydrogen phosphate dihydrate: 2.0 (g)
Disodium hydrogen phosphate dodecahydrate: 1.0 (g)
Polyhexamethylene biguanide hydrochloride (PHMB): 0.1 (g)
Water for injection: 1000mL (split charging 20 bottle)
The preparation process comprises the following steps:
weighing 80% volume of water for injection into a liquid preparation tank, weighing the prescription amount of sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate, adding into the water, stirring for 15 minutes to completely dissolve, adding the prescription amount of recombinant human-derived type 3 collagen, and stirring for 15 minutes to completely dissolve the mixed solution.
Polyhexamethylene biguanide hydrochloride is prepared into mother solution (0.3%) with 100 times concentration, and the mother solution is added into the mixed solution in proportion to determine the pH, and then 8.5% sodium hydroxide solution is used for adjusting the pH to 7.3-7.4. Then, the water is added to a constant volume to full volume, the mixture is filtered by a 0.45 mu m filter membrane, and the filtrate is filtered by a 0.22 mu m filter membrane. Packaging the filtrate (50 mL/bottle), and sealing.
Example 4:
in this example, female SD rats (purchased from animal experiment center of university of Nanjing medical science) of 8-12 weeks old were selected to establish interstitial cystitis model as shown in FIG. 1, and the purchased SD rats were treated to obtain
PBS control group, IC model group, ic+col experimental group, ic+ha positive group.
Wherein, PBS control group is obtained by the following method: the rats were anesthetized with pentobarbital sodium, the female SD rats of 8-12 weeks old were catheterized with an epidural catheter as a rat catheter, the catheterization depth was about 3cm, the bladder was not injured, and after connecting a one-mL syringe, 0.5mL PBS bladder was infused, left for 75min, and then the rats were returned to their cages.
The IC model group is obtained by the following method: the rats were anesthetized with sodium pentobarbital, the female SD rats of 8-12 weeks old were catheterized with an epidural catheter as a catheter for rats, the catheterization depth was about 3cm, the urinary bladder was not injured, 0.5mL of protamine sulfate (PS, 10 mg/mL) was given to the urinary bladder after connecting a one-mL syringe, the urinary bladder was emptied after 45min of retention, the urinary bladder was flushed 3 times with Phosphate Buffer Solution (PBS), 2mg/mL of LPS was again injected, the urinary bladder was emptied after 30min of 0.5mL action, and the rats were returned to the squirrel cage.
The ic+col experimental group was obtained as follows: the rats are anesthetized by pentobarbital sodium, an epidural catheter is used as a rat catheter, female SD rats with the age of 8-12 weeks are catheterized, the insertion depth of the catheter is about 3cm, the bladder is not damaged, 0.5mL of protamine sulfate (PS, 10 mg/mL) is infused into the bladder after the catheter is connected with a milliliter syringe, the bladder is emptied after the bladder is reserved for 45min, phosphate Buffer Solution (PBS) is used for flushing the bladder for 3 times, 2mg/mL of LPS is infused again, and the bladder is emptied after 0.5mL acts for 30 min. After 3 times rinsing the bladder with PBS, 0.5mL of the recombinant human collagen composition was perfused and allowed to act for 30 minutes, after which the rats were returned to their cages.
The ic+ha positive group was obtained as follows: the rats are anesthetized by pentobarbital sodium, an epidural catheter is used as a rat catheter, female SD rats with the age of 8-12 weeks are catheterized, the insertion depth of the catheter is about 3cm, the bladder is not damaged, 0.5mL of protamine sulfate (PS, 10 mg/mL) is infused into the bladder after the catheter is connected with a milliliter syringe, the bladder is emptied after the bladder is reserved for 45min, phosphate Buffer Solution (PBS) is used for flushing the bladder for 3 times, 2mg/mL of LPS is infused again, and the bladder is emptied after 0.5mL acts for 30 min. After 3 times rinsing the bladder with PBS, 0.5mL of sodium hyaluronate (Xishitai) was perfused for 30 minutes, and the rats were then returned to the squirrel cage.
For rats in each group, the above procedure was repeated once daily, and the urine was collected on day 6 after continuous infusion for 5 days. On day 7, rats were sacrificed, bladder tissues were taken for pathological sections, hematoxylin-eosin (HE), toluidine blue, and mackerel staining were performed on the sections, the degree of inflammation was observed, mast cell counts were performed, and the collagen fiber arrangement was observed.
FIG. 2 is a graph comparing the color of the urine of the bladder of rats in the PBS control group, the IC model group, the IC+COL experimental group, and the IC+HA positive group. As can be seen from the figure, protamine Sulfate (PS) used in the interstitial cystitis model is liable to cause bladder bleeding, and no significant bladder bleeding was seen in rats treated with the recombinant human collagen composition prepared in the present invention. Whereas rats in the ic+ha positive group treated with HA had significantly lighter hematuria than the IC model group. This is because recombinant human collagen acts on the bladder epithelium, forming a protein barrier that temporarily replaces the damaged GAG layer of the bladder epithelial cells, resisting bladder bleeding caused by the modeling drug PS.
Sections stained by hematoxylin-eosin staining (HE) were placed under 100-fold and 200-fold mirrors, respectively, and bladder inflammation was observed. FIG. 3 is a graph of HE staining of bladder tissue in PBS control group (A), IC model group (B), IC+COL experimental group (C) and IC+HA positive group (D). From the figure, compared with the PBS control group, the IC model group can obviously see damage, even shedding, obvious edema under the mucosa, loose collagen fibers and infiltration of more inflammatory cells, thus proving that the model is successfully established. Meanwhile, compared with an IC model group, the IC+COL experimental group has complete mucosal epithelium, no obvious shedding damage, no obvious edema, compact arrangement of urinary bladder submucosal fibers and lighter inflammatory infiltration. In addition, the IC+HA positive group can obviously thicken bladder mucosa, however, submucosal edema is obvious, collagen fibers are loosely arranged, local inflammatory cell infiltration is obviously reduced compared with the IC model group, and the IC+HA positive group and the IC+COL experimental group have no obvious difference in inflammatory cell infiltration.
Mast cells are an indicator of the relative specificity of interstitial cystitis, and in this example, sections stained with toluidine blue are placed under 100 fold and 200 fold mirrors, respectively, and the number of bladder mast cells is observed. FIG. 4 shows the mast cell count in PBS control group (A), IC model group (B), IC+COL test group (C), IC+HA positive group (D). As can be seen from the figure, the IC model group clearly showed a significantly increased number of mast cells compared to the PBS control group, thus proving that the model was established successfully. Meanwhile, compared with an IC model group, the number of bladder mast cells in the IC+COL experimental group is obviously reduced. Furthermore, the number of mast cells was also significantly reduced in the ic+ha positive group compared to the IC model group, but there was no statistical difference compared to the ic+col experimental group.
The sections after the Masen staining were placed under a 100-fold mirror and a 200-fold mirror, respectively, to observe the arrangement of the mucosae and the detrusor collagen fibers. Fig. 5 is a graph showing the arrangement of urinary bladder submucosal collagen fibers in the PBS control group (a), the IC model group (B), the ic+col experimental group (C) and the ic+ha positive group (D), and the right graph in A, B, C, D is an enlarged graph in the left black frame, from which it can be seen that the submucosal blue collagen fibers of the PBS group are closely arranged, the stripes are clear, and the IC model group is compared with the PBS group, so that the submucosal collagen fibers are remarkably loose and the arrangement is disordered. The submucosal collagen fibers of the ic+col experimental group were closely aligned with clear stripes with significant differences compared to the IC group. In contrast, the IC+HA group showed a loose and disordered arrangement of submucosal collagen fibers.
Since the recombinant collagen used in the preparation of the recombinant human collagen composition according to the present invention contains a histone (6 x his) tag, the 6 x his tag was also identified by immunohistochemical staining in this example. Fig. 6 is a graph showing the results of immunohistochemical staining in PBS control group (a), IC model group (B), ic+col experimental group (C) and ic+ha positive group (D), and it can be seen from the graph that no obvious 6 x his label staining was seen in PBS control group, IC model group and ic+ha group immunohistochemical staining, whereas no obvious 6 x his label staining was seen in ic+col experimental group.
Example 5:
in this example, the toxicity of the recombinant human collagen composition on SV-HUC-1 normal bladder epithelial cell line (China academy of sciences cell bank National Collection of Authenticated Cell Cultures) was also studied using the recombinant human collagen composition diluted 2 times as a stock solution (5 mg/mL). The specific operation steps are as follows:
SV-HUC-1 cell line which enters logarithmic growth phase after culture is plated into 96-well plates, wherein the cell content in each well is 3000 cells/well, and the number of the wells is 5, and the total number of the wells is 6. After incubation for 24h, the medium was discarded.
100uL of medium diluted PS/LPS was added to the first column, wherein the PS concentration was 5. Mu.g/mL and the LPS concentration was 1. Mu.g/mL, as a negative control.
In the second column, 100uL of a stock solution mixture of PS/LPS/recombinant human collagen composition diluted in culture medium was added, and the PS concentration was maintained at 5. Mu.g/mL, the LPS concentration was maintained at 1. Mu.g/mL, and the recombinant human collagen concentration was maintained at 5mg/mL, followed by further culturing.
100uL of a stock mixture of PS/LPS/recombinant human collagen composition diluted in the medium was added to the third column, and the culture was continued while maintaining a PS concentration of 5. Mu.g/mL, an LPS concentration of 1. Mu.g/mL, and a recombinant human collagen composition concentration of 2.5 mg/mL.
100uL of a stock solution mixture of PS/LPS/recombinant human collagen composition diluted by a culture medium is added to the fourth column, the PS concentration is maintained to be 5 mug/mL, the LPS concentration is maintained to be 1 mug/mL, and the recombinant human collagen composition concentration is maintained to be 1mg/mL, and the culture is continued.
The PS/LPS/recombinant human collagen composition stock solution mixture diluted with 100uL of medium was added to the fifth column, and the PS concentration was maintained at 5 μg/mL, the LPS concentration was maintained at 1 μg/mL, and the recombinant human collagen composition concentration was maintained at 0.5mg/mL, followed by further culture.
Column 6 is blank wells. The above-mentioned well plate was cultured for 24 hours, 10. Mu.L of CCK8 reagent was added to each well, absorbance at 450nm was measured with an ELISA reader after 4 hours of culture, and then the data was processed to analyze cell viability.
Fig. 7 is a graph showing the results of cytotoxicity verification of recombinant human collagen at different concentrations, and the graph shows that the cell viability can reach 80% after the stock solution is diluted by 2 times, and the cell viability can reach 97% after the stock solution is diluted by 5 times and diluted by 10 times, thus showing that the product has lower toxicity.
In conclusion, the recombinant human collagen composition prepared by the invention can be well applied to the preparation of medicines for treating interstitial cystitis and related diseases.
The examples are preferred embodiments of the present invention, but the present invention is not limited to the above-described embodiments, and any obvious modifications, substitutions or variations that can be made by one skilled in the art without departing from the spirit of the present invention are within the scope of the present invention.
Sequence listing
<110> left stand
<120> a recombinant human collagen composition and use thereof
<160> 1
<170> SIPOSequenceListing 1.0
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<211> 474
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<400> 2
Ala Gly Asn Thr Gly Ala Pro Gly Ser Pro Gly Val Ser Gly Pro Lys
1 5 10 15
Gly Asp Ala Gly Gln Pro Gly Glu Lys Gly Ser Pro Gly Ala Gln Gly
20 25 30
Pro Pro Gly Ala Pro Gly Pro Leu Gly Ile Ala Gly Ile Thr Gly Ala
35 40 45
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
50 55 60
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly
65 70 75 80
Leu Ser Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Leu Pro Gly Leu
85 90 95
Ala Gly Thr Ala Gly Glu Pro Gly Arg Asp Gly Asn Pro Gly Ser Asp
100 105 110
Gly Leu Pro Gly Arg Asp Gly Ser Pro Gly Gly Lys Gly Asp Arg Gly
115 120 125
Glu Asn Gly Ser Pro Gly Ala Pro Gly Ala Pro Gly His Pro Gly Pro
130 135 140
Pro Gly Pro Val Gly Pro Ala Gly Lys Ser Gly Asp Arg Gly Glu Ser
145 150 155 160
Gly Pro Ala Gly Pro Ala Gly Ala Pro Gly Pro Ala Gly Ser Arg Gly
165 170 175
Ala Pro Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly Glu Thr Gly Glu
180 185 190
Arg Gly Ala Ala Gly Ile Lys Gly His Arg Gly Phe Pro Gly Asn Pro
195 200 205
Gly Ala Pro Gly Ser Pro Gly Pro Ala Gly Gln Gln Gly Ala Ile Gly
210 215 220
Ser Pro Gly Pro Ala Glu Phe Thr Ala Gly Asn Thr Gly Ala Pro Gly
225 230 235 240
Ser Pro Gly Val Ser Gly Pro Lys Gly Asp Ala Gly Gln Pro Gly Glu
245 250 255
Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu
260 265 270
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
275 280 285
Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val Lys Gly Glu
290 295 300
Ser Gly Lys Pro Gly Ala Asn Gly Leu Ser Gly Glu Arg Gly Pro Pro
305 310 315 320
Gly Pro Gln Gly Leu Pro Gly Leu Ala Gly Thr Ala Gly Glu Pro Gly
325 330 335
Arg Asp Gly Asn Pro Gly Ser Asp Gly Leu Pro Gly Arg Asp Gly Ser
340 345 350
Pro Gly Gly Lys Gly Asp Arg Gly Glu Asn Gly Ser Pro Gly Ala Pro
355 360 365
Gly Ala Pro Gly His Pro Gly Pro Pro Gly Pro Val Gly Pro Ala Gly
370 375 380
Lys Ser Gly Asp Arg Gly Glu Ser Gly Pro Ala Gly Pro Ala Gly Ala
385 390 395 400
Pro Gly Pro Ala Gly Ser Arg Gly Ala Pro Gly Pro Gln Gly Pro Arg
405 410 415
Gly Asp Lys Gly Glu Thr Gly Glu Arg Gly Ala Ala Gly Ile Lys Gly
420 425 430
His Arg Gly Phe Pro Gly Asn Pro Gly Ala Pro Gly Ser Pro Gly Pro
435 440 445
Ala Gly Gln Gln Gly Ala Ile Gly Ser Pro Gly Pro Ala Asp His His
450 455 460
His His His His Thr Gly Leu Ala Arg Phe
465 470
Claims (7)
1. Use of a recombinant human collagen composition for the preparation of a medicament for the treatment or prevention of interstitial cystitis or related diseases, characterized in that the recombinant human collagen composition comprises recombinant human collagen, sodium chloride, disodium hydrogen phosphate monohydrate, sodium dihydrogen phosphate, polyhexamethylene biguanide hydrochloride and water for injection; in the recombinant human collagen composition, each 1L of water for injection contains 10g of recombinant human collagen, 7.0-9.0g of sodium chloride, 1.5-2.0g of sodium dihydrogen phosphate, 0.1-1.0g of disodium hydrogen phosphate and 0.01-0.1g of polyhexamethylene biguanide hydrochloride;
the recombinant human collagen is recombinant human type 3 collagen; the recombinant human-derived type 3 collagen has the total length of 474 amino acids, wherein 1-229 and 233-461 are identical human III type collagen fragments, EFT connection is arranged between the two human III type collagen fragments, and the human III type collagen fragments of 233-461 are modified by DHHHHHHTGLARF, and the amino acid sequence is shown as SEQ ID NO. 1.
2. The use according to claim 1, wherein the recombinant human collagen composition comprises 10g of recombinant human collagen, 8.5g of sodium chloride, 1.7g of sodium dihydrogen phosphate, 0.5g of disodium hydrogen phosphate, and 0.03g of polyhexamethylene biguanide hydrochloride per 1L of water for injection.
3. The use according to claim 1, comprising:
adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate into 80% volume of water for injection, stirring and mixing uniformly, then adding recombinant human collagen, and stirring until the recombinant human collagen is completely dissolved; then adding polyhexamethylene biguanide hydrochloride solution into the mixture, stirring the mixture uniformly, adjusting the pH value of the mixture, supplementing water for injection, filtering the mixture, filling the mixture, and sealing the mixture.
4. Use according to claim 3, characterized in that it comprises 10g of recombinant human collagen, 7.0-9.0g of sodium chloride, 1.5-2.0g of sodium dihydrogen phosphate, 0.1-1.0g of disodium hydrogen phosphate, 0.01-0.1g of polyhexamethylene biguanide hydrochloride per 1L of water for injection.
5. The use according to claim 4, wherein each 1L of water for injection contains 10g of recombinant human collagen, 8.5g of sodium chloride, 1.7g of sodium dihydrogen phosphate, 0.5g of disodium hydrogen phosphate, and 0.03g of polyhexamethylene biguanide hydrochloride.
6. The use according to claim 3, wherein the pH is adjusted to 7.3-7.4 using 8.5% sodium hydroxide solution.
7. The use according to claim 3, wherein the filtering operation is: the filtrate was filtered using a 0.45 μm filter and then the filtrate was filtered using a 0.22 μm filter.
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| CN101175474A (en) * | 2005-03-10 | 2008-05-07 | 3M创新有限公司 | Methods of reducing microbial contamination |
| CN101163749A (en) * | 2005-04-18 | 2008-04-16 | 洛曼-劳舍尔国际股份有限公司 | Self-sterilized, antiseptic collagen preparations, their use and method for producing them |
| CN103102407A (en) * | 2013-01-29 | 2013-05-15 | 西安益力欣生物科技有限公司 | Genetic recombinant human-like collagen |
| CN103861091A (en) * | 2014-03-20 | 2014-06-18 | 辽宁亿灵科创生物医药科技有限公司 | Medicine composition for treating urocystitis |
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