An external-use nano gel for male penile erectile dysfunction and its preparation method

Abstract

The present invention provides an external nanogel for male penile erectile dysfunction and a preparation method thereof, belonging to the technical field of medicine. The preparation method of the external nanogel for male penile erectile dysfunction of the present invention is as follows: S1. Dissolve zwitterionic ions in water, then add polyvinyl alcohol and stir well at 50-80 °C for 4-8 h, centrifuge after cooling to obtain material A; S2. Mix 1-3 mg / mL of aldehyde-modified hyaluronic acid and 3-7 mg / mL of arginine and react for 7-9 h, and obtain material B after dialysis and freeze-drying; S3. Disperse material B in an oily solvent, then concentrate and centrifuge, take the precipitate and disperse it in water to obtain material C; S4. Mix material A and material C evenly to obtain the nanogel. The nanogel of the present invention can significantly improve erectile dysfunction, has a rapid onset, can adapt to different sexual activity times, and improves the spontaneity of sexual life and the quality of life of patients.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to an external nano-gel for male penile erectile dysfunction and a preparation method thereof. Background Art

[0002] Erectile Dysfunction (ED) refers to the situation where a male continuously or repeatedly fails to obtain and maintain sufficient penile erection to complete satisfactory sexual intercourse. This is a common disease among adult males, related to factors such as cardiovascular diseases, psychological factors, endocrine disorders, and neurological signal transmission diseases. Moreover, the incidence rate increases significantly with age, seriously affecting the quality of life and mental health of patients.

[0003] Traditional treatment methods mainly include oral medications, penile local injection medications, application of paste-like medications, surgical treatment, etc. Among them, oral medications generally involve taking PDE5 inhibitors such as Viagra. It acts on vascular smooth muscle and can inhibit the activity of type 5 phosphodiesterase, causing smooth muscle relaxation. After the arterial smooth muscle of the penis relaxes, it can provide more blood supply, thereby promoting the congestion of the corpus cavernosum of the penis to achieve a state of rapid erection. However, it may bring side effects to the capillary smooth muscle of other tissues and organs of the body, usually accompanied by headache symptoms. And the drug metabolism rate of oral medications is relatively slow, making it difficult to achieve rapid onset after use. The delayed onset is difficult to improve the quality of male sexual life. For penile local injection medications, including intraurethral suppositories such as alprostadil, by placing the suppository in the urethra, it can help dilate the corpus cavernosum of the penis, improve the blood supply of the corpus cavernosum of the penis, and help patients improve the erectile state. However, the operation and use of such reagents are troublesome, easily causing damage to the urethral mucosa and leading to problems such as urethritis. And the drug may be brought into the female body after ejaculation, causing impacts. The paste-like medications are applied to the glans penis, and through the penetration of the drug into the corpus cavernosum tissue, it stimulates blood circulation and induces smooth muscle dilation to improve erectile dysfunction diseases. However, it is easily brought into the female body, causing negative impacts. Therefore, how to provide a medical material and its preparation method that can be conveniently used, have a rapid onset, and have no side effects for erectile dysfunction problems is a difficult problem that urgently needs to be solved at present. Summary of the Invention

[0004] Aiming at the defects of the prior art, the present invention mixes an amphiphilic carrier and a nano-gel dispersion to obtain a nano-gel that can be externally applied and smeared on the penis, which can significantly improve erectile dysfunction, has a rapid onset, can adapt to different sexual activity times, and improves the quality of life of patients.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions to solve the technical problems:

[0006] In the first aspect, the present invention provides a preparation method for an external nano-gel for male penile erectile dysfunction, and the preparation method includes the following steps:

[0007] S1. Dissolve the zwitterion in water, then add polyvinyl alcohol and stir well at 50 - 80 °C for 4 - 8 h. After cooling, centrifuge to obtain material A;

[0008] S2. Mix 1 - 3 mg / mL of aldehyde - modified hyaluronic acid and 3 - 7 mg / mL of arginine and react for 7 - 9 h. After dialysis and lyophilization, obtain material B;

[0009] S3. Disperse material B in an oily solvent, then concentrate and centrifuge. Take the precipitate, add water to disperse to obtain material C;

[0010] S4. Mix material A and material C evenly to obtain the nanogel.

[0011] In some of the embodiments, in step S1, the zwitterion is at least one of poly(2 - methacryloyloxyethyl phosphorylcholine) and poly(sulfobetaine methacrylate).

[0012] In some of the embodiments, in step S1, the centrifugation speed is 3000 - 8000 rmp and the centrifugation time is 25 - 35 min.

[0013] In some of the embodiments, 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.

[0014] In some of the embodiments, in step S2, the preparation of the aldehyde - modified hyaluronic acid solution includes:

[0015] First, dissolve hyaluronic acid in water, add sodium periodate and react for 3 - 5 h. After terminating the reaction with ethylene glycol, dialyze and lyophilize to obtain aldehyde - modified hyaluronic acid, and then add it to water to prepare the aldehyde - modified hyaluronic acid solution.

[0016] In some of the embodiments, in step S2, the volume ratio of the aldehyde - modified hyaluronic acid solution to the arginine solution is 1:1.

[0017] In some of the embodiments, in step S3, the oily solvent is one or more of ethyl acetate and ether.

[0018] In some of the embodiments, in step S3, the concentration is concentrated to 10 - 30% of the mass of the dispersion system, and the centrifugation speed is 500 - 1000 rpm.

[0019] In some of the embodiments, in step S4, the mass ratio of material A to material C is (1 - 3):(3 - 6).

[0020] In a second aspect, the present invention provides an external nano-gel for male penile erectile dysfunction prepared by the above-mentioned preparation method. After applying it to the penis, the first erection time of the penis is less than 70 s, and the erection state reaches grade III.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The nano-gel of the present invention can accelerate the release and volatilization of the solvent inside the gel under pressing, accelerate the heat exchange efficiency, and enhance the erection speed; at the same time, after the oily solvent is encapsulated, it avoids the disadvantage that the extremely short-time cooling caused by rapid release is not enough to stimulate the penis, and also reduces the risk of additional volatilization of the second solvent during multiple uses of the gel product after opening the cap, improving the stability of the product during multiple uses. Compared with the existing external drugs for male penile erectile dysfunction, the nano-gel of the present invention has a large specific surface area, can significantly improve erectile dysfunction, has a fast onset, can adapt to different sexual activity times, and improves the quality of life of patients. Detailed embodiments

[0023] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to specific 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.

[0024] In the present invention, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous and include the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when the range refers to integers, it includes each integer between the minimum and maximum values of the range. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0025] In the present invention, the test methods used are all conventional methods unless otherwise specified; the materials, reagents, etc. used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0026] In the present invention, the "poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)" used is obtained by polymerizing 2-methacryloyloxyethyl phosphorylcholine (MPC), with Mn 9000; the "poly(sulfobetaine methacrylate) (PSBMA)" used is obtained by polymerizing sulfobetaine methacrylate (SBMA) monomers, with Mn 20000.

[0027] 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 it does not contain any active pharmaceutical ingredients.

[0028] In the present invention, the term "disperse" refers to uniformly distributing solid powder in a solvent to form a stable mixture.

[0029] Example 1

[0030] A preparation method of an external nano - gel for male penile erectile dysfunction is as follows:

[0031] 1. Add 35 mL of water and 5 g of poly(2 - methacryloyloxyethyl phosphorylcholine) into a glass container, 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).

[0032] 2. The nano - gel freeze - dried powder is obtained by self - assembly of aldehyde - modified hyaluronic acid and arginine, and the specific operation is as follows:

[0033] (1) Dissolve 0.8 g of hyaluronic acid in 90 mL of deionized water, add 0.45 g of sodium periodate for oxidation reaction 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;

[0034] (2) Dissolve aldehyde - modified hyaluronic acid and arginine in deionized water respectively to obtain 3 mg / mL solutions. Mix the equal - volume solutions and react in the dark for 7 h. After dialysis with deionized water and freeze - drying, obtain the nano - gel freeze - dried powder (Material B).

[0035] 3. Disperse the nano - gel freeze - dried powder (Material B) in an oily solvent (ethyl acetate) for 30 min, then concentrate to 10% of the mass of its dispersion system, centrifuge at a low speed of 1000 rpm, take the lower - layer precipitate, and add an appropriate amount of water to disperse to obtain a nano - gel dispersion (Material C).

[0036] The oily solvent is 10% of the mass fraction of the nano - gel freeze - dried powder.

[0037] 4. Mix the amphiphilic carrier liquid gel (Material A) and the nano - gel dispersion (Material C) evenly according to a mass ratio of 1:6 to obtain the nano - gel.

[0038] Example 2

[0039] A preparation method of an external nano - gel for male penile erectile dysfunction is as follows:

[0040] 1. Add 40 mL of water and 5 g of poly(2-methacryloyloxyethyl phosphorylcholine) into a glass container, 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 air bubbles, and obtain the amphiphilic carrier liquid gel (Material A).

[0041] 2. The aldehyde-functionalized hyaluronic acid and arginine are self-assembled to obtain the nano-gel freeze-dried powder. The specific operation is as follows:

[0042] (1) Dissolve 0.8 g of hyaluronic acid in 90 mL of deionized water, add 0.45 g of sodium periodate for oxidation reaction for 4 h, terminate the reaction with 0.5 mL of ethylene glycol, and then dialyze and freeze-dry to obtain the aldehyde-functionalized hyaluronic acid;

[0043] (2) Dissolve the aldehyde-functionalized hyaluronic acid and arginine in deionized water to obtain 2 mg / mL and 5 mg / mL solutions respectively. Mix equal volumes and react in the dark for 8 h. After dialysis with deionized water, freeze-dry to obtain the nano-gel freeze-dried powder (Material B).

[0044] 3. Disperse the nano-gel freeze-dried powder (Material B) in an oily solvent (ethyl acetate) for 30 min, then concentrate to 20% of the mass of its dispersion system, centrifuge at 800 rpm at low speed, and take the lower layer precipitate and add an appropriate amount of water to disperse to obtain the nano-gel dispersion (Material C).

[0045] The oily solvent is 30% of the mass fraction of the nano-gel freeze-dried powder.

[0046] 4. Mix the amphiphilic carrier liquid gel (Material A) and the nano-gel dispersion (Material C) evenly according to the mass ratio of 2:5 to obtain the nano-gel.

[0047] Example 3

[0048] A preparation method of an external nano-gel for male penile erectile dysfunction, the specific steps are as follows:

[0049] 1. Add 10 mL of water and 5 g of poly(2-methacryloyloxyethyl phosphorylcholine) into a glass container, 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 air bubbles, and obtain the amphiphilic carrier liquid gel (Material A).

[0050] 2. The aldehyde-functionalized hyaluronic acid and arginine are self-assembled to obtain the nano-gel freeze-dried powder. The specific operation is as follows:

[0051] (1) Dissolve 0.8 g of hyaluronic acid in 90 mL of deionized water, add 0.45 g of sodium periodate for oxidation reaction for 5 h, terminate the reaction with 0.5 mL of ethylene glycol, and then dialyze and freeze-dry to obtain the aldehyde-functionalized hyaluronic acid;

[0052] (2) Dissolve aldehyde - modified hyaluronic acid and arginine in deionized water respectively to obtain 1 mg / mL and 7 mg / mL solutions. Mix them in equal volumes and react in the dark for 9 h. After dialysis with deionized water, lyophilize to obtain nano - gel lyophilized powder (Material B).

[0053] 3. Disperse the nano - gel lyophilized powder (Material B) in an oily solvent (ethyl acetate) for 30 min, then concentrate it to 30% of the mass of its dispersion system, and centrifuge at a low speed of 500 rpm. Take the lower - layer precipitate, add an appropriate amount of water to disperse it to obtain a nano - gel dispersion (Material C).

[0054] The oily solvent is 50% of the mass fraction of the nano - gel lyophilized powder.

[0055] 4. Mix the amphiphilic carrier liquid gel (Material A) and the nano - gel dispersion (Material C) evenly according to a mass ratio of 3:3 to obtain the nano - gel.

[0056] Comparative Example 1

[0057] The difference between Comparative Example 1 and Example 1 is that the nano - gel dispersion is different, and the others are the same.

[0058] Disperse the nano - gel lyophilized powder in ethanol for 30 min, then concentrate it to 30% of the mass of its dispersion system, and centrifuge at a low speed of 500 rpm. Take the lower - layer precipitate, add an appropriate amount of water to disperse it to obtain a nano - gel dispersion.

[0059] The ethanol is 10% of the mass fraction of the nano - gel lyophilized powder.

[0060] Comparative Example 2

[0061] The difference between Comparative Example 2 and Example 1 is that Comparative Example 2 does not add the nano - gel dispersion, and the others are the same.

[0062] Comparative Example 3

[0063] The difference between Comparative Example 3 and Example 1 is that an equal amount of Carbopol Ultrez 10 polymer is used to replace the amphiphilic carrier liquid gel, and the others are the same.

[0064] Test Example 1

[0065] Respectively conduct penile erectile dysfunction tests on the nano - gels, placebos prepared in Examples 1 - 3 and Comparative Examples 1 - 3, and analyze the performance of the nano - gels.

[0066] Subjects: Select 105 male subjects with similar physical conditions and aged between 25 - 50 years old. Randomly divide them into 7 groups, with 15 people in each group.

[0067] Inclusion criteria:

[0068] International Index of Erectile Function-5 (IIEF-5) score: 12 ≤ score ≤ 21; At least two nocturnal penile tumescence recordings (NPTR) showing that the average maximum penile erection hardness is less than 60%; After penile erection is induced by injecting 10 μg of alprostadil injection into the corpus cavernosum, color Doppler ultrasound examination of the corpus cavernosum artery is performed: peak systolic velocity (PSV) < 25 cm / s; No other ED drugs have been taken 14 days before enrollment, and sexual abstinence has been maintained for two weeks.

[0069] Exclusion criteria: Uncontrolled hypertension [systolic blood pressure ≥ 160 mmHg (1 mmHg ≈ 0.133 kPa), diastolic blood pressure > 100 mmHg]; Uncontrolled diabetes [fasting plasma glucose (FPG) > 10 mmol / L]; Mental abnormalities and inability to cooperate with the completion of the trial; History of neurological disorders, spinal cord injury, pelvic trauma or surgery; History of alcoholism or drug abuse; Currently taking antiandrogen drugs, nitrates; Abnormal liver and kidney functions; Allergic to the drugs in the study; NPTR result shows that the average maximum penile erection hardness ≥ 60%.

[0070] Withdrawal criteria: Those who experience severe adverse reactions during the study and cannot tolerate them; Those with aggravated symptoms and adjusted treatment plans; Those who do not take medicine on time during treatment and the efficacy cannot be evaluated; Those who do not follow up on time during the study.

[0071] The penile erection hardness is evaluated according to the International Erectile Hardness Grade Standard (EHGS), and the judgment criteria are shown in Table 1 below:

[0072] Table 1 Penile Erection Judgment Standard Table

[0073] I II III IV The penis becomes congested and enlarged but cannot erect and cannot be inserted The penis has a slight erection but is not yet sufficient to be inserted The penis reaches a hardness sufficient for insertion but is not firm or persistent enough Fully erect, very firm, and persistent enough

[0074] Table 2 Test Results Table of Penile Erectile Dysfunction

[0075] 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

[0076] As can be seen from Table 2, after the nano-gels prepared in Examples 1-3 are used for the male penis, the penile erection is basically above Grade III, indicating that compared with Comparative Examples 1-3 and the placebo, the nano-gels of the present invention can significantly improve erectile dysfunction, basically avoid the situation of inability to erect, and the probability of achieving an effect above Grade III is more than 86%.

[0077] Test Example 2

[0078] Fifty-six 24-month-old mature male rats were used to test the nanogels and placebo prepared in Examples 1-3 and Comparative Examples 1-3. Eight rats were in parallel for each group. A depilatory was used to assist in removing the hair on the pubic area of the rats. The rats were placed on the 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. The results are shown in Table 3:

[0079] Table 3 Test results of the onset time of different nanogels

[0080] Grouping Time of 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

[0081] As can be seen from Table 3, the first erection time of the nanogels prepared in Examples 1-3 was less than 70 s, 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 erectile promotion effect, and appropriately increasing the loading amount of the nanogels has a more obvious effect on the erectile effect.

[0082] In summary, in the present invention, an amphiphilic carrier liquid gel is first prepared by reacting zwitterions with polyvinyl alcohol; then a nanogel lyophilized powder is obtained by reacting aldehyde-functionalized hyaluronic acid with arginine, which is dispersed in an oily solvent and then dispersed in water after concentration to obtain an oil-in-water nanogel dispersion. The nanogel prepared by mixing with the amphiphilic carrier liquid gel is applied to the male penis and can release a volatile solvent, accelerating the heat exchange efficiency. The present invention treats penile erectile dysfunction problems through this physical cooling method, making the first erection time of the penis less than 70 s and the erection state reaching Grade III. The prepared nanogel significantly improves male erectile dysfunction and has a fast onset, and can adapt to different sexual activity times; moreover, after the nanogel is encapsulated with an oily solvent and then overloaded with an amphiphilic carrier liquid gel, the stability of the product is improved, and it also provides a new idea for topical drugs for male penile erectile dysfunction.

[0083] In addition, it should be understood that although this specification is described according to the embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments 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 poly (2-methacryloyloxyethyl phosphorylcholine) into water and dissolve it, then add polyvinyl alcohol and stir thoroughly at 50-80°C for 4-8h, cool and centrifuge to remove bubbles, and obtain material A; S2. Mix 1-3 mg / mL aldehyded hyaluronic acid solution and 3-7 mg / mL arginine solution for 7-9 hours, dialyze and freeze-dry to obtain material B; S3. Disperse material B in ethyl acetate, concentrate to 10-30% of the mass of the dispersion system, centrifuge at 500-1000 rpm, 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 centrifugal speed is 3000-8000 rpm, and the centrifugal time is 25-35 min.

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

4. 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.

5. 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.

6. 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).

7. A nanogel for external use for male penis erectile dysfunction prepared by the preparation method according to any one of claims 1 to 6.