CN110721393A

CN110721393A - Uterine stent and preparation method thereof

Info

Publication number: CN110721393A
Application number: CN201911033426.6A
Authority: CN
Inventors: 夏佩佩; 晏伟; 魏征
Original assignee: Yipurun (shanghai) Biotechnology Co Ltd
Current assignee: Yipurun (shanghai) Biotechnology Co Ltd
Priority date: 2019-10-28
Filing date: 2019-10-28
Publication date: 2020-01-24

Abstract

The invention provides a uterine support and a preparation method thereof, wherein the uterine support comprises a silicon rubber diaphragm and a medicament, the porosity of the outer side of the silicon rubber diaphragm is greater than the porosity of the central position of the silicon rubber diaphragm, the medicament is uniformly dispersed in the silicon rubber diaphragm, and the pores of the outer side of the silicon rubber diaphragm are formed by adding a pore-forming agent. According to the invention, the pore-forming agent is added in the process of preparing the uterine stent to achieve that the porosity of the outer side is different from the central position, so that the same uterine stent can release different medicines at different time periods.

Description

Uterine stent and preparation method thereof

Technical Field

The invention relates to the field of medical instruments, in particular to a uterine stent and a preparation method thereof, and more particularly relates to a preparation method of a uterine stent and a uterine stent capable of releasing drugs in a time period.

Background

The uterus is the organ which produces the menstruation and breeds the fetus, is located in the center of the pelvic cavity, and is the unique visceral organ of women. The main components of the uterus are muscles, the front wall and the back wall of the uterus body are almost contacted with each other, and the middle uterine cavity is only a crack. The wall of the uterus consists of three layers of tissues, namely a serosal layer, a muscular layer and a mucous layer; the mucosa layer is an endometrium layer and can be divided into three layers, namely a compact layer, a sponge layer and a basal layer. The stratum compactum and the stratum spongium are proliferative zones regenerated from the basal layer, collectively called the functional layer, sensitive to sex hormones, subject to cyclic changes under the influence of ovarian hormones, and if not pregnant, the functional layer falls off at the end of each cycle with uterine bleeding, clinically manifested as menstruation. The basal layer is close to the muscle layer and is insensitive to ovarian hormone without periodic changes. The normal endometrial glands secrete a thin alkaline fluid to keep the uterine cavity moist so that the anterior and posterior walls of the normal uterus, although in close proximity, do not adhere and grow together.

After intrauterine operation, the basement layer of endometrium is damaged, especially the front wall and the back wall at the same position are simultaneously damaged, and the uterine cavity is adhered. It is now agreed that trauma to the pregnant uterus is the major cause of intrauterine adhesions. The trauma often occurs after delivery or 1-4 weeks after abortion, and the patient needs to be curetted due to excessive bleeding. During this susceptible period, any trauma can cause the basal layer of the endometrium to fall off, causing the walls of the uterus to adhere to each other, forming permanent adhesions, resulting in the disappearance of the deformation and symmetry of the uterus. Second, trauma to non-pregnant endometrium can also cause intrauterine adhesions. The literature reports that intrauterine adhesions can occur after diagnostic uterine curettage, abdominal myoma removal, cervical biopsy, endometrial polyp retrieval, intrauterine contraceptive devices or application of radiation therapy. In addition, intrauterine adhesions may also occur after various hysteroscopic procedures, such as hysteromyomectomy, mediastinectomy, etc.

Therefore, after minimally invasive surgery, as uterine cavities are damaged, the probability that the uterine cavities are adhered together after being attached relative to a wound surface is high, menstrual blood cannot be smoothly discharged after the uterine cavities are adhered, women of childbearing age cannot normally conceive, and the common method is to divide the adhered parts by hysteroscope adhesion incision again. However, although the hysteroscopic surgery is widely used, the treatment of the intrauterine adhesion is still very difficult, the prognosis of the treatment of the intrauterine adhesion is still not ideal, the parts such as uterine horn and the like are adhered or the intrauterine adhesion is serious, and even after the hysteroscopic separation, the recurrence phenomenon still easily occurs and the radical treatment is difficult. And the pregnancy after the intrauterine adhesion is high-risk pregnancy with high abortion risk and placenta abnormality, and needs to be closely monitored to prevent and treat complications. Therefore, the treatment of the intrauterine adhesion not only comprises the restoration of the normal shape of the uterine cavity through the hysteroscope operation, but also adopts measures to promote the repair of endometrium, prevent the recurrence of the intrauterine adhesion and finally restore the normal life and the fertility of the patient.

At present, a plurality of methods and means for preventing re-adhesion after the uterine cavity adhesion separation are available, and the methods mainly comprise drug treatment, intrauterine barrier medium, balloon dilatation, biogel treatment, amnion transplantation, hysteroscopy exploration and blunt separation. However, there is still a lack of absolutely effective means for completely avoiding re-adhesion and a lack of uniform treatment criteria.

Oral estradiol drugs have an effective effect on preventing adhesion, but most of oral sex hormone drugs are intercepted by the liver due to the liver first-pass effect of the oral drugs and the relative independence of the pelvic blood circulation system, so that the blood concentration of the whole body is not high, the concentration reaching the interior of the uterus is very low, and the bioavailability is very low.

Most of the treatment methods only temporarily reduce the adhesion probability, and after the action of the apparatus or the medicament disappears, the probability of re-adhesion is high, especially for patients with moderate and severe adhesion. While it is a problem to grow endometrium, especially endometrium destroyed to the basal layer, large dose of oral drug has little effect on endometrium destroyed to the basal layer and has great side effect on patients. Insufficient endometrial thickness is one of the major factors in infertility. Therefore, how to activate the cells of the basal layer and activate and differentiate the cells of the basal layer again to form a functional layer so as to enable the thickness of the intima to reach the thickness of reasonable conception is the key to prevent adhesion and recover fertility. However, after the intima has been repaired, physicians often need to release the drug in stages or use different drugs in stages, and it is difficult to control the sequential release rate of estrogen and progestin, for example.

Therefore, there is a great need to develop a uterine stent that releases drugs in divided periods of time.

Disclosure of Invention

In order to solve the problem of poor treatment effect of endometrial adhesion in the prior art, the invention aims to provide a preparation method of a uterine stent and the uterine stent capable of releasing drugs in a time period.

The invention provides a uterine stent which comprises a silicon rubber membrane and a medicament, wherein the porosity of the outer side of the silicon rubber membrane is greater than that of the central position of the silicon rubber membrane, the medicament is uniformly dispersed in the silicon rubber membrane, and pores on the outer side of the silicon rubber membrane are formed by adding a pore-forming agent.

The outer side of the silicone membrane (referred to as a silicone membrane for short) may be understood as a second space enclosed in a three-dimensional space of the silicone membrane, the second space is not adjacent to any side of the silicone membrane, the second space is defined as a central position of the silicone membrane, and a space outside the central position is the outer side of the silicone membrane. When the porosity of the central position is smaller than the porosity of the outer side of the silica gel membrane, when the uterus needs the first medicine, the medicine dispersed on the outer side of the silica gel membrane is preferentially released, the release time is controlled, and when the uterus needs the second medicine, the medicine dispersed on the central position is released again.

The porosity of the outer side of the silica gel membrane is larger than that of the central position of the silica gel membrane, so that the silica gel with the same unit area can be understood, and the outer side has more pores than the central position; or the same number of apertures, the outer apertures being larger than the central aperture. The porosity can be generally analyzed by measuring the specific surface area.

It is understood herein that the first and second agents may be the same agent or different agents. Preferably different kinds of drugs. Preferably, the release rate of the drug particles can be further controlled by controlling the particle size thereof.

In general, a common silicon membrane has the same porosity, and how to form different areas on the same silicon membrane has different porosity difficulties.

Preferably, the pore-foaming agent is a water-soluble pore-foaming agent. The silicon rubber is insoluble in water, so that the pore-foaming agent can be washed away by water washing in the preparation process, and the silicon rubber is free from residue, safe, simple and convenient. The added pore-forming agent occupies non-pore positions in the silicone rubber in a particle form in the process of forming the silicone rubber, and then pores are left after the pore-forming agent is washed by water, so that the silicone rubber added with the pore-forming agent has larger pore density or larger pores than the silicone rubber without the pore-forming agent.

Preferably, the water-soluble pore-forming agent is selected from any one of polyvinyl alcohol (PVA), gelatin, gum arabic, guar gum, chondroitin sulfate, Hyaluronic Acid (HA), sodium carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), Methylcellulose (MC), Hydroxypropylmethylcellulose (HPMC), starch, pectic acid, heparin, glucose, β -cyclodextrin, chitosan, or sodium alginate, or a combination of at least two thereof.

Preferably, the medicament comprises an estrogen and a progestin.

Preferably, the estrogen is dispersed on the outer side of the silica gel membrane, and the progestogen is dispersed in the central position of the silica gel membrane.

Generally, estrogen and progestogen have different division in human body, the estrogen is a substance for promoting the development of the second sexual characteristics and the maturation of the sexual organs of female animals, the progestogen ensures that the endometrium proliferated under the action of the estrogen has secretion phenomenon, cervical mucus becomes sticky, sperms do not easily pass through, but the progestogen and the estrogen have antagonistic action and synergistic action, and after the estrogen repairs the endometrium in the treatment process, the progestogen can convert the endometrium in the proliferation stage into the endometrium in the secretion stage, thereby better treating infertility.

Preferably, the particle size of the progestogen is larger than that of the estrogen, and further the slow release of the progestogen at the central position of the silica gel membrane is controlled.

Preferably, the progestogen is selected from any one of progesterone, norethindrone, levogestrel, demegestone, promeggestone, netigesterone, dydrogesterone, caproic acid progesterone, drospirenone, or a combination of at least two thereof.

Preferably, the estrogen is selected from one or a combination of at least two of estradiol benzoate, estradiol valerate, ethinylestradiol ether, gestestriol, ethylestrenol, nilestriol or promestrene.

Preferably, the silicone rubber comprises any one of self-modified HTV silicone rubber, RTV solid silicone rubber, LTV solid silicone rubber, RTV liquid silicone rubber or LTV liquid silicone rubber or a combination of at least two of the above.

The invention also provides a preparation method of the uterine stent, which comprises the following steps:

1) mixing silicon rubber, a catalyst, a cross-linking agent and a medicament uniformly to form a process central membrane;

2) mixing silicon rubber, a catalyst, a cross-linking agent, a pore-forming agent and a medicament uniformly to form a process side membrane;

3) placing a piece of the middle center membrane in the step 1) between two pieces of the middle side membrane in the step 2) to form a sandwich shape, and completely vulcanizing the middle center membrane;

4) cutting into required shape to obtain the uterus support.

The process center diaphragm and the process side diaphragm are formed in the step 1) and the step 2) firstly, and then are completely vulcanized through the step 3), so that the center diaphragm and the side diaphragm do not have obvious boundaries directly, the forming effect is equal to that of integral forming, and meanwhile, different areas and different pore densities are provided.

Preferably, the silicone rubber is a solid silicone rubber.

Preferably, the silicone rubber is a liquid silicone rubber; the process center membrane of step 1) and the process side membrane of step 2) are semi-cured to a semi-solid state.

Preferably, the drugs in steps 1) and 2) are the same drug.

Preferably, the drugs in steps 1) and 2) are different drugs.

Preferably, the medicament in step 1) comprises estrogen, and can be selected from any one or combination of at least two of estradiol benzoate, estradiol valerate, ethinyl estradiol ether, pregnant marestrone, diethylstilbestrol, nilestriol or promestrene; the medicament in the step 2) comprises progestogen selected from any one or the combination of at least two of progesterone, norethindrone, levogestrel, demegestone, promegestone, nergestrel, dydrogesterone, caproic acid progesterone and drospirenone.

Preferably, the pore-forming agent in the step 2) is a water-soluble pore-forming agent, and the sandwich structure in the step 3) is washed with water after being completely vulcanized.

Preferably, a surfactant is added in the water washing stage. And the surfactant is added in the water washing stage, so that the water-soluble pore-forming agent in the uterine scaffold is cleaned completely without residue.

Preferably, the water-soluble pore-forming agent is: polyvinyl alcohol (PVA), gelatin, Arabic gum, guar gum, chondroitin sulfate, Hyaluronic Acid (HA), sodium carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), Methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), starch, pectic acid, heparin, glucose, beta-cyclodextrin, chitosan, sodium alginate, or any combination thereof.

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, the pore-forming agent is added in the process of preparing the uterine stent to achieve that the porosity of the outer side is different from the central position, so that the same uterine stent can release different medicines at different time periods.

Drawings

FIG. 1 is a graph showing the amount of drug released in example 1 of the present invention;

FIG. 2 is a graph showing the amount of drug released in example 2 of the present invention;

FIG. 3 is a graph showing the amount of drug released in example 3 of the present invention;

FIG. 4 is a graph showing the amount of drug released in comparative example 1 of the present invention;

fig. 5 is a graph showing the amount of drug released in comparative example 2 of the present invention.

Detailed Description

The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached drawings.

Example 1

Taking liquid silicon rubber, hydrogen-containing silicon oil, a platinum catalyst and estradiol benzoate (the average grain diameter is 5000 meshes), mixing the liquid silicon rubber, the hydrogen-containing silicon oil, the platinum catalyst and the estradiol benzoate uniformly according to the weight ratio of 80:0.2:0.1:20, and semi-vulcanizing to obtain a semi-solid central membrane;

taking liquid silicon rubber, hydrogen-containing silicone oil, a platinum catalyst, chitosan and estradiol benzoate (the average particle size is 5000 meshes), mixing the five materials according to the weight ratio of 80:0.2:0.1:3:20 to be uniform, and semi-vulcanizing to form a semi-solid side membrane;

placing a semi-solid central membrane in the step 1) between two semi-solid side membranes in the step 2) to form a sandwich shape, and completely vulcanizing the semi-solid central membrane into a sheet with the thickness of 2mm through hot pressing; cutting into required shape to obtain uterus support; soaking in water for 2 hr.

In the release effect test performed in example 1, the drug dissolution was performed in PBS solution at 37 ℃ by an effect drug dissolution tester, the amount of the drug dissolved was measured by HPLC, and the test result is shown in fig. 1, where the central position of the additive release of estradiol benzoate showed a peak again on day 21, and the second stage of drug release was formed.

Example 2

Mixing liquid silicon rubber, hydrogen-containing silicon oil, a platinum catalyst and estradiol valerate (the average particle size is 6000 meshes) according to the weight ratio of 80:0.2:0.1:15 to be uniform, and semi-vulcanizing to form a semi-solid central membrane;

mixing liquid silicon rubber, hydrogen-containing silicon oil, a platinum catalyst, chitosan and progesterone (the average particle size is 4000 meshes) according to the weight ratio of 80:0.2:0.1:2:15 to be uniform, and semi-vulcanizing to form a semi-solid side membrane;

The release effect test was performed on the above example 2, the drug dissolution was performed on the sample in PBS solution at 37 ℃ by an effect drug dissolution tester, the amount of the dissolved drug was measured by HPLC, and the test result is shown in fig. 2, where the release of progesterone reached a peak at day 19 and became stable at day 30.

Example 3

Mixing solid silicon rubber, hydrogen-containing silicon oil, a platinum catalyst and ethinylestradiol (the average particle size is 5000 meshes) in a weight ratio of 60:0.2:0.1:15 uniformly to form a process central membrane;

mixing solid silicon rubber, hydrogen-containing silicon oil, a platinum catalyst, hyaluronic acid and norethindrone (the average particle size is 3500 meshes) according to the weight ratio of 60:0.2:0.1:3:15 to be uniform to form a process side membrane;

placing a semi-solid central membrane in the step 1) between two semi-solid side membranes in the step 2) to form a sandwich shape, and completely vulcanizing the semi-solid central membrane into a sheet with the thickness of 2mm through hot pressing; cutting into required shape to obtain uterus support; adding into water solution containing quaternary ammonium salt, and soaking for 2 hr.

The release effect test was performed on the above example 3, the drug dissolution was performed on the sample in PBS solution at 37 ℃ by an effect drug dissolution tester, the amount of the drug dissolved was measured by HPLC, and the test result is shown in fig. 3, in which ethinylestradiol reached a peak on day 15 and was released in a relatively steady trend.

Comparative example 1

mixing liquid silicon rubber, hydrogen-containing silicon oil, a platinum catalyst and progesterone (the average particle size is 4000 meshes) according to the weight ratio of 80:0.2:0.1:15 until the mixture is uniform, and semi-vulcanizing the mixture to form a semi-solid side membrane;

placing a semi-solid central membrane in the step 1) between two semi-solid side membranes in the step 2) to form a sandwich shape, and completely vulcanizing the semi-solid central membrane into a sheet with the thickness of 2mm through hot pressing; cutting into required shape to obtain uterus support; the release effect test in comparative example 1 was conducted, and the drug dissolution was conducted in a PBS solution at 37 c by an effect drug dissolution tester, and the amount of the dissolved drug was measured by HPLC, and the test results are shown in fig. 4. From the test results, it can be seen that the uterine stent has the same outside porosity and center position porosity during the preparation process due to the absence of the addition of the pore-forming agent chitosan, the release rate of estradiol valerate is slightly decreased, but the release amount of progesterone becomes faster instead, reaching a peak at day 5.

Comparative example 2

This comparative example is essentially the same as example 3 except that ethinyl estradiol has an average particle size of 3000 mesh and norethindrone has an average particle size of 5000 mesh.

The release effect test of comparative example 2 was performed, and the drug dissolution was performed on the sample in PBS solution at 37 ℃ by an effect drug dissolution tester, and the amount of the dissolved drug was measured by HPLC, and the test results are shown in fig. 5. From the test results it can be seen that the progestogen norethindrone, which peaks at day 3 due to its significantly faster release rate with a smaller average particle size than the estrogen ethinyl estradiol.

The above embodiments are merely preferred embodiments of the present invention, which are not intended to limit the scope of the present invention, and various changes may be made in the above embodiments of the present invention. All simple and equivalent changes and modifications made according to the claims and the content of the specification of the present application fall within the scope of the claims of the present patent application. The invention has not been described in detail in order to avoid obscuring the invention.

Claims

1. The utility model provides a uterus support, its characterized in that, uterus support includes silicon rubber diaphragm and medicine, the porosity in the silicon rubber diaphragm outside is greater than the porosity that silicon rubber diaphragm central point put, medicine homodisperse is inside silicon rubber diaphragm, silicon rubber diaphragm outside hole is through adding the pore-forming agent and forming.

2. The uterine scaffold according to claim 1, wherein the pore-forming agent is a water-soluble pore-forming agent selected from any one of polyvinyl alcohol (PVA), gelatin, gum arabic, guar gum, chondroitin sulfate, Hyaluronic Acid (HA), sodium carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), Methylcellulose (MC), Hydroxypropylmethylcellulose (HPMC), starch, pectic acid, heparin, glucose, β -cyclodextrin, chitosan or sodium alginate, or a combination of at least two thereof.

3. The uterine scaffold according to claim 1, characterized in that said drug comprises an estrogen and a progestin.

4. A uterine stent according to claim 3, wherein the oestrogen is dispersed on the outer side of the silicone membrane and the progestogen is dispersed in the central position of the silicone membrane.

5. Uterine support according to claim 3, characterized in that the progestogen is selected from any one or a combination of at least two of the group consisting of progesterone, norethindrone, levogestrel, demegestone, promeggestone, netigesterone, dydrogesterone, progesterone caproate or drospirenone;

6. The uterine stent according to claim 1, wherein the silicone rubber for the silicone rubber membrane comprises any one of self-modified HTV silicone rubber, RTV solid silicone rubber, LTV solid silicone rubber, RTV liquid silicone rubber or LTV liquid silicone rubber or a combination of at least two thereof.

7. A method of preparing a uterine scaffold according to any one of claims 1 to 6, wherein said method of preparation comprises the steps of:

3) placing a piece of the process center membrane in the step 1) between two pieces of the process side membrane in the step 2) to form a sandwich shape, and completely vulcanizing;

4) cutting into required shape to obtain the uterus support.

8. The method for preparing the uterine scaffold according to claim 7, wherein the pore-forming agent in step 2) is a water-soluble pore-forming agent, and the sandwich structure in step 3) is completely vulcanized and then washed with water.

9. The method for preparing the uterine stent according to claim 8, wherein a surfactant is added at the stage of the water washing.

10. The method for preparing the uterine stent according to claim 7, wherein the silicone rubber of the steps 1) and 2) is liquid silicone rubber, and the process center diaphragm of the step 1) and the process side diaphragm of the step 2) are semi-cured into a semi-solid state.