External nanogel for male penile erectile dysfunction and preparation method thereof

Abstract

The invention provides external nanogel for treating male penile erectile dysfunction and a preparation method of the external nanogel, and belongs to the technical field of medicines. The preparation method of the external nanogel for male penile erectile dysfunction comprises the following steps: S1, dissolving zwitterions in water, adding polyvinyl alcohol, fully stirring at 50-80 DEG C for 4-8 hours, cooling, and centrifuging to obtain a material A; s2, 1-3 mg / mL formylated hyaluronic acid and 3-7 mg / mL arginine are subjected to a mixed reaction for 7-9 h, dialysis and freeze-drying are performed, and a material B is obtained; s3, dispersing the material B into an oily solvent, concentrating, centrifuging, taking precipitate, adding water, and dispersing to obtain a material C; and S4, uniformly mixing the material A and the material C to obtain the nanogel. The nanogel can obviously improve erectile dysfunction, takes effect quickly, can adapt to different sexual activity opportunities, and improves spontaneity of sexual life and life quality of patients.

Description

Technical Field

[0001] The invention relates to the technical field of medicine, and in particular to an externally applied nano gel for treating male penis erectile dysfunction and a preparation method thereof. Background Art

[0002] Erectile dysfunction (ED) refers to the persistent or repeated inability of men to obtain and maintain sufficient penile erection to complete satisfactory sexual intercourse. It is a common disease in adult males and is related to cardiovascular disease, psychological factors, endocrine and neural signal transmission diseases. The incidence rate increases significantly with age, seriously affecting the patient's quality of life and mental health.

[0003] Traditional treatment methods mainly include oral medications, local injections of drugs into the penis, ointment-type drug application, surgical treatment, etc. Oral medications are generally oral Viagra and other PDE5 inhibitors, which act on vascular smooth muscle and can inhibit the activity of type 5 phosphodiesterase, causing smooth muscle relaxation. After the penis' arterial smooth muscle relaxes, it can provide more blood supply, thereby promoting the congestion of the penis cavernous body to achieve a state of rapid erection. However, it may have side effects on the capillary smooth muscle of other tissues and organs in the body, usually accompanied by headache symptoms, and oral medications have a slow metabolism rate, making it difficult to achieve rapid onset of effect after use. Delayed onset makes it difficult to improve the quality of male sexual life; local injection of drugs into the penis, including urethral suppositories such as alprostadil, can help expand the corpus cavernosum of the penis, improve the blood supply of the corpus cavernosum of the penis, and help patients improve their erectile state through suppositories placed in the urethra. However, such agents are cumbersome to operate and use, and are prone to damage to the urethral mucosa, leading to problems such as urethritis, and the drugs may be brought into the female body after ejaculation to cause effects; paste-like drugs are applied to the glans penis, and the drugs penetrate into the corpus cavernosum tissue to stimulate blood circulation, induce smooth muscle expansion, and improve erectile dysfunction, but they are easily brought into the female body and cause negative effects. Therefore, how to provide a medical material and its preparation method, which can be conveniently used for erectile dysfunction, quickly take effect, and have no side effects, is a problem that needs to be solved urgently. Summary of the invention

[0004] In view of the defects of the prior art, the present invention mixes an amphiphilic carrier and a nanogel dispersion to prepare a nanogel that can be applied externally to the penis, which can significantly improve erectile dysfunction, has a fast onset of action, can adapt to different sexual activity times, and improve the quality of life of patients.

[0005] In order to achieve the above purpose, the present invention solves the technical problem by adopting the following technical solutions: In a first aspect, the present invention provides a method for preparing a nanogel for external use for male penis erectile dysfunction, the preparation method comprising the following steps: S1. Add zwitterions to water and dissolve them, then add polyvinyl alcohol and stir thoroughly at 50-80°C for 4-8h, cool and centrifuge to obtain material A; S2.1-3 mg / mL aldehyded hyaluronic acid and 3-7 mg / mL arginine were mixed and reacted for 7-9 hours, and material B was obtained after dialysis and freeze-drying; S3. Disperse material B in an oily solvent, concentrate and centrifuge, take the precipitate and add water to disperse to obtain material C; S4. Mix material A and material C evenly to obtain nanogel.

[0006] In some embodiments, in step S1, the zwitterion is at least one of poly(2-methacryloyloxyethyl phosphorylcholine) and polysulfobetaine methacrylate.

[0007] In some embodiments, in step S1, in step S1, the centrifugal speed is 3000-8000 rpm, and the centrifugal time is 25-35 min.

[0008] In some of the embodiments, in step S1, the mass ratio of the zwitterion to the polyvinyl alcohol is 1:(1-2); the molecular weight of the polyvinyl alcohol is 70-100 kDa.

[0009] In some embodiments, in step S2, the preparation of the aldehyde-modified hyaluronic acid solution comprises: First, hyaluronic acid is dissolved in water, sodium periodate is added to react for 3-5 hours, the reaction is terminated with ethylene glycol, and then dialyzed and freeze-dried to obtain aldehyded hyaluronic acid, which is then added to water to obtain aldehyded hyaluronic acid solution.

[0010] In some embodiments, in step S2, the volume ratio of the aldehyded hyaluronic acid solution to the arginine solution is 1:1.

[0011] In some embodiments, in step S3, the oily solvent is one or more of ethyl acetate and diethyl ether.

[0012] In some embodiments, in step S3, the concentration is concentrated to 10-30% of the mass of the dispersed system, and the centrifugal speed is 500-1000 rpm.

[0013] In some embodiments, in step S4, the mass ratio of material A to material C is (1-3): (3-6).

[0014] In a second aspect, the present invention provides a nanogel for external use for male penis erectile dysfunction prepared by the above preparation method. After applying the nanogel to the penis, the first erection time of the penis is less than 70s, and the erection state reaches level III.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The nanogel of the present invention can accelerate the release and volatilization of the solvent inside the gel under pressure application, accelerate the heat exchange efficiency, and improve the erection speed; at the same time, the oily solvent is encapsulated to avoid the disadvantage that the extremely short-term cooling caused by the burst release is insufficient to stimulate the penis, and the risk of additional volatilization of the second solvent during the multiple use of the gel product after opening the cover is reduced, thereby improving the stability of the product for multiple use. Compared with the existing external medicines for male penis erectile dysfunction, the nanogel of the present invention has a larger specific surface area, can significantly improve erectile dysfunction, and has a fast onset, can adapt to different sexual activity opportunities, and improve the quality of life of patients. DETAILED DESCRIPTION

[0016] The following is a clear and complete description of the technical solutions in the embodiments of the present invention in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0017] In the present invention, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0018] In the present invention, the test methods used are conventional methods unless otherwise specified; the materials, reagents, etc. used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0019] In the present invention, the "poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC)" used is obtained by polymerizing 2-methacryloyloxyethyl phosphorylcholine (MPC), with Mn 9000; the "polysulfobetaine methacrylate (PSBMA)" used is obtained by polymerizing sulfobetaine methacrylate (SBMA) monomer, with Mn 20000.

[0020] In the present invention, the "placebo" used is a preparation that is identical or similar to the test drug in appearance, shape, color, size and taste, but does not contain any active drug ingredient.

[0021] In the present invention, the term "dispersing" refers to uniformly distributing solid powder in a solvent to form a stable mixture.

[0022] Example 1 A method for preparing a nanogel for external use for male penis erectile dysfunction, the specific steps are as follows: 1. Add 35 mL of water and 5 g of poly (2-methacryloyloxyethyl phosphorylcholine) to a glass container and stir to dissolve. Then add 10 g of polyvinyl alcohol and stir at 80 ° C for 4 h. After cooling, centrifuge at 3000 rpm for 30 min to remove bubbles to obtain an amphiphilic carrier liquid gel (material A).

[0023] 2. The aldehyde-modified hyaluronic acid and arginine are self-assembled to obtain a nanogel freeze-dried powder, and the specific operation is as follows: (1) Dissolve 0.8 g of hyaluronic acid in 90 mL of deionized water, add 0.45 g of sodium periodate and react for 3 h, terminate the reaction with 0.5 mL of ethylene glycol, and then dialyze and freeze-dry to obtain aldehyde-modified hyaluronic acid; (2) Aldehyde-modified hyaluronic acid and arginine were dissolved in deionized water to obtain 3 mg / mL and 3 mg / mL solutions, respectively. Equal volumes were mixed and reacted in the dark for 7 h. After dialyzing with deionized water, the solution was freeze-dried to obtain a nanogel freeze-dried powder (material B).

[0024] 3. Disperse the nanogel freeze-dried powder (material B) in an oily solvent (ethyl acetate) for 30 minutes, then concentrate to 10% of the mass of the dispersed system, centrifuge at 1000 rpm, remove the lower precipitate, add appropriate amount of water and disperse to obtain a nanogel dispersion (material C).

[0025] The oily solvent accounts for 10% of the mass fraction of the nanogel freeze-dried powder.

[0026] 4. The amphiphilic carrier liquid gel (material A) and the nanogel dispersion (material C) are uniformly mixed in a mass ratio of 1:6 to obtain the nanogel.

[0027] Example 2 A method for preparing a nanogel for external use for male penis erectile dysfunction, the specific steps are as follows: 1. Add 40 mL of water and 5 g of poly (2-methacryloyloxyethyl phosphorylcholine) into a glass container and stir to dissolve. Then add 5 g of polyvinyl alcohol and stir at 65 ° C for 6 h. After cooling, centrifuge at 5000 rpm for 30 min to remove bubbles to obtain an amphiphilic carrier liquid gel (material A).

[0028] 2. The aldehyde-modified hyaluronic acid and arginine are self-assembled to obtain a nanogel freeze-dried powder, and the specific operation is as follows: (1) Dissolve 0.8 g of hyaluronic acid in 90 mL of deionized water, add 0.45 g of sodium periodate and react for 4 h, terminate the reaction with 0.5 mL of ethylene glycol, and then dialyze and freeze-dry to obtain aldehyde-modified hyaluronic acid; (2) Aldehyde-modified hyaluronic acid and arginine were dissolved in deionized water to obtain 2 mg / mL and 5 mg / mL solutions, respectively. Equal volumes were mixed and reacted in the dark for 8 h. After dialyzing with deionized water, the solution was freeze-dried to obtain a nanogel freeze-dried powder (material B).

[0029] 3. Disperse the nanogel freeze-dried powder (material B) in an oily solvent (ethyl acetate) for 30 minutes, then concentrate to 20% of the mass of the dispersed system, centrifuge at 800 rpm, take the lower precipitate and add appropriate amount of water to disperse to obtain a nanogel dispersion (material C).

[0030] The oily solvent accounts for 30% of the mass fraction of the nanogel freeze-dried powder.

[0031] 4. The amphiphilic carrier liquid gel (material A) and the nanogel dispersion (material C) are uniformly mixed in a mass ratio of 2:5 to obtain the nanogel.

[0032] Example 3 A method for preparing a nanogel for external use for male penis erectile dysfunction, the specific steps are as follows: 1. Add 10 mL of water and 5 g of poly (2-methacryloyloxyethyl phosphorylcholine) into a glass container and stir to dissolve. Then add 5 g of polyvinyl alcohol and stir at 50 ° C for 8 h. After cooling, centrifuge at 8000 rpm for 30 min to remove bubbles to obtain an amphiphilic carrier liquid gel (material A).

[0033] 2. The aldehyde-modified hyaluronic acid and arginine are self-assembled to obtain a nanogel freeze-dried powder, and the specific operation is as follows: (1) Dissolve 0.8 g of hyaluronic acid in 90 mL of deionized water, add 0.45 g of sodium periodate and perform oxidation reaction for 5 h, terminate the reaction with 0.5 mL of ethylene glycol, and then dialyze and freeze-dry to obtain aldehyde-modified hyaluronic acid; (2) Aldehyde-modified hyaluronic acid and arginine were dissolved in deionized water to obtain 1 mg / mL and 7 mg / mL solutions, respectively. Equal volumes were mixed and reacted in the dark for 9 h. After dialyzing with deionized water, the solution was freeze-dried to obtain a nanogel freeze-dried powder (material B).

[0034] 3. Disperse the nanogel freeze-dried powder (material B) in an oily solvent (ethyl acetate) for 30 minutes, then concentrate to 30% of the mass of the dispersed system, centrifuge at 500 rpm, remove the lower precipitate, add an appropriate amount of water and disperse to obtain a nanogel dispersion (material C).

[0035] The oily solvent accounts for 50% of the mass fraction of the nanogel freeze-dried powder.

[0036] 4. The amphiphilic carrier liquid gel (material A) and the nanogel dispersion (material C) are uniformly mixed in a mass ratio of 3:3 to obtain the nanogel.

[0037] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the nanogel dispersion is different, and the others are the same.

[0038] The freeze-dried powder of the nanogel was dispersed in ethanol for 30 minutes, and then concentrated to 30% of the mass of the dispersed system, centrifuged at a low speed of 500 rpm, and the lower precipitate was removed and dispersed in an appropriate amount of water to obtain a nanogel dispersion.

[0039] The ethanol is 10% of the mass fraction of the nanogel freeze-dried powder.

[0040] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that no nanogel dispersion is added in Comparative Example 2, and the other aspects are the same.

[0041] Comparative Example 3 Comparative Example 3 differs from Example 1 in that an equal amount of Carbopol Ultrez 10 polymer is used to replace the amphiphilic carrier liquid gel, and the other contents are the same.

[0042] Test Example 1 The nanogels and placebos prepared in Examples 1-3 and Comparative Examples 1-3 were respectively subjected to erectile dysfunction tests to analyze the performance of the nanogels.

[0043] Subjects: A total of 105 male subjects with similar physical condition and age between 25 and 50 years old were selected and randomly divided into 7 groups, with 15 subjects in each group.

[0044] Inclusion criteria: International Questionnaire for Erectile Function-5 (IIEF-5) 12 points ≤ score ≤ 21 points; at least 2 nocturnal penile erectile function tests (NPTR) showed that the average hardness of the maximum penile erection was less than 60%; after 10 μg of alprostadil injection was injected into the corpus cavernosum to induce penile erection, a color Doppler ultrasound examination of the corpus cavernosum artery was performed: the maximum systolic blood flow velocity (PSV) was <25 cm / s; no other ED treatment drugs were taken 14 days before enrollment, and sexual abstinence was performed for two weeks.

[0045] Exclusion criteria: uncontrolled hypertension [systolic blood pressure ≥ 160 mmHg (1 mmHg ≈ 0.133 kPa), diastolic blood pressure > 100 mmHg]; uncontrolled diabetes [fasting blood glucose (FPG) > 10 mmol / L]; mental disorder, unable to cooperate with the trial; history of nervous system disease, spinal cord injury, pelvic trauma or surgery; history of alcoholism or drug abuse; taking anti-androgen drugs, nitrate drugs; abnormal liver and kidney function; allergy to the drugs in the study; NPTR result is the average hardness of the maximum erection of the penis ≥ 60%.

[0046] Dropout criteria: patients who had severe adverse reactions during the study and could not tolerate them; patients whose symptoms worsened and whose treatment plans needed to be adjusted; patients who did not take medication on time during treatment and whose efficacy could not be evaluated; and patients who did not follow up on time during the study.

[0047] The erection hardness of the penis was evaluated by the International Penile Erection Hardness Grading Standard (EHGS), and the judgment criteria are shown in Table 1 below: Table 1 Penile erection judgment standard table I II III IV The penis becomes engorged and enlarged, but cannot become erect or penetrated The penis is slightly erect, but not strong enough for penetration The penis is hard enough for penetration but not hard enough to last Fully erect and firm, long lasting Table 2 Penile erectile dysfunction test results Group I II III IV Example 1 0 2 5 8 Example 2 0 0 6 9 Example 3 1 1 5 8 Comparative Example 1 2 8 3 2 Comparative Example 2 3 10 1 1 Comparative Example 3 2 10 2 1 Placebo 7 6 2 0 As can be seen from Table 2, after the nanogels prepared in Examples 1-3 are used on the male penis, the penile erection is basically above Grade III, indicating that compared with Comparative Examples 1-3 and placebo, the nanogels of the present invention can significantly improve erectile dysfunction, basically avoid the situation of being unable to have an erection, and have a probability of more than 86% to achieve an effect above Grade III.

[0048] Test Example 2 The nanogels and placebos prepared in Examples 1-3 and Comparative Examples 1-3 were tested on 56 24-month-old mature male rats, with 8 rats in each group. The rats were depilated with a depilatory agent to remove the pubic hair. The rats were placed on an operating table in a quiet environment, and the samples were evenly applied to the pubic area. The number of penile erections within 30 minutes was monitored by video recording. The results are shown in Table 3: Table 3 Test results of different nanogel onset time Grouping Time to first erection Average number of erections Example 1 54s 6 Example 2 42s 7 Example 3 66s 5 Comparative Example 1 140s 3 Comparative Example 2 186s 2 Comparative Example 3 172s 3 Placebo No erection No erection As can be seen from Table 3, the first erection time of the nanogels prepared in Examples 1-3 was less than 70s, and the number of erections was significantly more than that of Comparative Examples 1-3 and the placebo, indicating that the nanogels of the present invention have a good erection-promoting effect, and appropriately increasing the loading amount of the nanogel has a more obvious erection effect.

[0049] In summary, the present invention firstly prepares an amphiphilic carrier liquid gel by reacting zwitterions with polyvinyl alcohol; then, the aldehyded hyaluronic acid and arginine are reacted to obtain a nanogel freeze-dried powder, which is dispersed in an oily solvent, dispersed in water after concentration to obtain an oil-in-water nanogel dispersion, and the nanogel prepared by mixing with the amphiphilic carrier liquid gel is applied to the male penis, which can release the volatile solvent and accelerate the heat exchange efficiency. The present invention treats the problem of penile erectile dysfunction by this physical cooling method, so that the first erection time of the penis is less than 70s, and the erection state reaches grade III. The prepared nanogel significantly improves male erectile dysfunction, and has a fast onset, and can adapt to different sexual activity times; and the nanogel is encapsulated with an oily solvent and then loaded with an amphiphilic carrier liquid gel, which improves the stability of the product and also provides a new idea for external drugs for male penile erectile dysfunction.

[0050] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for preparing a nanogel for external use for male penis erectile dysfunction, characterized in that: The preparation method comprises the following steps: S1. Add zwitterions to water and dissolve them, then add polyvinyl alcohol and stir thoroughly at 50-80°C for 4-8h, cool and centrifuge to obtain material A; S2. 1-3 mg / mL aldehyded hyaluronic acid and 3-7 mg / mL arginine were mixed and reacted for 7-9 hours, and material B was obtained after dialysis and freeze-drying; S3. Disperse material B in an oily solvent, concentrate and centrifuge, take the precipitate and add water to disperse to obtain material C; S4. Mix material A and material C evenly to obtain nanogel.

2. The preparation method according to claim 1, characterized in that: In step S1, the zwitterion is at least one of poly(2-methacryloyloxyethyl phosphorylcholine) and polysulfobetaine methacrylate.

3. The preparation method according to claim 1, characterized in that: In step S1, the centrifugal speed is 3000-8000 rpm, and the centrifugal time is 25-35 min.

4. The preparation method according to claim 1, characterized in that: In step S1, the mass ratio of the zwitterion to polyvinyl alcohol is 1:(1-2); the molecular weight of the polyvinyl alcohol is 70-100 kDa.

5. The preparation method according to claim 1, characterized in that: In step S2, the preparation of the aldehyde-modified hyaluronic acid solution comprises: First, hyaluronic acid is dissolved in water, sodium periodate is added to react for 3-5 hours, the reaction is terminated with ethylene glycol, and then dialyzed and freeze-dried to obtain aldehyded hyaluronic acid, which is then added to water to obtain aldehyded hyaluronic acid solution.

6. The preparation method according to claim 1, characterized in that: In step S2, the volume ratio of the aldehyded hyaluronic acid solution to the arginine solution is 1:

1.

7. The preparation method according to claim 1, characterized in that: In step S3, the oily solvent is one or more of ethyl acetate and diethyl ether.

8. The preparation method according to claim 1, characterized in that: In step S3, the concentration is to 10-30% of the mass of the dispersed system, and the centrifugal speed is 500-1000 rpm.

9. The preparation method according to claim 1, characterized in that: In step S4, the mass ratio of material A to material C is (1-3): (3-6).

10. A nanogel for external use for male penis erectile dysfunction prepared by the preparation method according to any one of claims 1 to 9.