CN115814065A - Preparation method and application of high-viscosity collagen gel - Google Patents
Preparation method and application of high-viscosity collagen gel Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method and application of high-viscosity collagen gel. The components of the high-viscosity collagen gel comprise carbomer, triethanolamine, recombinant human type III collagen and a solvent, the collagen gel prepared under the condition of the components has the characteristic of high viscosity, can avoid flowing out when in use, prolongs the action time of hydrogel at the uterine cavity adhesion part, and effectively treats the uterine cavity adhesion; meanwhile, the recombinant collagen can enhance the anti-adhesion and uterus repair effects, and can gradually release from the carbomer gel into the uterine cavity to play a role. In addition, the prepared collagen gel has the advantages of small wound, convenient administration, drug release delay, close contact with tissues, good affinity to endometrium and the like, is not influenced by the quick secretion of endometrial mucus, can promote the quick recovery of endometrium, and effectively solves the technical problems that the conventional endometrium repair preparation cannot maintain effective concentration for a long time and has poor treatment effect.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method and application of high-viscosity collagen gel.
Background
Intrauterine adhesion (IUA) is a common uterine disease seriously harming fertility and treating more troublesome in gynecology, and seriously affects female reproductive physiology and physical and mental health. Uterine cavity adhesion refers to a group of diseases in which the uterine cavity is partially or completely occluded due to intimal damage, and may be manifested as abnormal menstruation, infertility, recurrent abortion, etc. Intrauterine adhesion is considered to be intrauterine adhesion or fibrosis accompanied by one or more clinical symptoms such as reduced menstruation, amenorrhea, recurrent abortion, infertility and abnormal formation of placenta, and is called asymptomatic intrauterine adhesion without the symptoms.
The normal endometrium can be repaired and regenerated by itself, but the endometrium is damaged due to artificial abortion, induction of labor, uterine curettage, serious endocrine disorder, intrauterine infection and the like, so that the normal structure of the endometrium is damaged, tissue fibrosis is improved, glands are reduced, and the uterine cavity or (and) the cervical canal is partially or completely blocked, so that the uterine cavity is adhered. Currently, uterine cavity adhesion has become the second leading cause of secondary infertility in women. Moreover, the treatment of uterine cavity adhesion is a difficult problem in clinical practice at present, and particularly, the effect of the existing treatment means is poor in moderate and severe uterine cavity adhesion. For example, hysteroscopic adhesion detachment and postoperative adhesion prevention include physical barriers such as intrauterine devices, cook balloons, regenerated cellulose anti-adhesion membranes and the like placed in the uterine cavity during operation, and are combined with postoperative use of a large dose of estrogen to promote endometrial growth, so that the method is a main treatment method of the current IUA. But has poor treatment effect on moderate and severe uterine cavity adhesion patients. At present, pessaries, douches and oral tablets have been reported as endometrium repair preparations, but the curative effect is poor, mainly because the existing preparations cannot ensure that the therapeutic medicine is closely contacted with the damaged part of the endometrium and can maintain effective concentration for a long time.
In addition, due to the rapid secretion and renewal of endometrial mucus, the therapeutic drug in the cavity of the damaged uterus is rapidly lost, so that the effective drug therapeutic concentration cannot be reached, and the factors become a bottleneck for preventing the current preparation from being applied to the repair of endometrial injury.
Disclosure of Invention
Aiming at the defects of the prior art and solving the problems, the invention provides a preparation method and application of high-viscosity collagen gel; the gel prepared by the invention is transparent semisolid, has the characteristics of uniform texture and water-soluble matrix, can form a transparent film on skin and mucous membrane, has strong adhesiveness, no greasy feeling, good coupling effect with the skin and mucous membrane, quick drug release and quick action, is beneficial to the drug effect of the drug on the local focus of infection, and has good application prospect and important scientific significance for the treatment of intrauterine adhesion.
In order to achieve the technical purpose, the technical scheme provided by the invention is as follows:
the invention firstly provides a high-viscosity collagen gel which comprises the following components in percentage by mass:
carbomer: 1.5 to 3 percent;
triethanolamine: 1.5 to 3 percent;
recombinant human type iii collagen: 0.5 to 1 percent.
Preferably, the carbomer type is carbomer 934.
Preferably, the solvent of the high viscosity collagen gel is water.
Preferably, the water includes deionized water, water for injection, or physiological saline.
Preferably, the solvent can also be replaced by a phosphate buffer.
Preferably, the mass fraction of the carbomer is 1.5%, the mass fraction of the triethanolamine is 1.5%, and the mass fraction of the recombinant human type III collagen is 0.5%.
The invention also provides a preparation method of the high-viscosity collagen gel, which is characterized by comprising the following steps of:
dissolving carbomer in a solvent to obtain a solution A; dissolving the recombinant human III type collagen in a solvent, adding triethanolamine and uniformly mixing to obtain a solution B: and then uniformly mixing the solution A and the solution B, standing at a certain temperature to obtain a clear solution, namely the high-viscosity collagen gel.
Preferably, the certain temperature condition is 0-4 ℃.
Preferably, the standing time is 20-24h.
The high-viscosity collagen gel prepared by the invention is applied to preparing products for preventing and treating uterine cavity adhesion, uterine fibrosis and promoting endometrial recovery.
Finally, the present invention provides a complex formulation comprising the high viscosity collagen gel prepared according to the present invention.
Preferably, the composite preparation is used for preparing products for repairing various injuries of the endometrium.
Preferably, the repair of various endometrial injuries includes the treatment of uterine cavity adhesions, uterine fibrosis, and promotion of endometrial recovery.
Preferably, the application mode is specifically an in-situ injection mode in the uterine cavity.
The beneficial effect of this patent technique lies in:
(1) The high-viscosity collagen gel is prepared by carbomer, triethanolamine and recombinant human type III collagen; the collagen gel prepared under the condition of the components has the characteristic of high viscosity, can avoid flowing out when in use, prolongs the action time of the hydrogel at the uterine cavity adhesion part, and can effectively treat the uterine cavity adhesion; meanwhile, the used recombinant collagen can enhance the anti-adhesion and uterus repair effects, and can gradually release from the carbomer gel into the uterine cavity to play a role.
(2) The high-viscosity collagen gel prepared by the invention has the advantages of injectability, small wound, convenient administration, drug release delay, close contact with tissues and the like, and is suitable for in-vivo local or implanted administration. The injection site has no obvious foreign body sensation, no toxicity or stimulation, good biocompatibility, no pollution to the affected part of the patient and clothes, and high comfort level.
(3) The release speed of the high-viscosity collagen gel prepared by the invention is controlled to be about 4-6 days, and the physiology and menstrual cycle are not influenced; and has good affinity to endometrium, and is not affected by rapid secretion of endometrium mucus.
(4) The invention further sets the mass fraction of the carbomer 934 in the high-viscosity collagen gel to be 1.5-3%, the mass fraction of the recombinant human type III collagen to be 0.5-1%, and the mass fraction of the triethanolamine to be 1.5-3%; the dosage is very important, and the invention realizes the treatment of uterine cavity adhesion by dosage control and obtains unexpected technical effects.
If only carbomer is used, the repairing effect cannot be achieved; likewise, if the amount of carbomer 934 is not within the limits of the present invention, the objectives of the present invention are not achieved at all; if the amount of carbomer 934 is too low, the viscosity of the high-viscosity collagen gel is low, which is not satisfactory; if the amount of the carbomer 934 is too high, the viscosity of the high-viscosity collagen gel is too high, the effect of the medicine is not exerted, and the treatment effect is influenced.
In addition, the dosage of the recombinant human type III collagen is not within the limited range of the invention, and good treatment effect cannot be realized; if the dosage of the recombinant human type III collagen is too low, the repairing effect cannot be realized; if the dosage is too high, the gel cannot be formed uniformly.
Drawings
FIG. 1 is a kinetic viscosity chart of the high viscosity collagen gel of example 1 at various temperatures and amounts of carbomer 934.
FIG. 2 is a diagram of the morphology of rat uterine tissue in the model group.
Fig. 3 is a morphology of rat uterine tissue in the treatment group.
Fig. 4 is a white light scan of the scar of the left uterus of rats in the model group.
Fig. 5 is a white light scan of the scar of the uterus on the right side of rats in the model group.
Fig. 6 is a white light scan of the left uterine scar from rats in the treatment group.
Fig. 7 is a white light scan of the right uterine scar of rats in the treatment group.
FIG. 8 is a white light scan of endometrial cells from the left side of a rat in a model group.
FIG. 9 is a white light scan of right endometrial cells from a rat model.
Fig. 10 is a white light scan of endometrial cells from the left side of rats in the treatment group.
Fig. 11 is a white light scan of endometrial cells on the right side of rats in the treatment group.
Figure 12 is the endometrial thickness of rats in the model and treatment groups.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The present specification and examples are illustrative only, and provide carbomer 934 and recombinant human type iii collagen, but the present invention is not so limited and carbomers and collagen having the same or similar effect are considered to be routine alternatives to the present invention.
The present invention first provides a high viscosity collagen gel, which comprises:
a. carbomer 934;
b. triethanolamine;
c. recombinant human type III collagen;
d. solvent: water;
the high-viscosity collagen gel comprises 1.5-3% of carbomer 934, 1.5-3% of triethanolamine and 0.5-1% of recombinant human type III collagen.
The preparation method of the high-viscosity collagen gel comprises the following specific operations:
dissolving carbomer 934 in a solvent to obtain a solution A; dissolving the recombinant human III type collagen in a solvent, adding triethanolamine and uniformly mixing to obtain a solution B: and then uniformly mixing the solution A and the solution B, and placing the mixture in a refrigerator at the temperature of 4 ℃ for 24 hours to obtain a clear solution, namely the high-viscosity collagen gel.
Wherein, the recombinant human type III collagen is collagen obtained by genetic engineering; recombinant human type iii collagen has been disclosed in patents, patent publications: CN103102407A, patent name: the gene recombines the human collagen.
Pre-experiment:
dissolving carbomer 934 in deionized water to obtain solution A; dissolving the recombinant human III type collagen in deionized water, adding triethanolamine and uniformly mixing to obtain a solution B: uniformly mixing the solution A and the solution B, and placing the mixture in a refrigerator at 4 ℃ for 24 hours to obtain a clear solution, namely the high-viscosity collagen gel; 5 groups of experiments with different component ratios are set, and the specific component ratios are shown in Table 1.
TABLE 1 Mass fractions of the components and the corresponding gelling temperatures
TABLE 1 proportions of the components
According to preliminary experiments, high-viscosity collagen gel is prepared according to the proportion of each component listed in table 1, and is subjected to rheological detection, for example, fig. 1 is a dynamic viscosity chart based on rheology, and one of the components, namely carbomer, is selected, and the dosage of carbomer is used as an abscissa value; under the condition of a fixed shear rate of 0.25 (1/s), the viscosities of the high-viscosity collagen gel prepared under the conditions of different component mass fractions are corresponding to the viscosities at 25 ℃ and 37 ℃, and the viscosities are reduced along with the rise of the temperature according to the property that the viscosities change along with the temperature; therefore, it can be seen from the figure that the viscosity of the high viscosity collagen gel prepared under the condition of different mass fractions is lower at 37 ℃ than at 25 ℃. Meanwhile, as can be seen from FIG. 1, the viscosity of the composition is very low at 25 ℃ and 37 ℃ under the condition that the amount of the carbomer 934 is 1%, so that the use requirement is not met. The corresponding viscosity of the high-viscosity collagen gel prepared by the components under other dosage conditions at 25 ℃ and 37 ℃ is suitable for the adhesion of uterine cavities, and the high-viscosity collagen gel is supported in the application of uterine anti-adhesion.
Example 1:
1. selecting raw materials:
a. carbomer 934;
b. triethanolamine;
c. recombinant human type III collagen;
d. solvent: deionized water;
the high-viscosity collagen gel comprises 1.5% of carbomer 934, 1.5% of triethanolamine and 0.5% of recombinant human type III collagen.
2. The preparation method of the high-viscosity collagen gel comprises the following steps:
dissolving carbomer 934 in deionized water to obtain a solution A; dissolving the recombinant human III type collagen in deionized water, adding triethanolamine and uniformly mixing to obtain a solution B: and mixing the solution A and the solution B uniformly, and placing the mixture in a refrigerator at the temperature of 4 ℃ for 24 hours to obtain a clear solution, namely the high-viscosity collagen gel.
3. Animal experiments
(1) Selecting experimental objects:
female rats aged 8 weeks and having a body weight of about 250g and sexually mature were selected, acclimatized for one week, and operated in estrus (estrus cycle 4-5 days).
(2) The required materials are as follows:
reagent: normal saline, PBS buffer solution, 95% ethanol, 75% ethanol (or iodophor for disinfection), 0.1% crystal violet solution, 10% sodium pentobarbital, and 4% paraformaldehyde;
4% of paraformaldehyde: weighing 40g of paraformaldehyde powder, dissolving in 1000ml of Phosphate Buffer Solution (PBS), heating to 60 ℃, fully dissolving, cooling to normal temperature, sealing, and storing in shade for no more than 1 month.
Cleaning solution: 30% hydrochloric acid or 5% phenol aqueous solution for 24 hours, and then fully washing after being taken out. The method can be used for cleaning the cover glass or the glass slide.
(3) The group setting and processing mode is as follows:
randomly dividing 10 rats into 2 groups of 5 rats each; the 2 groups were a model group and a treatment group (high-viscosity collagen gel group), respectively.
Model group: performing uterine curettage on two sides, and establishing a model of uterine cavity adhesion; 00 μ L of physiological saline was injected into both sides of the uterus.
Treatment groups: based on the established uterine cavity adhesion model, 100 μ L of high-viscosity collagen gel was injected into both sides of the uterus.
(4) Determining the estrus:
examination of exfoliated vaginal cells:
note: vaginal smear collection and oestrus cycle assessment 8:30-9:30 min, prevent cells to the next stage, and evaluate for at least one week.
Open the jaw of the left hand, insert the thumb and forefinger under the root of the rat tail, press the other three fingers and palm against the back half of the rat body, and pay attention to avoid applying too much force. The tail is lifted, the front claw of the tail is arranged on the squirrel cage, the hind limb is suspended, and the opening of the vaginal orifice can be seen. Sucking (50 μ L) physiological saline with a pipette and a pipette tip, placing the pipette tip at 3-5mm of the female mouse vaginal orifice, slowly releasing the liquid into the vagina, sucking back again, repeating for 4-5 times, dropping the liquid onto a glass slide, drying, fixing with 95% alcohol, staining with 0.1% crystal violet solution for 3min, washing, and observing under a microscope.
(5) Operation:
uterine curettage was used: shaving and disinfecting the abdomen, and anesthetizing and fixing.
The abdominal wall skin was cut longitudinally about 3cm above the pubic symphysis 2-3cm, the tissues were cut layer by layer into the abdominal cavity, and the Y-uterus of the rat was slowly picked up.
Bilateral simultaneous uterine horn surgery
The ophthalmology department is directly cut at the position about 5mm above the cervix uteri to make a longitudinal incision with the length of about 5mm, a homemade rat uterine cavity curettage is adopted to conduct uterine curettage through the incision above the cervix uteri, and the uterine curettage is stopped when the four walls of the uterine cavity are rough.
Thoroughly stopping bleeding with sterile gauze, suturing the uterus with 7-0 sutures intermittently, returning the uterus to the abdominal cavity, flushing the abdominal cavity with physiological saline, closing the abdominal cavity with 3-0 sutures, and injecting 200mg/kg of antibiotics every 48h after the operation.
Model group making longitudinal incisions of the same length only in the uterus
After the second estrus cycle, each is sacrificed, fixed in 4% paraformaldehyde for more than 24 hours, dehydrated in an ethanol gradient, then embedded in paraffin, and stained for sections.
(6) Result processing (detection):
the effect of uterine healing in each group was evaluated by a masson stain, hematoxylin-eosin (HE) stain on the uterus. The tissue morphology, masson, HE, intimal cells and endometrial thickness were examined.
(1) Morphology observation of rat uterus tissue:
respectively disinfecting the abdomens of the two groups of rats, and anaesthetizing and fixing; the abdominal wall skin is longitudinally incised about 3cm above the pubic symphysis, the tissues are incised layer by layer, the abdominal cavity is entered, and the Y-shaped uterus of the rat is slowly picked out. As shown in fig. 2 and 3, the morphology of rat uterus tissue of the model group and the treatment group are shown; the left side of the uterus of the rats in the model group has obvious abnormal hyperplasia of tissues, while the left side of the uterus of the rats in the treatment group is relatively flat and has no obvious hyperplasia. The right side of the uterus of the rats in the same model group has obvious hyperplasia and thickening compared with the uterus tissue shape of the model rats, and compared with the uterus tissue shape of the model rats, the uterus tissue shape of the rats treated by the high-viscosity collagen gel is obviously improved, which shows that the high-viscosity collagen gel has obvious effect on the recovery of the uterus tissue shape of the rats.
(2) Uterine scar (MASSON):
two groups of rats are sacrificed after the second estrus cycle, fixed by 4% of poly methanol for more than 24 hours, dehydrated by using ethanol gradient, embedded in paraffin, sliced and dewaxed to distilled water; staining with Weigert iron hematoxylin staining solution for 3 minutes; alcohol differentiation is carried out for 15s (the differentiation time can be properly increased by the over-deep staining of the hematoxylin) by hydrochloric acid, and washing is carried out; returning the Masson bluing solution to blue, washing with water, and washing with distilled water for 1min; dyeing with ponceau fuchsin staining solution for 8s (controlling staining time according to tissue density), washing with 0.2% weak acid for 1min; washing with phosphomolybdic acid solution for 2min, washing with 0.2% weak acid for 1min; staining with aniline blue staining solution for 90s (controlling staining time according to tissue density), and washing with 0.2% weak acid for 1min; dehydrating with 95% ethanol for 3s, and dehydrating with anhydrous ethanol for 3 times, each time for 10s; the xylene is transparent for 3 times, each time for 2min, and sealed.
The rat uterine scar is observed through MASSON staining, as shown in figures 4 and 5, white light scanning images of the left and right uterine scar (MASSON) of the rat in the model group are shown, and it can be obviously seen that the left and right uteruses of the rat in the model group are respectively obviously adhered; as shown in fig. 6 and 7, which are white light scans of the left and right uterine scar (MASSON) of the rats in the treatment group, the left and right uterine morphology of the rats in the treatment group is normal, and no adhesion phenomenon occurs, which indicates that the high-viscosity collagen gel has a significant effect on the adhesion of the uterus.
In addition, the optical density and the area of the collagen fibers (blue) on the left and right sides of the rats in the treatment group are obviously smaller than those of the uteruses of the rats in the model group, and further the high-viscosity collagen gel has obvious effect on resisting fibrosis of the uteruses of the rats.
(3) Endometrial cells (HE):
two groups of rats are sacrificed after the second estrus period respectively, fixed by 4 percent of poly-methanol for more than 24 hours, dehydrated by ethanol gradient, embedded in paraffin, sliced and dewaxed to distilled water, hematoxylin staining cell nucleus, sliced and Harris hematoxylin staining for 5min, washed by tap water, and then washed by 1 percent of hydrochloric acid alcohol for several seconds, washed by tap water, and then by 0.6 percent of ammonia water for returning blue, and washed by running water. Eosin staining of cytoplasm sections were stained in eosin stain for 3min. And (4) dehydrating and sealing the slices by gradient ethanol, taking the slices out of the xylene, slightly drying the slices, and sealing the slices by neutral gum.
Rat endometrial cells (chromatin in nuclei and nucleic acid in cytoplasm are bluish in color; components in cytoplasm and extracellular matrix are reddish in color) were observed by HE staining, as shown in fig. 8, 9, 10, 11, left and right endometrial cells of rat uterus of model group were significantly reduced compared to left and right endometrial cells of rat uterus of treatment group; meanwhile, as can be seen from the picture, the area of the left and right uterine cavities of the rat in the model group is larger, and the area of the uterine cavity of the treatment group is smaller than that of the model group, which indicates that the recovery effect of the endometrium after treatment is better, and the basic shape of the uterine cavity is maintained without adhesion.
(4) Endometrial thickness:
observation of endometrial thickness by HE staining in rats (mean endometrial thickness = area/circumference, endometrial area and circumference were calculated using Image analysis software (Image Pro-Plus)) with results as shown in fig. 12, the endometrial thickness (Left uterus,619.5 μm) was significantly thicker in the Left side of rats in the treated group compared to the endometrial thickness (Left uterus,467.5 μm) in the Left side of rats in the model group; the endometrium thickness of the treated rat was significantly thicker in comparison with the Right endometrium thickness of the model rat (Right uterus,376.5 μm), indicating that the high-viscosity collagen gel had a significant effect on the recovery of the rat endometrium.
In conclusion, according to the tissue morphology of the uterus, the scar of the uterus, the endometrial cells and the thickness of the endometrium, the high-viscosity collagen gel has a good repairing effect on the damaged endometrium, and has remarkable anti-fibrosis and anti-adhesion effects.
Description of the drawings: the above embodiments are only used to illustrate the present invention and do not limit the technical solutions described in the present invention; thus, while the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted; all such modifications and variations are intended to be included herein within the scope of this disclosure and the present invention and protected by the following claims.
Claims (14)
1. A high viscosity collagen gel, characterized by comprising the following components in percentage by mass:
carbomer: 1.5 to 3 percent;
triethanolamine: 1.5 to 3 percent;
recombinant human type iii collagen: 0.5 to 1 percent.
2. A high viscosity collagen gel according to claim 1, wherein said carbomer type is carbomer 934.
3. A high viscosity collagen gel according to claim 1, wherein the solvent of said high viscosity collagen gel is water.
4. The high viscosity collagen gel according to claim 3, wherein said water comprises deionized water, water for injection or physiological saline.
5. A high viscosity collagen gel according to claim 3, wherein said solvent is further replaced by phosphate buffer.
6. The high viscosity collagen gel according to claim 1, wherein said carbomer 934 is present in an amount of 1.5% by weight, said triethanolamine is present in an amount of 1.5% by weight, and said recombinant human type iii collagen is present in an amount of 0.5% by weight.
7. The method for preparing a high viscosity collagen gel according to any one of claims 1 to 6, comprising the steps of:
dissolving carbomer in a solvent to obtain a solution A; dissolving the recombinant human III type collagen in a solvent, adding triethanolamine and uniformly mixing to obtain a solution B: and then uniformly mixing the solution A and the solution B, standing at a certain temperature to obtain a clear solution, namely the high-viscosity collagen gel.
8. The method for preparing high viscosity collagen gel according to claim 7, wherein said certain temperature condition is 0-4 ℃.
9. The method for preparing high viscosity collagen gel according to claim 7, wherein said standing time is 20-24 hours.
10. Use of a high viscosity collagen gel according to any one of claims 1 to 6 for the preparation of a product for the prevention and treatment of uterine cavity adhesion, uterine fibrosis and for promoting endometrial recovery.
11. A complex formulation comprising the high viscosity collagen gel according to any one of claims 1 to 6.
12. Use of a complex formulation according to claim 11 for the preparation of a product for the repair of various lesions of the endometrium.
13. Use according to claim 12, characterized in that the repair of various lesions of the endometrium comprises the treatment of uterine cavity adhesion, uterine fibrosis and the promotion of endometrial recovery.
14. Use according to claim 13, characterized in that the mode of application is in particular an in situ injection in the uterine cavity.
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| CN108524866A (en) * | 2018-05-08 | 2018-09-14 | 中商华夏物产（贵州）贵和堂药业有限公司 | A kind of Traditional Chinese medicine bacteriostatic gelling agent and preparation method thereof |
| KR20210018639A (en) * | 2019-08-07 | 2021-02-18 | 가천대학교 산학협력단 | Endometrial complex for treating endometrial damage, manufacturing method of endometrial complex and endometrial complex using the same |
| CN114632146A (en) * | 2022-03-01 | 2022-06-17 | 康膝生物医疗(深圳)有限公司 | Preparation method and application of temperature-sensitive composite hydrogel preparation for repairing endometrium |
| CN114903981A (en) * | 2022-06-24 | 2022-08-16 | 广州百川医药生物科技开发有限公司 | Wound repair formula containing recombinant type III collagen |
| CN114904046A (en) * | 2022-06-09 | 2022-08-16 | 江苏扬子江医疗科技股份有限公司 | Recombinant III-type humanized collagen composition and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108524866A (en) * | 2018-05-08 | 2018-09-14 | 中商华夏物产（贵州）贵和堂药业有限公司 | A kind of Traditional Chinese medicine bacteriostatic gelling agent and preparation method thereof |
| KR20210018639A (en) * | 2019-08-07 | 2021-02-18 | 가천대학교 산학협력단 | Endometrial complex for treating endometrial damage, manufacturing method of endometrial complex and endometrial complex using the same |
| CN114632146A (en) * | 2022-03-01 | 2022-06-17 | 康膝生物医疗(深圳)有限公司 | Preparation method and application of temperature-sensitive composite hydrogel preparation for repairing endometrium |
| CN114904046A (en) * | 2022-06-09 | 2022-08-16 | 江苏扬子江医疗科技股份有限公司 | Recombinant III-type humanized collagen composition and preparation method and application thereof |
| CN114903981A (en) * | 2022-06-24 | 2022-08-16 | 广州百川医药生物科技开发有限公司 | Wound repair formula containing recombinant type III collagen |
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