Drug delivery method for injecting targeted uterus ovary through vein interstitial channel and application

Abstract

The invention relates to a drug delivery method for injecting targeted uterus ovary through a Ren vessel interstitial channel and application of the drug delivery method. The method comprises the following steps: positioning an abdominal median line interstitial channel, positioning an injection point of the abdominal median line interstitial channel, injecting a water-soluble tracer injection into the abdominal median line interstitial channel, observing a migration track of the water-soluble tracer injection along the abdominal median line interstitial channel by using a fluorography method, and detecting the content of the water-soluble tracer in the uterus ovary. And the metroovary-targeted high-efficiency drug delivery is realized. According to the invention, by taking the abdominal midline interstitial channel tissue of the abdomen of the rat, namely the position corresponding to the circulating distribution of the channels in the traditional Chinese medicine, as a key way for linking the body surface with the uterus and the ovary, and by adopting a method of injecting in the abdominal midline interstitial channel, the delivery safety and the efficacy of the drug targeting the uterus and the ovary are improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug delivery, and particularly relates to a drug delivery method and application for injecting drugs targeting the uterus and ovaries through the interstitial channels of the Conception Vessel. Background Art

[0002] To effectively carry out the prevention and treatment of major chronic diseases such as cardiovascular and cerebrovascular diseases and cancers, it is crucial to improve the drug efficacy and reduce the drug consumption.

[0003] Different administration routes directly affect the pharmacokinetic characteristics of drugs, as well as the bioavailability of drugs and the speed of drug efficacy exertion. Selecting an appropriate administration route is an important link to improve drug efficacy, improve therapies, and reduce drug consumption. Research shows that the drug delivery efficiency of traditional oral, intravenous injection and other administration routes is extremely low. Even when using a nano-drug delivery system, the targeting efficiency is only about 0.7% (Nat Rve Mater 2016), which is difficult to meet the actual treatment needs of diseased tissues and organs, especially those with poor blood supply.

[0004] Compared with traditional oral and intravenous administration, vaginal administration is a relatively common and effective administration route for the uterus and ovaries clinically. However, delivering drugs through the vagina is not only affected by the physiological factors of the administration site, namely the menstrual cycle, and the administration time is restricted; in addition, it is also affected by the dosage form and the nature of the drug itself. Due to the physiological structure limitations of the administration site, the difficulties of vaginal administration are insufficient drug retention and complex mucus barriers, both of which will lead to a decrease in drug utilization rate. In addition, vaginal administration is also affected by the patient acceptance and has poor compliance. Therefore, there is no particularly ideal and efficient delivery route for the drug treatment of primary diseases of the uterus and ovaries at present. Summary of the Invention

[0005] Aiming at the defects existing in the prior art, the purpose of the present invention is to provide a drug delivery method and application for injecting drugs targeting the uterus and ovaries through the interstitial channels of the Conception Vessel. By using the interstitial channel tissue in the midline of the rat abdomen, that is, the position corresponding to the distribution of the Conception Vessel in traditional Chinese medicine, as the key route for the body surface to connect with the uterus and ovaries, and through the method of injecting in the interstitial channels in the midline of the abdomen, an excellent drug delivery targeting the uterus and ovaries is realized.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is: a drug delivery method for injecting drugs targeting the uterus and ovaries through the interstitial channels of the Conception Vessel, and the method comprises the following steps:

[0007] S1. Locate the interstitial channels in the midline of the abdomen: After anesthetizing the rat and preparing the skin of the rat abdomen during preoperative preparation, detect the low-resistance points on the skin of the rat abdomen, and connect the traced low-resistance points on the skin in the midline of the abdomen to determine the projection of the position of the interstitial channels in the midline of the abdomen on the abdominal skin;

[0008] S2. Locate the injection point of the interstitial channel on the ventral midline: Divide the line connecting the xiphoid process to the external genitalia on the ventral midline into 5 equal segments and mark them. Define the skin low-resistance point on the ventral midline between the two endpoints of the 3rd segment on the said line as the injection point;

[0009] S3. Inject the water-soluble tracer injection: Use a syringe to draw a certain amount of water-soluble tracer injection. Insert the injection needle perpendicularly into the abdominal wall at the injection point, and inject the water-soluble tracer injection into the interstitial channel of the ventral midline;

[0010] S4. Observe the migration trajectory of the water-soluble tracer injection along the interstitial channel of the ventral midline by fluorescence photography;

[0011] S5. Detect the content of the water-soluble tracer in the uterus and ovaries.

[0012] Furthermore, in step S1, a WQ6F30 meridian locator is used to detect the skin low-resistance points on the abdomen.

[0013] Furthermore, in step S1, when using a WQ6F30 meridian locator to detect the skin low-resistance points on the abdomen, the detection direction of the electrode probe is perpendicular to the ventral midline;

[0014] When the current of the meridian locator increases significantly and is closest to the ventral midline, stop sliding and use a marker pen to mark. These marked points are the skin low-resistance points on the ventral midline.

[0015] Furthermore, the number of the marked skin low-resistance points on the ventral midline is 10 - 15.

[0016] Furthermore, in step S3, the water-soluble tracer injection includes sodium fluorescein injection, fluorescent marker injection, radionuclide marker injection, nanoparticle injection, protein injection, polypeptide injection, and traditional Chinese medicine decoction body injection.

[0017] Furthermore, in step S3, use an insulin syringe to draw ≤0.1 ml of the water-soluble tracer injection. Insert the insulin injection needle perpendicularly into the abdominal wall at the injection point, and inject the water-soluble tracer injection into the interstitial channel of the ventral midline.

[0018] Furthermore, in step S3, after the insulin injection needle is perpendicularly inserted into the abdominal wall at the injection point and the needle tip reaches 3 mm under the skin, steady the needle body and inject the water-soluble tracer injection into the interstitial channel of the ventral midline.

[0019] Further, in step S4, 30 minutes after the injection of the water-soluble tracer injection solution, a fluorescence imaging picture of the abdomen of the rat is taken with a fluorescence imaging system; then the abdominal cavity is opened through surgery, and the fluorescence images of the abdominal inner wall and internal organs are taken again.

[0020] Further, in step S5, based on the fluorescence imaging picture of the abdomen of the rat, the fluorescence images of the abdominal inner wall and internal organs, the fluorescence intensities of the water-soluble tracer injection solution migrating and transporting along the interstitial channels of the midline of the abdomen to the bladder wall, uterus, and ovaries are analyzed, and then the contents of the water-soluble tracer injection solution in the bladder wall, uterus, and ovaries are obtained.

[0021] Further, in step S5, the liquid after each internal organ is soaked in ultrapure water is extracted, and the content of the water-soluble tracer injection solution in each internal organ is detected.

[0022] The present invention also provides an application of the drug delivery method for injecting through the interstitial channels of the Conception Vessel to target the uterus and ovaries, and the application includes delivering drugs to pelvic organs through the drug delivery method for injecting through the interstitial channels of the Conception Vessel to target the uterus and ovaries.

[0023] Further, the pelvic organs include the uterus, ovaries, bladder, colorectum, and prostate.

[0024] The beneficial effects of the present invention are as follows: By using the drug delivery method and application for injecting through the interstitial channels of the Conception Vessel to target the uterus and ovaries provided by the present invention, through locating the interstitial channels of the midline of the abdomen, locating the injection points of the interstitial channels of the midline of the abdomen, injecting the water-soluble tracer injection solution into the interstitial channels of the midline of the abdomen, observing the migration trajectory of the water-soluble tracer injection solution along the interstitial channels of the midline of the abdomen by fluorescence imaging method, and detecting the content of the water-soluble tracer in the uterus and ovaries, excellent drug delivery targeting the uterus and ovaries is achieved. The present invention uses the interstitial channel tissue of the midline of the abdomen of the rat, that is, the position corresponding to the circulation and distribution of the Conception Vessel in traditional Chinese medicine, as the key pathway for the body surface to connect with the uterus and ovaries, and improves the safety and efficacy of drug delivery targeting the uterus and ovaries by injecting into the interstitial channels of the midline of the abdomen.

[0025] Meanwhile, after injecting sodium fluorescein through the interstitial channel in the midline of the abdomen for 30 minutes, the present invention took fluorescence imaging pictures of each organ using small animal in vivo imaging and analyzed the fluorescence intensity; the liquid after soaking each organ in ultrapure water was extracted to detect the content of sodium fluorescein in each organ; and it was compared with the content of sodium fluorescein in each organ of rats after injecting sodium fluorescein through the tail vein for 30 minutes. The results showed that the content of sodium fluorescein in the uterus and ovaries of rats injected through the interstitial channel in the midline of the abdomen was significantly higher than that injected through the tail vein, about 5 times or more. Moreover, less sodium fluorescein was enriched in other major organs such as the heart, lungs, and liver, which could reduce drug side effects and improve the drug delivery efficiency. In addition, for the treatment of uterine and ovarian diseases, drug delivery through the interstitial channel in the midline of the abdomen was not affected by the physiological cycle, and the drug delivery time was flexible; if it was translated into clinical application, the acceptance of patients was high, and the compliance of drug use could be improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channel along the Conception Vessel according to the embodiment of the present invention;

[0027] Figure 2 is the schematic diagram of the distribution of the Conception Vessel in the human body according to the embodiment of the present invention;

[0028] Figure 3 is the three-dimensional reconstruction diagram of the migration trajectory of sodium fluorescein injected through the interstitial channels along the meridians of the four limbs of minipigs according to the embodiment of the present invention;

[0029] Figure 4 is the positioning diagram of the low-resistance points on the abdominal skin and the injection points of the interstitial channel in the midline of the abdomen of rats according to the embodiment of the present invention;

[0030] Figure 5 is the fluorescence photography diagram of the long-range transmission along the interstitial channel in the midline of the abdomen after injecting the sodium fluorescein injection solution through the interstitial channel in the midline of the abdomen of rats according to the embodiment of the present invention;

[0031] Figure 6 is the comparison diagram of the content of sodium fluorescein in the pelvic organs of rats after injecting sodium fluorescein through the interstitial channel in the midline of the abdomen, injecting beside the abdominal wall tissue, and injecting through the tail vein according to the embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0032] The technical solutions in the embodiments of the present invention will be further clearly and completely described below with reference to the drawings and embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0033] In traditional understanding, information communication and material transportation are mainly achieved through the circulatory system of the human body. However, in the early stages of evolution or embryonic development, the specific structures responsible for material information communication have not been fully formed, but the living organisms can still develop and take shape. Although the roles of the interstitium and interstitial tissue fluid are not yet clear at present, they may contribute to this process.

[0034] The interstitium refers to the space and substances between blood vessel walls and cells, and plays an important role in intercellular communication, the clearance of nutrients and metabolic wastes, the maintenance of cellular environmental homeostasis, and the physiological regulation of inflammation and cancer.

[0035] In 2018, Benias et al. discovered a large number of fluid-filled spaces in human tissues and demonstrated the existence of a large amount of liquid tissue fluid in the interstitial space of the human body. By monitoring the movement of non-biological particles in the interstitium, they proved the wide continuity of the interstitium within and between organs. The interstitial structure rich in liquid tissue fluid is considered an organ unknown before in the human body, which has attracted great attention and heated discussions. These interstitial spaces can serve as conduits for particle movement, and the flow of tissue fluid in the interstitial space may provide the necessary medium. Interstitial tissue fluid may also provide complementary connections that do not exist in the nervous, vascular, and lymphatic systems. They believe that the whole-body network formed by the interstitial spaces filled with tissue fluid is of great significance for molecular signal transduction, cell transportation, and the spread of malignancies and infectious diseases.

[0036] Li Hongyi et al. observed through magnetic resonance imaging that after tracers were injected into the interstitium of the human body and amputated limbs, they could show long-range flow along the adventitia of arteries and veins, nerves, and skin tissues, thus believing that there are unknown fluid pathways outside the circulatory system. Han Dong et al. found that compared with oral administration, intrathecal space injection in the limbs can significantly increase the drug concentration in the lungs. Zhang Weibo et al. proposed the concept of low-flow-resistance tissue fluid channels running along the meridians in the interstitium. And long-range migrating interstitial tissue fluid channels of tracers were observed in transparent fish, rats, miniature pigs, and humans. Through the three-dimensional visualization of the interstitial channels in the limbs of the organisms and the study of some functions, it is considered that the interstitial channels have the functions of transporting tissue fluid and transporting substances towards the viscera connected to the meridians, which highly coincides with traditional Chinese medicine meridians.

[0037] Based on the histological characteristics of the interstitial structure and its transport characteristics, the development of interstitial local or targeted drug delivery may become a potentially efficient drug delivery method. Moreover, in traditional Chinese medicine clinical practice, the hydro-acupuncture therapy, that is, injecting medicine into acupoints, treats local and meridian-related visceral diseases through interstitial transport, and this therapy has been widely used in clinical practice. In recent years, more and more studies have shown that interstitial drug delivery is a potentially efficient drug delivery method. Different from the traditional oral and intravenous drug delivery routes, interstitial drug delivery can be directly injected into the interstitium of diseased tissues or target organs, greatly increasing the drug enrichment degree at the lesion site, reducing the drug dosage, reducing the drug accumulation in other organs, and improving both drug safety and efficacy simultaneously.

[0038] Traditional Chinese medicine theory points out that the Conception Vessel originates from the uterus of women, and the Conception Vessel is closely related to the development and function of the uterus of women, such as Figure 2 the schematic diagram of the circulation and distribution of the Conception Vessel in the human body shown. In traditional Chinese medicine theory, it is believed that the uterus of women should be an overall system with reproductive functions centered around the uterus, and anatomically, it should be summarized as: ① the internal and external reproductive organs of women; ② the Chong and Conception Vessels that originate from the uterus; ③ the pelvic cavity is where the uterus of women is located, belonging to the lower jiao, and the bladder, rectum, fascia, muscles, etc. that maintain the internal reproductive organs in the pelvic cavity. Clinically, acupuncture at acupoints on the Conception Vessel can treat diseases of the female reproductive system, that is, the ovaries and uterus.

[0039] Previous studies of our team have confirmed that there are meridional low-flow resistance channels conducive to the flow of interstitial fluid in the interstitium, abbreviated as interstitial channels; and the three-dimensional visualization of interstitial channels has been achieved, proving that it has the material transport functions of running tissue fluid and tending to the viscera related to the meridians, which highly coincides with traditional Chinese medicine meridians, that is, continuous interstitial channels are distributed in the limbs and trunk of the body where the meridians of traditional Chinese medicine circulate and distribute, such as Figure 3 the three-dimensional reconstruction map of the migration trajectory of fluorescein sodium injected through the meridional interstitial channels in the limbs of minipigs shown.

[0040] In this embodiment, we selected the interstitial channel tissue on the midline of the abdomen of rats, that is, the position corresponding to the circulation and distribution of the Conception Vessel of traditional Chinese medicine, as the key pathway for the body surface to connect with the uterus and ovaries, and through injection through the midline interstitial channels of the abdomen, excellent drug delivery targeting the uterus and ovaries is achieved, providing a new idea for drug delivery targeting the uterus and ovaries.

[0041] As Figure 1 shown, a drug delivery method for injecting through the interstitial channels of the Conception Vessel of rats to target the uterus and ovaries provided by this embodiment selects this special pathway of the midline interstitial channels for fixed-point interstitial injection and targeted drug delivery to the uterus and ovaries. The method includes the following steps:

[0042] S1. Locate the interstitial channel on the ventral midline: After anesthetizing the rat and preparing the abdominal skin during preoperative preparation, detect the low-resistance points on the abdominal skin of the rat, and connect the traced low-resistance points on the ventral midline skin to determine the projection of the position of the interstitial channel on the ventral midline on the abdominal skin;

[0043] In a specific embodiment, the specific method of the preoperative preparation is as follows: After weighing the rat, anesthetize it by intraperitoneal injection of 2% sodium pentobarbital (30 ml / kg). Then, fix it in a supine position on the experimental table, depilate the entire abdominal skin below the xiphoid process with depilatory cream, and disinfect it with 75% alcohol.

[0044] Optionally, in step S1, a WQ6F30 meridian locator is used to detect the low-resistance points on the abdominal skin.

[0045] In another specific embodiment, the method for detecting the low-resistance points on the abdominal skin of the rat is as follows: Wrap absorbent cotton soaked in normal saline around the root of the rat's tail, put it into a copper ring electrode plate, and connect the WQ6F30 meridian locator. Gently and slowly scan and measure the surface of the depilated abdominal skin and the upper surface of the ventral midline from the xiphoid process to the external genitalia with a detection electrode; the direction of the electrode probe is perpendicular to the ventral midline; when the current of the meridian locator increases significantly and it is closest to the ventral midline (i.e., the projection connection line of the meridian of Renmai on the abdominal skin), stop sliding and use a marker pen to mark. These marked points are the low-resistance points on the ventral midline skin (that is, the low-resistance points on the projection of the meridian of Renmai on the abdominal skin), which are the projections of the position of the interstitial channel on the ventral midline on the abdominal skin.

[0046] Optionally, the number of the traced low-resistance points on the ventral midline skin is 10 - 15. Connect the low-resistance points on the ventral midline skin and compare with the position of the ventral midline to locate the injection points on the interstitial channel on the ventral midline.

[0047] S2. Locate the injection points of the interstitial channel on the ventral midline: As Figure 4 shown in the positioning diagram of the low-resistance points on the ventral midline skin and the injection points of the interstitial channel of the rat, divide the connection line between the xiphoid process and the external genitalia on the ventral midline into 5 equal segments and make marks, and define the low-resistance points between the two end points of the 3rd segment on the connection line as the injection points;

[0048] In a specific embodiment, the low-resistance points in the 1st segment, 2nd segment, 3rd segment, 4th segment, and 5th segment from the xiphoid process to the external genitalia on the connection line are respectively used as the injection points, and through steps S3 - S5, inject the water-soluble tracer sodium fluorescein injection, observe the migration trajectory of sodium fluorescein injection along the interstitial channel on the ventral midline by fluorescence photography method, and analyze the sodium fluorescein content in the uterus and ovaries through microscopic tissue structure.

[0049] In this embodiment, the inventor found through the fluorescence signal trajectory and the content of sodium fluorescein that when the low-resistance point in the third segment was used as the injection point, the water-soluble tracer sodium fluorescein was transported over a long distance along the interstitial channel of the ventral midline. It can be seen that sodium fluorescein migrated along the interstitial channel of the ventral midline to the bladder wall and the uterus. However, due to the influence of the microscopic tissue structure, the sodium fluorescein injected at other low-resistance points (the low-resistance points in the first, second, fourth, and fifth segments) could not be transported over a long distance or only a small amount was transported over a long distance to the bladder wall or the uterus. It has been proven by the embodiment that when the low-resistance point in the third segment of the line is used as the injection point, the injection solution can migrate over a long distance along the smooth interstitial channel of the Conception Vessel to the bladder wall and the uterus.

[0050] S3. Inject the water-soluble tracer injection solution: Use a syringe to draw a certain amount of the water-soluble tracer injection solution, vertically insert the injection needle into the abdominal wall at the injection point, and inject the water-soluble tracer injection solution into the interstitial channel of the ventral midline.

[0051] Optionally, in step S3, the water-soluble tracer injection solution includes but is not limited to sodium fluorescein injection solution, fluorescent marker injection solution, radionuclide marker injection solution, nanoparticle injection solution, protein injection solution, polypeptide injection solution, traditional Chinese medicine decoction particle injection solution, etc.

[0052] Optionally, use an insulin syringe to draw ≤0.1 ml of the water-soluble tracer injection solution, vertically insert the insulin injection needle into the injection point, and slowly inject the water-soluble tracer injection solution into the interstitial channel of the ventral midline.

[0053] Specifically, after the insulin injection needle is vertically inserted into the injection point on the abdominal wall and the tip of the needle reaches about 3 mm under the skin, steady the needle body and slowly inject the water-soluble tracer injection solution into the interstitial channel of the ventral midline. After the injection, keep the tip of the needle in the tissue for 10 s, and gently press the injection point with a cotton swab after pulling out the needle.

[0054] S4. Observe the migration trajectory of the water-soluble tracer injection solution along the interstitial channel of the ventral midline by fluorescence photography.

[0055] Optionally, in step S4, 30 minutes after the injection of the water-soluble tracer injection solution, take a fluorescence imaging picture of the rat's abdomen with a fluorescence photography system.

[0056] In a specific embodiment, 30 minutes after the injection of sodium fluorescein, place the rat horizontally on the experimental table, and take a fluorescence imaging picture of the rat's abdomen with a fluorescence photography system. As Figure 5 shown in the left picture, it can be seen that a long-distance migration trajectory of the fluorescence signal appears along the ventral midline position, indicating that sodium fluorescein has been successfully injected into the interstitial channel of the ventral midline; then open the abdominal cavity through surgery and take a fluorescence image of the inner abdominal wall and organs again. As Figure 5As shown in the right figure, it can be seen that the fluorescent signal is transmitted to the uterus and ovaries through the interstitial channels in the midline of the abdominal wall.

[0057] S5. Detect the content of water-soluble tracer in the uterus and ovaries: Analyze the content of water-soluble tracer in each organ of the rat, and compare it with the content of water-soluble tracer in each organ of the rat after intravenous injection of water-soluble tracer.

[0058] In a specific embodiment, 30 minutes after the injection of sodium fluorescein, fluorescence imaging pictures of each organ were taken with in vivo imaging of rats (such as Figure 5 ), and through analysis, the fluorescence intensity of sodium fluorescein migrating and transmitting along the interstitial channels in the midline of the abdomen to the bladder wall, uterus, and ovaries can be obtained, and then the content of sodium fluorescein in the bladder wall, uterus, and ovaries can be obtained.

[0059] In another specific embodiment, the liquid after soaking each organ in ultrapure water was extracted to detect the content of sodium fluorescein in each organ; and it was compared with the content of sodium fluorescein in each organ of the rat 30 minutes after intravenous injection of sodium fluorescein; the content of sodium fluorescein in the uterus and ovaries of the rats injected through the interstitial channels in the midline of the abdomen was significantly higher than that injected through the tail vein (as Figure 6 shown), about more than 5 times.

[0060] It can be seen that the drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the rat's conception vessel provided in this embodiment solves the problem of low targeting efficiency of drugs targeting the uterus and ovaries through traditional drug delivery routes such as oral administration and intravenous injection, and also solves the problem of low drug delivery efficiency caused by the influence of the menstrual cycle, physiological structure, and patient compliance in the vaginal drug delivery route for drugs targeting the uterus and ovaries, improves the drug enrichment degree at the lesion site, reduces the drug administration dose, and reduces the drug accumulation in other organs, achieving the improvement of the safety and efficacy of drugs targeting the uterus and ovaries.

[0061] Based on this, this embodiment also provides an application of a drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the rat's conception vessel, and the application includes delivering drugs to pelvic organs such as the uterus, ovaries, bladder, colorectum, and prostate through the drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the rat's conception vessel, so as to reduce the drug delivery dose and reduce the drug accumulation in other important organs.

[0062] Example of a drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the rat's conception vessel

[0063] This embodiment provides a drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the rat's conception vessel, and the method includes the following steps:

[0064] S11. Preoperative preparation: The rats were anesthetized by intraperitoneal injection of 2% sodium pentobarbital (30 ml / kg). After the rats were fully anesthetized, they were fixed in a supine position on the experimental table. The entire abdominal skin below the xiphoid process was depilated with depilatory cream and disinfected with 75% alcohol.

[0065] S12. Locate the low-resistance points of the interstitial channels on the ventral midline: Wrap absorbent cotton soaked in normal saline around the root of the rat's tail, put on a copper ring electrode plate, and connect it to the WQ6F30 meridian locator. Gently and slowly scan and measure on the surface of the depilated abdominal skin and the upper surface of the ventral midline from the xiphoid process to the external genitalia with a detection electrode; the direction of the electrode probe is perpendicular to the ventral midline; when the current of the meridian locator increases significantly and it is closest to the ventral midline (i.e., the projection of the meridian line of the Conception Vessel on the abdominal skin), stop sliding and mark it with a green marker pen. These marked points are the low-resistance points on the meridian line of the Conception Vessel on the ventral midline, that is, the low-resistance points of the interstitial channels on the ventral midline. A total of 10 - 15 low-resistance points of the interstitial channels on the ventral midline were detected and marked on the ventral midline. Connect the low-resistance points of the interstitial channels on the ventral midline and compare them with the position of the ventral midline to locate the injection points on the interstitial channels on the ventral midline.

[0066] S13. Locate the injection points of the interstitial channels on the ventral midline: As Figure 4 shown, divide the connection line between the xiphoid process and the external genitalia on the ventral midline into 5 equal segments and make marks, and define the low-resistance point of the 3rd segment on the connection line as the injection point.

[0067] S14. Inject the water-soluble tracer injection: Take the low-resistance point of the 3rd segment on the connection line between the xiphoid process and the external genitalia on the ventral midline as the injection point, draw 0.1 ml of fluorescein sodium injection with an insulin syringe, insert the insulin injection needle vertically into the injection point with the abdominal wall, and when the needle tip reaches about 3 mm under the skin, stabilize the needle body and slowly inject the injection into the interstitial channels on the ventral midline. After the injection is completed, keep the needle tip in the tissue for 10 s, and gently press the injection point with a cotton swab after removing the needle.

[0068] S15. Observe the migration trajectory of fluorescein sodium injection along the interstitial channels on the ventral midline by fluorescence photography: 30 minutes after the fluorescein sodium injection, place the rat horizontally on the experimental table and take fluorescence imaging pictures of the rat's abdomen with a fluorescence photography system. As Figure 5 shown in the left picture, it can be seen that a long-range migration trajectory of fluorescence signal appears along the ventral midline position, indicating that the fluorescein sodium was successfully injected into the interstitial channels on the ventral midline; then open the abdominal cavity through surgery and take fluorescence images of the abdominal inner wall and organs again. As Figure 5 shown in the right picture, it can be seen that the fluorescence signal is transmitted to the uterus and ovaries through the interstitial channels on the ventral midline of the abdominal wall.

[0069] Figure 5It is a fluorescence photograph of the long-range transmission of sodium fluorescein injection along the interstitial channel in the midline of the rat abdomen. Figure 5 The left picture is a fluorescence photograph of the abdominal skin of a live rat after injecting sodium fluorescein into the interstitial channel in the midline of the abdomen; it can be seen that a bright fluorescence signal trajectory is shown at the midline of the abdomen, which is the trajectory of the migration and transmission of sodium fluorescein along the interstitial channel in the midline of the abdomen. Figure 5 The right picture is a fluorescence image taken of the inner abdominal wall of a live rat. It can be seen that sodium fluorescein migrates and is transmitted along the interstitial channel in the midline of the abdomen to organs such as the bladder wall and uterus in the pelvic cavity.

[0070] S16. Detect the content of sodium fluorescein in the uterus and ovaries: 30 minutes after injecting sodium fluorescein, use in vivo imaging of rats to take fluorescence imaging pictures of each organ (such as Figure 5 ). Through analysis, the fluorescence intensity of sodium fluorescein migrating and being transmitted along the interstitial channel in the midline of the abdomen to the bladder wall, uterus, and ovaries can be obtained, and then the content of sodium fluorescein in the bladder wall, uterus, and ovaries can be obtained. Then, extract the liquid after soaking each organ in ultrapure water to detect the content of sodium fluorescein in each organ; and compare it with the content of sodium fluorescein in each organ of rats 30 minutes after injecting sodium fluorescein into the tail vein; the content of sodium fluorescein in the uterus and ovaries of rats injected through the interstitial channel in the midline of the abdomen is significantly higher than that injected through the tail vein (as Figure 6 shown), about more than 5 times.

[0071] Figure 6 It is a comparison of the content of sodium fluorescein in the abdominal organs of rats after injecting sodium fluorescein through the interstitial channel in the midline of the abdomen, injecting beside the abdominal wall tissue, and injecting into the tail vein. From Figure 6 it can be seen that for rats injected through the interstitial channel in the midline of the abdomen, the content of sodium fluorescein in the uterus and ovaries is about 5 times that of rats injected into the tail vein. Relatively speaking, for rats injected through the interstitial channel in the midline of the abdomen, the content of sodium fluorescein in other important organs such as the heart, liver, and lungs has not increased significantly.

[0072] That is to say, for drugs targeting abdominal organs such as the uterus, ovaries, and bladder, by injecting drugs targeting the uterus and ovaries through the interstitial channel in the midline of the abdomen, only 1 / 5 of the amount injected by the delivery method of injecting into the tail vein is needed; at the same time, it is not restricted by the physiological cycle. Moreover, due to the reduction of the total amount of injected drugs, the enrichment of the drug in other important organs such as the heart, liver, and lungs can also be reduced, and the side effects of the drug can be alleviated.

[0073] It can be seen that the drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the Ren Meridian in rats provided in this embodiment solves the problem of low targeting efficiency of drugs targeting the uterus and ovaries through traditional drug delivery routes such as oral administration and intravenous injection, and also solves the problem of low drug delivery efficiency caused by the influence of the menstrual cycle, physiological structure, and patient compliance in the drug delivery route through vaginal administration. It improves the drug enrichment degree at the lesion site, reduces the drug dosage, and alleviates the drug accumulation in other organs, achieving the improvement of the safety and efficacy of drugs targeting the uterus and ovaries.

[0074] The method described in the present invention is not limited to the specific embodiments. The above embodiments are only illustrative examples of the present invention. The present invention can also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described embodiments should be regarded as illustrative rather than restrictive in any aspect. The scope of the present invention should be defined by the appended claims, and any equivalent changes to the intention and scope of the claims should also be included within the scope of the present invention.

Claims

1. A drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the Conception Vessel, characterized in that, The method includes the following steps: S1. Locate the interstitial channel of the ventral midline: After anesthetizing the rat and preparing the abdominal skin during preoperative preparation, detect the low-resistance points on the abdominal skin of the rat, connect the traced low-resistance points on the ventral midline skin, and determine the projection of the position of the interstitial channel of the ventral midline on the abdominal skin; S2. Locate the injection point of the interstitial channel of the ventral midline: Divide the line connecting the xiphoid process to the external genitalia on the ventral midline into 5 equal segments and make marks, and define the low-resistance points on the ventral midline skin between the two endpoints of the 3rd segment on the said line as the injection points; S3. Inject a water-soluble tracer injection: Use a syringe to draw a certain amount of water-soluble tracer injection, insert the injection needle perpendicular to the abdominal wall into the said injection point, and inject the water-soluble tracer injection into the interstitial channel of the ventral midline; S4. Observe the migration trajectory of the water-soluble tracer injection along the interstitial channel of the ventral midline by fluorescence photography; S5. Detect the content of the water-soluble tracer in the uterus and ovaries.

2. The drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the Conception Vessel according to claim 1, characterized in that, In step S1, a WQ6F30 meridian locator is used to detect the low-resistance points on the abdominal skin.

3. A drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channels of the Conception Vessel according to claim 2, characterized in that, In step S1, when using a WQ6F30 meridian locator to detect the low-resistance points on the abdominal skin, the detection direction of the electrode probe is perpendicular to the ventral midline; When the current of the meridian locator increases significantly and is closest to the ventral midline, stop sliding and use a marker pen to trace. These traced points are the low-resistance points on the ventral midline skin.

4. A drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channel of the Conception Vessel according to claim 3, characterized in that, The traced low-resistance points on the ventral midline skin are 10 to 15.

5. A drug delivery method for targeted injection into the uterus and ovaries through the interstitial channels of the Conception Vessel according to claim 1, characterized in that, In step S3, the water-soluble tracer injection includes sodium fluorescein injection, fluorescent marker injection, radionuclide marker injection, nanoparticle injection, protein injection, polypeptide injection, and traditional Chinese medicine decoction body injection.

6. A drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channel of the Conception Vessel according to claim 5, characterized in that, In step S3, use an insulin syringe to draw ≤0.1 ml of the water-soluble tracer injection, insert the insulin injection needle perpendicular to the abdominal wall into the injection point, and inject the water-soluble tracer injection into the interstitial channel of the ventral midline.

7. A drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the Conception Vessel according to claim 5, characterized in that, In step S3, after the insulin injection needle is inserted perpendicular to the abdominal wall into the injection point and the needle tip reaches 3 mm under the skin, stabilize the needle body and inject the water-soluble tracer injection into the interstitial channel of the ventral midline.

8. A drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the Conception Vessel according to claim 1, characterized in that, In step S4, 30 minutes after injecting the water-soluble tracer injection, use a fluorescence photography system to take fluorescence imaging pictures of the rat's abdomen; then open the abdominal cavity through surgery and take fluorescence images of the abdominal inner wall and organs again.

9. A drug delivery method for targeting the uterus and ovaries by injecting through the interstitial channels of the Conception Vessel according to claim 8, wherein, In step S5, through the fluorescence imaging pictures of the rat's abdomen and the fluorescence images of the abdominal inner wall and organs, analyze and obtain the fluorescence intensity of the water-soluble tracer injection migrating and transmitting along the interstitial channel of the ventral midline to the bladder wall, uterus, and ovaries, and further obtain the content of the water-soluble tracer injection in the bladder wall, uterus, and ovaries.

10. A drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channels of the Conception Vessel according to claim 8, characterized in that, In step S5, extract the liquid after soaking each organ in ultrapure water and detect the content of the water-soluble tracer injection in each organ.

11. Use of a drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channels of the Conception Vessel according to any one of claims 1-10, said use comprising delivering a drug to pelvic organs by means of the drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channels of the Conception Vessel.

12. Use of the drug delivery method for injecting a drug targeting the uterus and ovaries through the interstitial channel of the Conception Vessel according to claim 11, characterized in that, The pelvic organs include the uterus, ovaries, bladder, colorectum, and prostate.

Images