Use of organosilicon quaternary ammonium salt in preparation of medical material for typing diagnosis of prostatitis

Abstract

The application discloses application of a silicone quaternary ammonium salt in preparation of a prostatitis typing diagnosis medical material, and the silicone quaternary ammonium salt can improve typing diagnosis of prostatitis, forms a biocompatible film of a molecular level or a nanotube in a urethra, prevents or destroys a bacterial biofilm, and the prostatic fluid flows out through the tube and is not polluted by bacteria and leukocytes, thereby improving a typing diagnosis rate, providing a basis for prostatitis treatment, and providing a new method for typing diagnosis of prostatitis.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of prostatitis typing diagnosis, and relates to application of a urethral biocompatible material film in medical materials. BACKGROUND

[0002] The current status and problems of prostatitis typing diagnosis at home and abroad. The typing diagnosis of prostatitis needs laboratory examination of prostatic fluid, but the prostatic fluid collected through the urethra under non-invasive conditions may be contaminated by bacteria and leukocytes in the urethra, resulting in false positive or false negative results and affecting the treatment effect due to misdiagnosis. At present, the guidelines of various countries in the world use the '3 urine + prostatic fluid' Meares-Stamey four-cup method to perform prostatic fluid detection typing, collect urine twice before collecting prostatic fluid, collect urine once again after collecting prostatic fluid, and separate and culture the collected prostatic fluid, the urethra, the bladder and the prostate infection of the male, and divide the types of prostatitis. Although '3 urine + prostatic fluid' improves the diagnosis rate, the urethra itself is contaminated by bacteria and leukocytes, the four-cup method cannot completely exclude the contamination of bacteria and leukocytes, and due to the complex operation, the application compliance of doctors is very poor, and the application rate of doctors in various countries in the world is less than 50%.

[0003] At present, there is no ideal method for typing diagnosis of prostatitis, therefore, it is an urgent need for clinical diagnosis and treatment to find a simple and accurate new method for typing diagnosis of prostatitis, to provide a basis for the treatment of prostatitis, and to perfect the diagnosis and treatment guideline scheme with higher clinical value. SUMMARY

[0004] This section aims to summarize some aspects of the embodiments of the application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, abstract and title, and such simplifications or omissions cannot be used to limit the scope of the application.

[0005] The application provides application of an organic silicon quaternary ammonium salt in preparation of a medical material for typing diagnosis of prostatitis.

[0006] As a preferred scheme of the application of the organic silicon quaternary ammonium salt in preparation of a medical material for typing diagnosis of prostatitis, the organic silicon quaternary ammonium salt includes organic silicon monoquaternary ammonium salt, organic silicon diquaternary ammonium salt and organic silicon double long-chain diquaternary ammonium salt.

[0007] As a preferred scheme of the application of the organic silicon quaternary ammonium salt in preparation of a medical material for typing diagnosis of prostatitis, the structural formula of the organic silicon quaternary ammonium salt is:

[0008]

[0009] As a preferred scheme of the application of the organosilicon quaternary ammonium salt in preparing the prostatitis disease diagnostic medical material, the structural formula of the organosilicon double quaternary ammonium salt is as follows:

[0010]

[0011] wherein, R1, R2 are each independently selected from C 11 alkyl; R3 is (EtO)3Si-, (MeO)3Si-, (EtO)3Si(CH2)nCO-, (EtO)3Si(CH2)3NHCO-, (MeO)3Si(CH2)3CO- or (MeO)3Si(CH2)3NHCO-; X is F, Cl, Br or I; Y1 and Y2 are each independently selected from O, NH; n is 3.

[0012] As a preferred scheme of the application of the organosilicon quaternary ammonium salt in preparing the prostatitis disease diagnostic medical material, the structural formula of the organosilicon double long-chain double quaternary ammonium salt is as follows:

[0013]

[0014] In the technical scheme of the application, the organosilicon quaternary ammonium salt forms a self-assembled nanomaterial layer in the body in the form of an aqueous solution, and further preferably, the concentration of the organosilicon quaternary ammonium salt aqueous solution is 0.1-20wt%.

[0015] As the application of the organosilicon quaternary ammonium salt in preparing the prostatitis disease diagnostic medical material.

[0016] The preferred scheme is that the prostatitis includes acute and chronic prostatitis, and the chronic prostatitis includes leukocyte and bacteria positive type, leukocyte positive and bacteria negative type, and leukocyte and bacteria negative type.

[0017] As the application of the organosilicon quaternary ammonium salt in preparing the prostatitis disease diagnostic medical material, the preferred scheme is that the organosilicon quaternary ammonium salt is administered in the body.

[0018] As the application of the organosilicon quaternary ammonium salt in preparing the prostatitis disease diagnostic medical material, the preferred scheme is that the organosilicon quaternary ammonium salt is administered in the form of a bolus injection.

[0019] In the technical scheme of the application, the organosilicon quaternary ammonium salt forms a nanoscale or molecular scale pipeline film after being injected into the urethra.

[0020] In the technical scheme of the application, the organosilicon quaternary ammonium salt prevents or destroys the formation of bacterial biofilms.

[0021] In the technical scheme of the application, the organosilicon quaternary ammonium salt isolates bacteria and leukocytes.

[0022] In the technical scheme of the present application: the prostatitis includes acute prostatitis and chronic prostatitis. Preferably: the chronic prostatitis includes leukocyte and bacteria positive type, leukocyte positive and bacteria negative type, and cell and bacteria negative type. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 For Figure 1 For scanning electron microscope images, wherein a. normal urethral membrane cells (group 1); b. urethral membrane forms an antimicrobial on the surface of the normal urethra (group 2); c. bacterial biofilm on the urethra (group 3); d. bacterial biofilm is destroyed by nano-antimicrobial membrane (group 4). DETAILED DESCRIPTION

[0024] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below.

[0025] In the following description, a large number of specific details are set forth in order to facilitate a thorough understanding of the present application, but the present application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the concept of the present application, therefore the present application is not limited to the specific embodiments disclosed below.

[0026] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0027] Example 1:

[0028]

[0029] 1L single-necked flask was added KH791 (50g, 1.0 eq), dissolved in 250ml dichloromethane and cooled to -5℃ to 5℃, then N-methylmorpholine dichloromethane solution (47.83g, 2.5 eq dissolved in 125ml dichloromethane) and chloroacetyl chloride dichloromethane solution (44.85g, 2.1 eq dissolved in 125ml dichloromethane) were added dropwise at the same time, and the reaction was incubated for 18h after dropwise addition. Spot test, developing agent methanol: dichloromethane 1:10, iodine cylinder coloration. After the reaction was completed, the filtrate was washed with 125ml saturated potassium dihydrogen phosphate three times and 125ml saturated sodium chloride three times, and the organic layer was dried over anhydrous sodium sulfate. Dried under reduced pressure. The product was a yellow liquid, weighing 50g, with a yield of 63.3%.

[0030] 2L single mouth flask was added intermediate (50g, 1.0eq), 1L isopropyl alcohol was added to heat and dissolve, slowly drop N, N-dimethyl dodecyl tertiary amine (64g, 2.5eq), reflux at 80℃ for 8h. Every 2h point plate detection, developing agent PE: EA 2:1, after the reaction liquid cooled to room temperature after the reaction was completed under reduced pressure to dryness to 61.9g target product, yield 81.9%.

[0031] 1 H NMR (500 MHz, Chloroform-d) δ 8.15 (t, J = 6.1 Hz, 1H), 4.32 (s, 2H), 4.20 (s, 2H), 3.81 (q, J = 8.0 Hz, 6H), 3.66 - 3.58 (m, 6H), 3.49 (tdd, J = 7.1, 6.1, 0.8 Hz, 2H), 3.43 (d, J = 2.2 Hz, 11H), 3.39 (t, J = 7.1 Hz, 2H), 1.70 (p, J = 7.1 Hz, 2H), 1.57 (p, J = 7.1 Hz, 4H), 1.38 - 1.19 (m, 46H), 0.92 - 0.86 (m, 6H), 0.68 (t, J = 7.1 Hz, 2H).

[0032] Example 2

[0033] Water-soluble self-assembled nanomaterial method, organosilicon double long chain double quaternary ammonium salt (example 1) was added to water and stirred (the mass concentration of organosilicon double long chain double quaternary ammonium salt was 1.5%), to obtain a water-soluble preparation, and the particle size of the organosilicon double long chain double quaternary ammonium salt was detected by a three-function particle system manufactured by Brookhaven Company (BIC) in New York, USA, as 37 nanometers.

[0034] Example 3

[0035] Animal urinary tract bacterial biofilm establishment. Methods 12 Beagle dogs aged 24 months were randomly divided into test group (6) and control group (6). The test group was given 2.5 ml of standard pathogenic bacteria Escherichia coli (ATCC25922), and the control group was given the same volume of sterile saline for bladder irrigation. Bacterial culture, drug sensitivity test, and pathological observation were performed. Results Compared with the control group, the bacterial culture in the model group showed statistically significant difference (P<0.05), and the bacteria were identified as the same type of Escherichia coli, which was most resistant to ampicillin and most sensitive to meropenem. In the pathological section, the tissue formed, and in the SEM image of the control group, a. normal urethral membrane cells (group 1) were observed, while in the SEM image of the test group, c. bacterial biofilm on the urethra (group 3), a large number of inflammatory cell infiltrates were observed under the microscope. Conclusion Escherichia coli can cause lower urinary tract infection in Beagle dogs, and has similarities with human lower urinary tract infection. Multiple bladder irrigation is a simple and effective experimental method for establishing an animal model, and it is confirmed that the drug resistance of bacterial biofilm is one of the main causes of lower urinary tract infection.

[0036] Example 4

[0037] A 1.5% aqueous formulation of silicone double long-chain double quaternary ammonium salt forms a molecular or nanoscale tube biofilm in the urethra, a new method for collecting expressed prostatic secretions (EPS). Methods 70 Beagle dogs were randomly divided into 7 groups, 10 dogs in each group. A urinary tract infection model was established, and urine, EPS, and prostate tissue were collected for bacterial culture and white blood cell microscopy. Histopathology and electron microscopy were performed on urethral and prostate tissue. Results are shown in Figure 1 (b and d). Conclusion The EPS collected by the tube biofilm formed in the urethra can exclude the possibility of contamination by the urethra (false positive) and interference by the urethral membrane (false negative), and the new method is feasible. After injection into the urethra, a nanoscale or molecular tube biofilm was formed, and after injection of the urethral membrane product into the urethra of Beagle dogs, a uniform, dense, and regular physical antimicrobial membrane was formed, Figure 1 b. Antimicrobial membrane formed by urethral membrane on normal urethral surface (group 2); Figure 1 d. Bacterial biofilm destroyed by nanoscale antimicrobial membrane (group 4).

[0038] Example 5:

[0039] Objective: To evaluate the diagnostic value of the organic silicon double long chain double quaternary ammonium salt 1.5% water-soluble preparation in the diagnosis of prostatitis. Methods: 720 cases of chronic prostatitis were enrolled, and 240 cases in the control group were randomly selected for "3 urine + EPS" test. The remaining 480 cases in the test group were divided into two groups: the first test group (240 cases) and the second test group (240 cases). The urine and prostatic fluid specimens of all subjects were collected for microscopic examination and bacteriological examination. Results: Table 1. Conclusion: The new method can more accurately diagnose chronic prostatitis.

[0040] Table 1 Prostatitis detection rate of each group

[0041] Group Example Leukocyte and bacteria positive type Leukocyte positive and bacteria negative type Leukocyte negative and bacteria negative type Epidemiology 5--8％ 45％ 45％ Test group 240 7.1％ 47％ 42％ Control group 240 56％ 32％ 37％ Control group 240 24％ 52％ 37％

[0042] Note: There was no statistical difference between the first test group (organic silicon double long chain double quaternary ammonium salt 1.5% water-soluble preparation) and the epidemiological group (P>0.05), while the other two groups had statistical differences with the epidemiological group (P<0.05 or 0.001).

[0043] Example 6 Biocompatibility test

[0044] According to GB / T16886.5-2017 "Biological evaluation of medical devices Part 5: In vitro cytotoxicity test"; GB / T16886.1⒎2017 "Biological evaluation of medical devices Part 10: Irritation and skin sensitization test", the biocompatibility test of Example 2 was carried out, and the results were as follows:

[0045] Cytotoxicity test results

[0046]

[0047] Under the conditions of this test, the cell survival rate of the test solution was 88%, and there was no potential cytotoxicity.

[0048]

[0049]

[0050] Under the conditions of this test, the test animals did not show redness and edema at the injection site, and the grade was less than 1 according to the Magnusson and Kligman grading standard. Therefore, under the conditions of this test, the test solution did not cause skin sensitization reaction in guinea pigs.

[0051] Animal individual vaginal irritation observation score:

[0052] Clinical observation:

[0053]

[0054] Histological evaluation:

[0055] Microscopic score table of vaginal tissue reaction

[0056]

[0057] Under the conditions of the experiment, the sample rabbit vaginal irritation index is 0, and the reaction degree is no irritation

[0058] According to CN 103977435 B, the experimental sample prepared has a cell survival rate of 35% after biocompatibility detection, has potential cytotoxicity, is higher than the sample prepared by the application, and has a grade less than 1 according to the Magnusson and Kligman grading standard. Therefore, under the conditions of the experiment, the test liquid does not cause skin sensitization reaction of guinea pigs. According to GB / T16886.1⒍2017 'Medical devices - Biological evaluation - Part 10: Irritation and skin sensitization tests', the vaginal mucosa irritation test has an irritation index of 1, and has a certain vaginal mucosa irritation test.

Claims

1. Use of a silicone quaternary ammonium salt for the preparation of a medical material for the diagnosis of chronic prostatitis, characterized in that, The organic silicon double long chain double quaternary ammonium salt is as follows: ； The chronic prostatitis is divided into leukocyte and bacterial positive type, leukocyte positive and bacterial negative type, cell and bacterial negative type.

2. Use according to claim 1, characterized in that: The organic silicon quaternary ammonium salt forms a self-assembled nanomaterial layer in the body in the form of an aqueous solution, and the concentration of the organic silicon quaternary ammonium salt aqueous solution is 0.1-20 wt%.

3. Use according to claim 1, characterized in that: The biological compatibility requirement of medical devices is met, including cytotoxicity test, skin sensitization test and vaginal irritation test.

4. Use according to claim 2, characterized in that: The organic silicon quaternary ammonium salt aqueous solution is administered in the body in the form of a bolus.

5. The use according to claim 1, characterized in that: A nanoscale or molecular scale pipeline film is formed after being injected into the urethra.

6. Use according to claim 1, characterized in that: Bacterial biofilm formation is prevented or destroyed.

7. The use according to claim 1, characterized in that: Bacteria and leukocytes are isolated.

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