Tadalafil nano preparation for external use as well as preparation method and application of tadalafil nano preparation

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an external tadalafil nano preparation as well as a preparation method and application thereof. Compared with the prior art, the external tadalafil preparation provided by the invention avoids oral administration and local use, drug absorption is not influenced by factors such as pH in the digestive tract and food, the external tadalafil preparation directly acts on the penis to play a drug effect after external use, toxic and side effects on other tissues are reduced, the dosage of the external tadalafil preparation is obviously lower than that of a commercially available oral tadalafil drug, and the external tadalafil preparation has a good application prospect. Meanwhile, the tadalafil pharmaceutical composition is suitable for patients with liver / kidney function impairment, dysphagia and gastrointestinal tract fragility, so that the application scene of tadalafil is further expanded. The external tadalafil preparation provided by the invention can efficiently meet the requirements of erectile dysfunction (ED) patients in China and in the whole world, and has a wide market prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a topical tadalafil nano-formulation, its preparation method, and its application. Background Technology

[0002] Tadalafil, marketed as Cialis, is a medication used to treat erectile dysfunction (ED), and can also be used to treat ED patients with concurrent benign prostatic hyperplasia (BPH). Tadalafil is a selective phosphodiesterase type 5 (PDE-5) inhibitor that promotes erection by increasing penile blood flow. Due to its importance in treating ED and conditions such as pulmonary hypertension, tadalafil enjoys a large global market demand. With the fast pace of life and an aging population, the number of ED patients continues to rise, directly driving the steady growth of the tadalafil market. According to market research data, global sales of tadalafil have repeatedly broken records in recent years, reaching $737 million in 2023, and is projected to grow at a rate of 5% annually, reaching $1.1 billion by 2030. In China, the prevalence of ED among men over 40 years old exceeds 40%, and the tadalafil market is estimated at approximately 3 billion RMB, with an annual growth rate of 10% to 15%.

[0003] Because tadalafil is a poorly soluble drug, it is almost insoluble in water and alcohol solvents, and its bioavailability is low. It needs to be improved by micronization or special formulation technology. At present, the market is mainly dominated by oral tablets. However, oral tadalafil has the following pain points: (1) Significant toxic side effects: Due to the first-pass effect of the gastrointestinal tract, the incidence of side effects such as headache and indigestion is about 30%, which makes it unsuitable for patients with chronic diseases, especially patients with liver and kidney damage. Although oral thiamin tablets can reduce the first-pass metabolism effect of the liver, they still need to reach the reproductive organs through the systemic blood circulation, which will still cause toxic side effects on other tissues in the system; (2) Limited onset time: Oral medication needs to be taken 30 minutes to 2 hours in advance; (3) Psychological burden factors: Some patients refuse to take the medication due to psychological burden. According to statistics, about 30% of patients discontinue the medication due to the side effects of oral anti-ED drugs or psychological factors. In order to better meet the needs of patients for convenience, timeliness and safety of medication, it is still necessary to develop innovative dosage forms of tadalafil.

[0004] Topical tadalafil has significant advantages in addressing the side effects of existing oral medications, increasing drug efficacy, and improving ease of use, and it effectively meets the needs of ED patients in China and around the world. Topical tadalafil has the following advantages: (1) Reduced systemic side effects: Topical preparations can act locally on the genital area, reducing systemic adverse reactions such as headache, flushing, and indigestion caused by oral medications; (2) Faster onset and more flexible use: Through transdermal absorption, it can achieve a faster onset time. Combined with condoms, lubricants, or anesthetics such as lidocaine, it can improve the convenience, flexibility, and diversity of the product, making it more suitable for meeting the needs of young male consumers and increasing consumption power and market space; (3) Expanded applicable population: It can be applied to middle-aged and elderly men with cardiovascular and cerebrovascular diseases, liver and kidney damage, chronic disease patients, patients with difficulty swallowing or gastrointestinal sensitivity, and may reduce the risk of interaction with other drugs; (4) Differentiated competitive advantage: At present, there are no approved topical tadalafil products in the global ED treatment field. Therefore, topical gels, sprays, or combined use with condoms have significant differentiated advantages and can fill such market gaps.

[0005] Because of the physicochemical properties of tadalafil, it is difficult to apply it directly to the skin. Therefore, it is necessary to develop corresponding topical formulations to improve the solubility and permeability of the drug and promote its absorption through the skin or mucous membranes. Summary of the Invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a topical tadalafil nano-formulation, its preparation method and application.

[0007] This invention provides a topical tadalafil formulation, comprising a dispersed phase and a continuous phase; the dispersed phase comprises tadalafil and a nonionic solubilizing emulsifier;

[0008] The continuous phase includes an aqueous matrix.

[0009] Preferably, the tadalafil in the dispersed phase is 0.01% to 5% of the mass of a nonionic solubilizing emulsifier.

[0010] Preferably, the nonionic solubilizing emulsifier is selected from polyoxyethylene solubilizing emulsifiers and / or polyoxyethylene hydrogenated castor oil;

[0011] The polyoxyethylene solubilizing emulsifier is selected from one or more of polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene copolymer, and poloxamer.

[0012] Preferably, the dispersed phase further includes an oil phase matrix; the oil phase matrix is ​​selected from glycerides.

[0013] Preferably, the glyceride is selected from one or more of medium-chain triglycerides, long-chain triglycerides, natural glycerides, glyceryl stearate, and polyglycerol fatty acid esters.

[0014] Preferably, the mass of the nonionic solubilizing emulsifier is 10% to 80% of the mass of the dispersed phase;

[0015] The mass of tadalafil is 0.1% to 2% of the mass of the dispersed phase;

[0016] The mass of the glyceride is 10% to 70% of the mass of the dispersed phase.

[0017] Preferably, the dispersed phase further includes a co-emulsifier; the mass of the co-emulsifier is 5% to 50% of the mass of the dispersed phase.

[0018] Preferably, the co-emulsifier is selected from one or more of alcohol co-emulsifiers, polyol co-emulsifiers, phospholipid co-emulsifiers, and surfactant co-emulsifiers;

[0019] The alcohol-based co-emulsifier is selected from one or more of ethanol, propanol, n-butanol and cetyl alcohol;

[0020] The polyol co-emulsifier is selected from one or more of glycerin, propylene glycol, polyethylene glycol and sorbitol;

[0021] The phospholipid co-emulsifier is selected from one or more of lecithin, soybean lecithin, and hydrogenated phospholipids;

[0022] The surfactant-type co-emulsifier is selected from one or more of high HLB Span co-emulsifiers, polyglycerol fatty acid esters, and sucrose fatty acid esters; the high HLB Span co-emulsifier has an HBL value greater than or equal to 5.

[0023] Preferably, the dispersed phase further includes a penetration enhancer; the mass of the penetration enhancer is 0.1% to 5% of the mass of the dispersant.

[0024] Preferably, the penetration enhancer is selected from one or more of lipid disruptors, solvent-based penetration enhancers, surfactant-based penetration enhancers, hydration enhancers, biotransformation-based penetration enhancers, and physical penetration enhancers.

[0025] The lipid-disrupting agent is selected from one or more of laurocapram, menthol, carvone, and limonene;

[0026] The solvent-based penetration enhancer is selected from one or more of propylene glycol, glycerol, dimethyl sulfoxide, and ethanol;

[0027] The surface-active penetration enhancer is selected from one or more of Tween, Span and sodium lauryl sulfate;

[0028] The hydration enhancer is selected from hyaluronic acid and / or polyethylene glycol;

[0029] The biotransformation-type penetration enhancer is selected from one or more of ethyl oleate, trioleic acid glyceride, monolaurate glyceride and dicetyl phosphate.

[0030] The physical penetration enhancer is selected from one or more of the following: natural polymer viscosity agents, synthetic polymer viscosity agents, nonionic wetting agents, polyol wetting agents, siloxane wetting agents, natural film-forming agents, synthetic film-forming agents, siloxane film-forming agents, hair follicle targeting aids, charge-type aids, and hydrophilicity / hydrophobicity regulating aids.

[0031] Preferably, the aqueous matrix is ​​selected from one or more of water, physiological saline, glucose solution and buffer solution.

[0032] Preferably, the continuous phase further includes a water-soluble polymeric thickener; the mass of the water-soluble polymeric thickener is 0.01% to 5% of the mass of the continuous phase.

[0033] And / or, the continuous phase further includes a pH adjuster; the mass of the pH adjuster is 0.001% to 0.05% of the mass of the continuous phase.

[0034] Preferably, the water-soluble polymeric thickener is selected from one or more of polypropylene, polysaccharides and their derivatives, and cellulose derivatives;

[0035] The pH adjuster is selected from alkaline pH adjusters.

[0036] Preferably, the average particle size of the topical tadalafil formulation is 10 nm to 10 μm.

[0037] Preferably, the average particle size of the topical tadalafil preparation is 50 nm to 500 nm; and the PDI of the topical tadalafil preparation is 0.1 to 0.4.

[0038] Preferably, it also includes pharmaceutically acceptable excipients; the pharmaceutically acceptable excipients include one or more of humectants, preservatives and antioxidants.

[0039] This invention also provides a method for preparing the above-mentioned topical tadalafil formulation, comprising the following steps:

[0040] S1) Provides a dispersion phase containing tadalafil and a nonionic solubilizing emulsifier;

[0041] Provides a continuous phase containing an aqueous matrix;

[0042] S2) The dispersed phase and the continuous phase are mixed to obtain a topical tadalafil formulation.

[0043] Preferably, the mixing method includes one or more of the following: ultrasonication, vortexing, stirring, high-speed dispersion, high-pressure homogenization, vacuum homogenization, and static mixer.

[0044] Preferably, the power of the ultrasound is 10~800 W;

[0045] And / or, the ultrasound is continuous ultrasound or intermittent ultrasound; the duty cycle of the intermittent ultrasound is 50%~90%; the duration of the ultrasound is 5~30 min;

[0046] And / or, the rotational speed of the vortex is 300~3500 rpm; the duration of the vortex is 5~60 min;

[0047] And / or, the stirring speed is 100~3500 rpm; the stirring time is 5~60 min;

[0048] And / or, the high-speed dispersion rotation speed is 1000~8000 rpm; the high-speed dispersion time is 5~60 min;

[0049] And / or, the pressure of the high-pressure homogenizer is 50~150 MPa;

[0050] And / or, the rotational speed of the vacuum homogenizer is 10,000 to 28,000 rpm.

[0051] Preferably, after mixing, centrifugation can be performed to obtain a topical tadalafil preparation; the centrifugal force is 500~2000 g; the centrifugation time is 1~10 min.

[0052] The present invention also provides the application of the above-mentioned topical tadalafil preparation in the preparation of products for treating erectile dysfunction.

[0053] The present invention also provides a product comprising the above-mentioned topical tadalafil preparation.

[0054] This invention provides a topical tadalafil formulation, comprising a dispersed phase and a continuous phase; the dispersed phase comprises tadalafil and a nonionic solubilizing emulsifier; the continuous phase comprises an aqueous matrix. Compared with existing technologies, the topical tadalafil formulation provided by this invention avoids oral administration, is applied topically, and drug absorption is not affected by factors such as pH and food in the digestive tract. After topical application, it acts directly on the penis to exert its efficacy, reducing toxic side effects on other tissues. Moreover, the dosage of topical tadalafil is significantly lower than that of commercially available oral tadalafil drugs, significantly improving medication adherence and timeliness. It is also suitable for patients with liver / kidney dysfunction, swallowing disorders, or gastrointestinal fragility, which will further expand the application market for tadalafil. The topical tadalafil formulation provided by this invention can effectively meet the needs of erectile dysfunction (ED) patients in China and globally, and has broad market prospects. Attached Figure Description

[0055] Figure 1 The high-performance liquid chromatogram of tadalafil;

[0056] Figure 2 This is a diagram showing the dissolution results of tadalafil in different oils in Example 1 of the present invention;

[0057] Figure 3 This is a diagram showing the dissolution results of tadalafil in medium-chain triglycerides in Example 1 of the present invention;

[0058] Figure 4 This is a diagram showing the dissolution results of tadalafil in polyoxyethylene castor oil in Example 1 of the present invention;

[0059] Figure 5 The graph shows the average particle size, uniformity, and degradation rate of the topical tadalafil nano-formulations prepared under different aqueous phase conditions in Example 1 of this invention after being stored for different times.

[0060] Figure 6 The graph shows the average particle size, uniformity, and degradation rate of the topical tadalafil nano-formulation prepared under different aqueous phase conditions in Example 1 of this invention after being placed for different times.

[0061] Figure 7 This is a graph showing the changes in concentration and particle size of the topical tadalafil nano-formulation prepared under condition 14-B in Example 1 of the present invention after long-term storage at room temperature in the dark.

[0062] Figure 8 This is a diagram showing the results of localized and efficient amplification of the rabbit penis using topical tadalafil nanoparticles in Example 1.3 of this invention.

[0063] Figure 9 This is a diagram showing the results of reducing the erectile latency in castrated ED rats using topical tadalafil nano-formulation in Example 1.3 of this invention.

[0064] Figure 10 This is a diagram showing the results of the topical application of tadalafil nano-formulation in Example 1.3 of this invention, which effectively promoted penile erection in monkeys.

[0065] Figure 11 This is a characteristic diagram of the topical tadalafil nanoformulation prepared in Example 5 of the present invention;

[0066] Figure 12 This is a graph showing the results of increasing the number of erections in castrated ED rabbits using topical tadalafil nano-formulation in Example 5.1 of this invention;

[0067] Figure 13 This is a graph showing the results of reducing the erectile latency in castrated ED rabbits using topical tadalafil nano-formulation in Example 5.1 of this invention.

[0068] Figure 14 This is a graph showing the results of increasing the mating frequency of castrated ED rabbits using topical tadalafil nano-formulation in Example 5.1 of this invention;

[0069] Figure 15 This is a graph showing the ICP / MCP results of the topical tadalafil nano-formulation used in Example 5.1 of this invention to increase the ICP / MCP of castrated ED rabbits;

[0070] Figure 16 This is a diagram showing the results of the topical tadalafil nano-formulation in Example 5.1 of this invention showing no irritation to rabbit skin. Detailed Implementation

[0071] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0072] Tadalafil is currently only available as an oral medication with extremely low water solubility (only 0.73 μg / ml). Oral tablets are the dominant form on the market (accounting for over 80%), but these have side effects such as low bioavailability, first-pass metabolism in the gastrointestinal tract, gastrointestinal adverse reactions, headaches, and slow onset of action. It is not suitable for patients with chronic diseases, especially those with impaired liver or kidney function. Although oral tadalafil tablets can reduce the first-pass metabolism in the liver, they still need to circulate throughout the body to reach the penis, potentially causing side effects on other tissues. To better meet patients' needs for convenience, timeliness, and safety, new topical tadalafil formulations still need to be developed.

[0073] Based on this, the present invention provides a topical tadalafil formulation comprising a dispersed phase and a continuous phase; the dispersed phase comprising tadalafil and a nonionic solubilizing emulsifier; the continuous phase comprising an aqueous matrix.

[0074] In one specific embodiment of the present invention, the mass of tadalafil in the dispersed phase is preferably 0.01% to 5% of the mass of the nonionic solubilizing emulsifier; optionally, the mass of tadalafil in the dispersed phase is 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.5%, 1.8%, 2%, 2.2%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.8%, 4%, 4.2%, 4.5%, 4.8%, 5% of the mass of the nonionic solubilizing emulsifier, or a range between any two of the above values.

[0075] In one specific embodiment of the present invention, the HLB of the nonionic solubilizing emulsifier is preferably 10 to 18; optionally, the HLB of the nonionic solubilizing emulsifier is 10, 11, 12, 13, 14, 15, 16, 17, 18 or any two of the above values.

[0076] In a specific embodiment of the present invention, the nonionic solubilizing emulsifier is preferably a polyoxyethylene solubilizing emulsifier and / or polyoxyethylene hydrogenated castor oil; the polyoxyethylene solubilizing emulsifier is preferably one or more of polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene copolymer and poloxamer; the polyethylene castor oil includes, but is not limited to, one or more of polyethylene (35) castor oil (CAS: 61791-12-6), polyethylene (40) castor oil (CAS: 61788-85-0), polyethylene (60) castor oil, etc.

[0077] In one specific embodiment of the present invention, the dispersed phase further includes an oil phase matrix; the oil phase matrix is ​​preferably a glycerol ester; the glycerol ester includes, but is not limited to, one or more of medium-chain triglycerides, long-chain triglycerides, natural glycerides, glyceryl stearate and polyglycerol fatty acid esters; the natural glycerides include, but are not limited to, one or more of olive oil, soybean oil, jojoba oil, almond oil, shea butter, coconut oil, etc.

[0078] In one specific embodiment of the present invention, the medium-chain triglyceride is preferably caprylic / capric triglyceride (CAS No.: 73398-61-5), such as one or more of Aladdin-M1456050, Yuanye-S25953 and Gedian Renfu-F347-025000.

[0079] In one specific embodiment of the present invention, the mass of the nonionic solubilizing emulsifier is preferably 10% to 80% of the mass of the dispersed phase; optionally, the mass of the nonionic solubilizing emulsifier is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% of the mass of the dispersed phase, or a range between any two of the above values; the mass of tadalafil is preferably 0.1% to 2% of the mass of the dispersed phase; optionally, the mass of tadalafil is preferably 0.1%, 0.2%, or 0.5% of the mass of the dispersed phase. The concentrations are 3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, or any two of the above values; the mass of the glyceride is preferably 10% to 70% of the mass of the dispersed phase; optionally, the mass of the glyceride is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% of the mass of the dispersed phase, or any two of the above values.

[0080] In one specific embodiment of the present invention, the dispersed phase further includes a co-emulsifier; the mass of the co-emulsifier is preferably 5% to 50% of the mass of the dispersed phase; optionally, the mass of the co-emulsifier is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% of the mass of the dispersed phase or a range between any two of the above values.

[0081] In a specific embodiment of the present invention, the co-emulsifier is preferably one or more of alcohol-based co-emulsifiers, polyol-based co-emulsifiers, phospholipid-based co-emulsifiers, and surfactant-based co-emulsifiers; the alcohol-based co-emulsifier includes, but is not limited to, one or more of ethanol, propanol, n-butanol, and cetyl alcohol; the polyol-based co-emulsifier includes, but is not limited to, one or more of glycerol, propylene glycol, polyethylene glycol, and sorbitol; the phospholipid-based co-emulsifier includes, but is not limited to, one or more of lecithin, soybean lecithin, and hydrogenated phospholipids; the surfactant-based co-emulsifier includes, but is not limited to, one or more of high HLB Span-type co-emulsifiers, polyglycerol fatty acid esters, and sucrose fatty acid esters; the high HLB Span-type co-emulsifier has an HBL value greater than or equal to 5.

[0082] In a specific embodiment of the present invention, the dispersed phase preferably further includes a penetration enhancer; the mass of the penetration enhancer is preferably 0.1% to 5% of the mass of the dispersant; optionally, the mass of the penetration enhancer is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.2%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.8%, 4%, 4.2%, 4.5%, 4.8%, 5% of the mass of the dispersant, or a range between any two of the above values.

[0083] In a specific embodiment of the present invention, the penetration enhancer is preferably one or more of the following: lipid disruptor, solvent-based penetration enhancer, surfactant-based penetration enhancer, hydration enhancer, biotransformation-based penetration enhancer, and physical penetration enhancer; the lipid disruptor includes, but is not limited to, one or more of laurocapram, menthol, carvone, and limonene; the solvent-based penetration enhancer includes, but is not limited to, one or more of propylene glycol, glycerol, dimethyl sulfoxide, and ethanol; the surfactant-based penetration enhancer includes, but is not limited to, one or more of Tween, Span, and sodium lauryl sulfate; the hydration enhancer includes, but is not limited to, hyaluronic acid and / or polyethylene glycol; the biotransformation-based penetration enhancer... The penetration enhancer includes, but is not limited to, one or more of ethyl oleate, trioleic acid glyceride, glyceryl monolaurate, and diceryl phosphate; the physical penetration enhancer includes, but is not limited to, one or more of natural polymeric viscosity agents, synthetic polymeric viscosity agents, nonionic wetting agents, polyol wetting agents, siloxane wetting agents, natural film-forming agents, synthetic film-forming agents, siloxane film-forming agents, hair follicle targeting aids, charge-type aids, and hydrophilicity / hydrophobicity regulating aids; the natural polymeric viscosity agent includes, but is not limited to, one or more of xanthan gum, guar gum, gum arabic, and sodium alginate; the synthetic polymeric viscosity agent includes, but is not limited to, carbomer. The nonionic wetting agent includes, but is not limited to, polyglycerol fatty acid esters (such as polyglycerol-4 isostearate), Tween 20, Tween 40, Span 80, etc.; the polyol wetting agent includes, but is not limited to, propylene glycol, glycerin, 1,3-butanediol, sorbitol; the siloxane wetting agent includes, but is not limited to, cyclopentamethoxysiloxane (D5), polydimethylsiloxane alcohol (PDMS alcohol), etc.; the natural film-forming agent includes, but is not limited to, chitosan, gelatin, starch derivatives (such as hydroxypropyl starch phosphate), etc.; the synthetic film-forming agent includes, but is not limited to, polyvinylpyrrolidone (PVP), polyacrylate copolymers (such as Acrylates), etc. The film-forming agent is one or more of the following: polymer, polyvinyl acetate (PVA); the siloxane film-forming agent includes, but is not limited to, one or more of the following: polytrimethylsiloxaneoxysilicate, amino-terminated polydimethylsiloxane; the hair follicle targeting aid includes, but is not limited to, one or more of the following: polylactic-co-hydroxyacetic acid copolymer (PLGA) nanoparticles, liposomes, chitosan microspheres; the charge-type aid includes, but is not limited to, one or more of the following: cationic polymers (such as polylysine, quaternized chitosan), anionic surfactants (such as sodium dodecyl sulfate, low concentration); the hydrophilicity / hydrophobicity regulating aid includes, but is not limited to, one or more of the following: caprylic / capric triglyceride (GTCC), squalane, polyethylene glycol stearate.

[0084] In one specific embodiment of the present invention, the aqueous phase matrix is ​​selected from one or more of water, physiological saline, glucose solution and buffer solution; the buffer solution includes, but is not limited to, PBS buffer solution.

[0085] In one specific embodiment of the present invention, the continuous phase further includes a water-soluble polymeric thickener; the mass of the water-soluble polymeric thickener is preferably 0.01% to 5% of the mass of the continuous phase; optionally, the water-soluble polymeric thickener is 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.2%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.8%, 4%, 4.2%, 4.5%, 4.8%, 5% of the mass of the continuous phase, or a range between any two of the above values.

[0086] In one specific embodiment of the present invention, the mass of the water-soluble polymeric thickener is preferably 0.1% to 1% of the mass of the continuous phase, more preferably 0.5%.

[0087] In a specific embodiment of the present invention, the water-soluble polymeric thickener may be any water-soluble polymeric thickener well known to those skilled in the art, and there are no special limitations. It includes, but is not limited to, one or more of polypropylene, polysaccharides and their derivatives, and cellulose derivatives. The polypropylene includes, but is not limited to, carbomer and / or polyvinylpyrrolidone. The polysaccharides and their derivatives include, but are not limited to, one or more of xanthan gum, carrageenan, sodium alginate, etc. The cellulose derivatives include, but are not limited to, one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, and methylcellulose. The carbomer includes, but is not limited to, one or more of carbomer 940, carbomer 980, carbomer 934, carbomer 971P, etc.

[0088] In a specific embodiment of the present invention, the continuous phase preferably further includes a pH adjuster; the mass of the pH adjuster is preferably 0.001% to 0.05% of the mass of the continuous phase; optionally, the mass of the pH adjuster is 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05% of the mass of the continuous phase, or a range between any two of the above values.

[0089] In a specific embodiment of the present invention, the pH adjuster is preferably an alkaline pH adjuster because tadalafil is a weakly basic drug, and using an alkaline pH adjuster can improve its stability in the formulation. The alkaline pH adjuster can be any alkaline pH adjuster well known to those skilled in the art, and there are no special limitations, including but not limited to one or more of organic alcohol amines, weak base salts, and weak base salt buffer pairs. The organic alcohol amine is preferably triethanolamine, which can not only neutralize acidic groups in the system, but also trigger a thickening effect and improve the stability of the formulation. The weak base salt is preferably sodium bicarbonate. The weak base salt buffer pair is preferably disodium hydrogen phosphate / sodium dihydrogen phosphate.

[0090] In a specific embodiment of the present invention, the topical tadalafil formulation preferably further includes pharmaceutically acceptable excipients; the pharmaceutically acceptable excipients include one or more of humectants, preservatives, antioxidants, and pH adjusters; the humectants include, but are not limited to, one or more of sodium hyaluronate, glycerin, allantoin, propylene glycol, polyethylene glycol, and sorbitol; the preservatives include, but are not limited to, one or more of ethylhexylglycerin, phenoxyethanol, and sorbitol; the antioxidants include, but are not limited to, vitamin E and / or sodium bisulfite. The above excipients may be selectively added to the dispersed phase or the continuous phase according to their properties.

[0091] In the topical tadalafil formulation provided by this invention, the dispersed phase is an oil phase and the continuous phase is an aqueous phase, with the dispersed phase dispersed in the continuous phase to form microparticles. In a specific embodiment provided by this invention, the average particle size of the topical tadalafil formulation is preferably 10 nm to 10 μm. Optionally, the average particle size of the topical tadalafil formulation is 10 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, or a range between any two of the above values.

[0092] In one specific embodiment of the present invention, the average particle size of the topical tadalafil preparation is preferably 50 nm to 500 nm.

[0093] In one specific embodiment of the present invention, the PDI of the topical tadalafil preparation is preferably 0.1 to 0.4; optionally, the PDI of the topical tadalafil preparation is 0.1, 0.2, 0.3, 0.4 or any two of the above values.

[0094] In one specific embodiment of the present invention, the topical tadalafil preparation is preferably a topical tadalafil nanopreparation.

[0095] In one specific embodiment of the present invention, the dosage form of the topical tadalafil preparation can be a paste, gel, emulsion or spray, requiring only the addition of a corresponding molding agent.

[0096] In one specific embodiment of the present invention, the topical tadalafil preparation is a gel or emulsion preparation.

[0097] The present invention also provides a method for preparing the above-mentioned topical tadalafil formulation, comprising the following steps: S1) providing a dispersed phase containing tadalafil and a nonionic solubilizing emulsifier; providing a continuous phase containing an aqueous matrix; S2) mixing the dispersed phase and the continuous phase to obtain the topical tadalafil formulation.

[0098] In this invention, there are no special restrictions on the source of any raw materials; commercially available materials are acceptable. The types and amounts of the nonionic solubilizing emulsifier and the aqueous matrix are the same as described above and will not be repeated here.

[0099] In one specific embodiment of the present invention, the dispersed phase further includes an oil phase matrix; the type and amount of the oil phase matrix are the same as described above, and will not be repeated here.

[0100] In one specific embodiment of the present invention, the dispersed phase further includes a co-emulsifier; the type and amount of the co-emulsifier are the same as described above, and will not be repeated here.

[0101] In one specific embodiment of the present invention, the dispersed phase further includes a penetration enhancer; the type and amount of the penetration enhancer are the same as described above, and will not be repeated here.

[0102] In one specific embodiment of the present invention, the continuous phase further includes a water-soluble polymeric thickener; the type and amount of the water-soluble thickener are the same as described above, and will not be repeated here.

[0103] The dispersed phase is mixed with the continuous phase; the volume of the dispersed phase is 20% to 80% of the total volume of the dispersed and continuous phases; optionally, the volume of the dispersed phase is 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% of the total volume of the dispersed and continuous phases, or a range between any two of the above values; the mixing method can be any method well known to those skilled in the art, and there are no special limitations, including but not limited to one or more of ultrasonication, vortexing, stirring, high-speed dispersion, high-pressure homogenization, vacuum homogenization, and static mixer. Specifically, the mixing method and condition parameters can be selected based on the prepared volume.

[0104] In a specific embodiment of the present invention, the mixing method is ultrasound; the power of the ultrasound is preferably 10-800 W; optionally, the power of the ultrasound is 10 W, 50 W, 100 W, 150 W, 200 W, 250 W, 300 W, 400 W, 500 W, 600 W, 700 W, 800 W, or any range between two of the above values; the ultrasound can be continuous ultrasound or intermittent ultrasound; specifically, the present invention uses intermittent ultrasound; the duty cycle of the intermittent ultrasound, i.e., the percentage of working time in each cycle, is preferably 50%-90%; optionally, the duty cycle of the intermittent ultrasound is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or any range between two of the above values; the duration of the ultrasound is preferably 5-30 min; optionally, the duration of the ultrasound is 5 min, 8 min, 10 min, 12 min, 15 min, 18 min, 20 min, 22 min, 25 min, 28 min, 30 min, or any range between two of the above values. min or any two of the above values. Ultrasound can separate the water and oil phases into tiny droplets.

[0105] In one specific embodiment of the present invention, the duration of each interval ultrasound operation is 1 to 5 minutes; optionally, the duration of each interval ultrasound operation is 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes or any two of the above values; the interval between two interval ultrasound operations is preferably 20 seconds to 2 minutes; optionally, the interval between two interval ultrasound operations is 20 seconds, 30 seconds, 40 seconds, 50 seconds, 60 seconds, 90 seconds, 2 minutes or any two of the above values.

[0106] In a specific embodiment of the present invention, the mixing method is a vortex; the rotational speed of the vortex is preferably 300~3500 rpm; optionally, the rotational speed of the vortex is 300 rpm, 500 rpm, 800 rpm, 1000 rpm, 1300 rpm, 1500 rpm, 1800 rpm, 2000 rpm, 2300 rpm, 2500 rpm, 2800 rpm, 3000 rpm, 3200 rpm, 3500 rpm or any two of the above values; the vortexing time is preferably 5~60 min; optionally, the vortexing time is 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min or any two of the above values.

[0107] In a specific embodiment of the present invention, the mixing method is stirring; the stirring can be one or more of manual stirring, magnetic stirring, and mechanical stirring; the stirring speed is preferably 100~3500 rpm; optionally, the stirring speed is 100 rpm, 300 rpm, 500 rpm, 800 rpm, 1000 rpm, 1300 rpm, 1500 rpm, 1800 rpm, 2000 rpm, 2300 rpm, 2500 rpm, 2800 rpm, 3000 rpm, 3200 rpm, 3500 rpm, or any two of the above values; the stirring time is preferably 5~60 min; optionally, the stirring time is 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, or any two of the above values.

[0108] In a specific embodiment of the present invention, the mixing method is preferably high-speed dispersion; the rotation speed of the high-speed dispersion is preferably 1000~8000 rpm; optionally, the rotation speed of the high-speed dispersion is 1000 rpm, 1500 rpm, 2000 rpm, 2500 rpm, 3000 rpm, 3500 rpm, 4000 rpm, 4500 rpm, 5000 rpm, 5500 rpm, 6000 rpm, 6500 rpm, 7000 rpm, 7500 rpm, 8000 rpm or any two of the above values; the high-speed dispersion time is preferably 5~60 min; optionally, the high-speed dispersion time is 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min or any two of the above values.

[0109] In a specific embodiment of the present invention, the mixing method is preferably high-pressure homogenization; the pressure of the high-pressure homogenization is preferably 50~150 MPa; optionally, the pressure of the high-pressure homogenization is 50 MPa, 60 MPa, 70 MPa, 80 MPa, 90 MPa, 100 MPa, 110 MPa, 120 MPa, 130 MPa, 140 MPa, 150 MPa or any two of the above values; the high-pressure homogenization can be a single-stage homogenization or a two-stage homogenization, without any special limitations.

[0110] In a specific embodiment of the present invention, the mixing method is preferably vacuum homogenization; vacuum homogenization has three main functions: stirring, homogenization, and vacuuming; the rotation speed of the vacuum homogenization is preferably 10,000~28,000 rpm; optionally, the rotation speed of the vacuum homogenization is 10,000 rpm, 11,000 rpm, 12,000 rpm, 13,000 rpm, 14,000 rpm, 15,000 rpm, 16,000 rpm, 17,000 rpm, 18,000 rpm, 19,000 rpm, 20,000 rpm, 21,000 rpm, 22,000 rpm, 23,000 rpm, 24,000 rpm, 25,000 rpm, 26,000 rpm, 27,000 rpm, 28,000 rpm, or any two of the above values.

[0111] In one specific embodiment of the present invention, the mixing is carried out using a static mixer; the dispersed phase and the continuous phase are repeatedly divided, recombined and sheared in the pipeline through a specially structured mixing unit (such as a spiral blade or a porous baffle), thereby achieving the purpose of mixing.

[0112] After mixing, centrifugation is preferably performed to obtain a topical tadalafil formulation. Centrifugation can remove unemulsified large particles, impurities, or excess carriers, improving the uniformity and stability of the formulation. The centrifugal force is preferably 500-2000 g; optionally, the centrifugal force is 500 g, 800 g, 1000 g, 1200 g, 1500 g, 1800 g, 2000 g, or any two of the above values. The centrifugation time is preferably 1-10 min; optionally, the centrifugation time is 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, or any two of the above values.

[0113] The present invention also provides the application of the above-mentioned topical tadalafil preparation in the preparation of products for treating erectile dysfunction.

[0114] In one specific embodiment of the present invention, the product includes a drug, a contraceptive product, or a lubricating composition.

[0115] The present invention also provides a product comprising the above-mentioned topical tadalafil preparation.

[0116] In one specific embodiment of the present invention, the product includes a drug, a contraceptive product, or a lubricating composition.

[0117] To further illustrate the present invention, the following detailed description, in conjunction with embodiments, provides a topical tadalafil nanoformulation, its preparation method, and its application.

[0118] All reagents used in the following examples are commercially available.

[0119] Example 1: Preparation of topical tadalafil nanoformulation

[0120] 1.1 Investigating the solubility of different tadalafil formulations in different solvent compositions

[0121] Tadalafil was detected by high-performance liquid chromatography (HPLC). The HPLC conditions were as follows: Agilent Zorbax SB-C18 column; mobile phase: acetonitrile:water (containing 0.1% trifluoroacetic acid) = 35:65; column temperature: 35℃; detection wavelength: 285 nm; flow rate: 1 mL / min. The HPLC chromatogram of tadalafil was obtained as shown below. Figure 1 As shown, by Figure 1 It can be seen that the peak corresponding to 10.19 min is the elution position of tadalafil.

[0122] 1) Tadalafil was dissolved using different neutral lipids. 2 mg of tadalafil was added to each according to the amounts shown in Table 1 for dissolution. The results are as follows: Figure 2 As shown, Figure 2 This is a graph showing the solubility of tadalafil in different oils. Figure 2 Image A shows the centrifugation results of tadalafil (numbers 1, 2, 3, 4, 5) mixed with 2 mg of tadalafil in Table 1. Image B shows the solubility of tadalafil in different formulations, with numbers 1, 2, 3, 4, 5 corresponding to the numbers in Table 1. The solubility of tadalafil in soybean oil is 90 μg / mL, in fish oil is 140 μg / mL, in coconut oil is 160 μg / mL, and in castor oil is 520 μg / mL, all significantly higher than its solubility in water (0.73 μg / mL).

[0123] Table 1. Tadalafil dissolution formulation 1

[0124]

[0125] 2) Tadalafil was dissolved in an oil phase based on medium-chain triglycerides (MCTs). 2 mg of tadalafil was added according to the amounts specified in Table 2 for dissolution. The medium-chain triglycerides in Table 2 were caprylic / capric triglycerides (CAS No.: 73398-61-5), Aladdin-M1456050. The results are as follows... Figure 3 As shown, Figure 3 This is a graph showing the solubility of tadalafil in medium-chain triglycerides. Figure 3 Image A shows the results of dissolving and mixing 2 mg of tadalafil with formulations 6, 7, 8, 9, 10, and 11 from Table 2. Image B is a bar chart showing the solubility of tadalafil in different formulations, with formulations 6, 7, 8, 9, 10, and 11 corresponding to their numbers in Table 2. Figure 3 It is known that the solubility of tadalafil in medium-chain triglycerides is 110 μg / mL. With the addition of cinnamon oil, the solubility of tadalafil is partially increased, reaching a maximum of 260 μg / mL.

[0126] Table 2. Tadalafil dissolution formulation 2

[0127]

[0128] 3) Tadalafil was dissolved in an oil phase based on Kolliphor EL polyoxyethylene (35) castor oil (CAS: 61791-12-6). 6 mg of tadalafil was added according to the amounts in Table 3 for dissolution, and the results are as follows: Figure 4 As shown, Figure 4 The figure shows the dissolution results of tadalafil in polyoxyethylene (35) castor oil. Figure 4 Image A shows the results of centrifugation after mixing 6 mg of tadalafil with formulations 12, 13, 14, 15, and 16 from Table 3. Image B is a bar chart showing the solubility of tadalafil in different formulations, with formulations 12, 13, 14, 15, and 16 corresponding to their numbers in Table 3. Figure 4 It is known that the solubility of tadalafil in polyoxyethylene (35) castor oil is 5.8 mg / mL, and the concentration of tadalafil gradually decreases with the addition of medium-chain triglycerides.

[0129] Table 3. Tadalafil dissolution formulation 3

[0130]

[0131] 1.2 Preparation of Tadalafil Nanoformulation

[0132] Based on the solubility results in section 1.1 and the viscosity of the formulation, conditions 12 and 14 were selected for the preparation of tadalafil nanoformulation.

[0133] The No. 12 sample (a mixture of 6 mg tadalafil and 500 mg polyoxyethylene castor oil) prepared according to method 1.1 was used as the dispersed phase (oil phase). 100 mg of the oil phase was taken and mixed with different aqueous phases: 12-A aqueous phase was 100 mg of 0.1% carbomer 940 aqueous solution (containing 0.03% triethanolamine); 12-B aqueous phase was 500 mg of 0.5% carbomer 940 aqueous solution (containing 0.03% triethanolamine); 12-C aqueous phase was 300 mg of 1% carbomer 940 aqueous solution (containing 0.03% triethanolamine); and 12-D aqueous phase was 100 mg of 2% carbomer 940 aqueous solution (containing 0.03% triethanolamine). Preparation was carried out by ultrasonication, three times, 3 minutes each time, with a 30-minute interval. The product obtained by ultrasound was obtained by using an ultrasonic instrument (model: SBL-10DT, power: 216W, water temperature: 25℃). The product was centrifuged at 1,000g for 5 min. After centrifugation, the middle component was collected, which was the final product, a topical tadalafil nano-formulation prepared under 12 different aqueous phase conditions.

[0134] The topical tadalafil nanoparticles prepared under 12 different aqueous phase conditions were placed, and their average particle size, uniformity, and degradation rate were then measured. The results are as follows. Figure 5 As shown, Figure 5Figure A shows the aqueous phase conditions; Figure B shows the average particle size of the topical tadalafil nanoparticle formulation after different storage times; Figure C shows the polydispersity index (PDI) of the topical tadalafil nanoparticle formulation after different storage times; and Figure D shows the degradation rate of the topical tadalafil nanoparticle formulation after different storage times. Specifically, the average particle size and PDI were measured using a dynamic light scattering instrument (model: BeNano 90 Zeta nanoparticle size analyzer). PDI, or Polydispersity Index, is an indicator used to measure the uniformity of nanoparticles; a smaller PDI indicates a more uniform particle size distribution. A PDI less than 0.4 is generally considered to indicate good uniformity, while a PDI greater than 0.4 indicates relatively poor uniformity. The degradation rate refers to the change in the concentration of tadalafil in the formulation after different storage days relative to the initial preparation concentration. Degradation rate = (1 - Tadalafil concentration after different storage days / Tadalafil concentration at initial preparation) x 100%.

[0135] Depend on Figure 5 It was found that the average particle size and PDI of the topical tadalafil nanoformulation prepared under oil phase condition 12 fluctuated significantly over time, with the particle size ranging from 2 μm to 8 μm and the PDI ranging from 0.2 to 2.0. The concentration of tadalafil decreased over time. Formulations 12-A and 12-D showed higher degradation rates of tadalafil, at 35% and 50%, respectively, while formulations 12-B and 12-C showed lower degradation rates, at 12% and 10%, respectively.

[0136] The 14-phase (tadalafil 6 mg + polyoxyethylene castor oil 500 mg + medium-chain triglycerides 200 mg + anhydrous ethanol 200 mg) prepared by method 1.1 was used as the dispersed phase (oil phase). 100 mg of the oil phase was taken and mixed with different aqueous phases: 14-A aqueous phase was 100 mg of 0.1% carbomer 940 aqueous solution (containing 0.03% triethanolamine); 14-B aqueous phase was 500 mg of 0.5% carbomer 940 aqueous solution (containing 0.03% triethanolamine); 14-C aqueous phase was 300 mg of 1% carbomer 940 aqueous solution (containing 0.03% triethanolamine); and 14-D aqueous phase was 100 mg of 2% carbomer 940 aqueous solution (containing 0.03% triethanolamine). Preparation was carried out by ultrasonication, three times for 3 minutes each time, with a 30-minute interval between each time. The ultrasonic product was obtained using an ultrasonic instrument (model: SBL-10DT, power: 216W, water temperature: 25℃). This product was centrifuged at 1000g for 5 min. After centrifugation, the middle fraction was collected, which was the final product, consisting of 14 topical tadalafil nano-formulations prepared under different aqueous phase conditions. The 14 topical tadalafil nano-formulations prepared under different aqueous phase conditions were then tested for their average particle size, uniformity, and degradation rate. The results are as follows: Figure 6 As shown, Figure 6 Figure A shows the aqueous phase conditions; Figure B shows the average particle size of the topical tadalafil nanoparticle formulation after different storage times; Figure C shows the polydispersity index (PDI) of the topical tadalafil nanoparticle formulation after different storage times; and Figure D shows the degradation rate of the topical tadalafil nanoparticle formulation after different storage times. Figure 6 It was found that, under oil-phase conditions (No. 14), the average particle size and PDI of the topical tadalafil nanoformulation remained stable over time, with particle size ranging from 60 nm to 150 nm and PDI ranging from 0.1 to 0.4. The concentration of tadalafil remained stable over time. The degradation rate of 14-D was 20%, while the degradation rates of tadalafil in formulations 14-A and 14-C were 4% and 5%, respectively, while 14-B showed almost no degradation.

[0137] 1.3 Topical tadalafil nanoformulations are stable over a long period.

[0138] The topical tadalafil nanoparticles prepared under condition 14-B in section 1.2 were stored at room temperature in the dark for an extended period, and their concentration and particle size changes were measured. The results are as follows: Figure 7 As shown, A is a photograph of tadalafil nanoparticles stored at room temperature and protected from light for a long period of time; B is the concentration of tadalafil nanoparticles after different storage days; and C is the average particle size of the tadalafil nanoparticles after different storage days. Figure 7 It can be seen that the concentration of tadalafil in the formulation is stable over a long period of time, and the average particle size of the formulation is stable.

[0139] Example 2: Topical application of tadalafil nanoformulation for highly efficient local amplification of rabbit penis

[0140] Rabbits were administered clinical oral tadalafil via gavage (0.14 mg / kg body weight). Topical tadalafil prepared under 14-B conditions was applied topically to the rabbit penis (400 μL applied topically, equivalent to 0.07 mg / kg body weight). A blank control group was prepared using a 0.5% carbomer 940 aqueous solution (containing 0.03% triethanolamine). The amplification effect of the central artery in the rabbit penis and ear was observed. The detection methods were as follows: Experimental animals underwent multiple acclimatization training sessions before the experiment to reduce stress during the experiment. The oral medication was crushed and administered to rabbits via gavage, while the topical preparation was applied directly to the rabbit penis. Before administration, the fur on the left ear of the animal was shaved to reduce external stimulation. After the animal adapted, the outer diameter of the central artery on the left ear and the upper, middle, and lower parts of the penis were measured using calipers (the locations of the detection points were marked). The penile diameter and the three points marked on the central auricular artery were measured using vernier calipers before administration of the drug and after oral gavage or application of the topical preparation to the penis at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 8 h. After the animals had adapted, the outer diameter of the penile diameter was measured using vernier calipers at the three points marked on the left side of the rabbit's ear or on the penis. The results are shown in the figure below. Figure 8 As shown, Figure 8 Table A shows the changes in the proportion of penile amplification in rabbits at different time points after different drug treatments; Table B shows the erectile effect of rabbits' penises 30 minutes after different drug treatments; Table C shows the changes in the proportion of amplification in the central auricular artery of rabbits at different time points after different drug treatments. Figure 8 It was found that the solvent group, serving as a blank control, had no effect on penile amplification. Both the oral medication and the topical preparation significantly amplified the rabbit penis, with the topical preparation showing superior efficacy compared to the oral medication, and the dosage of the topical preparation was half that of the oral medication. Furthermore, the oral medication significantly amplified the central auricular artery, while the topical preparation, like the solvent blank group, had no amplification effect on the central auricular artery. Because the oral medication, after absorption through the gastrointestinal tract, reaches other organs and tissues via blood circulation, leading to unnecessary amplification and resulting in higher dosages and side effects, the topical preparation, after local application, provides highly efficient penile amplification without causing amplification in other organs and tissues. Its efficacy is superior to clinical oral medication, and the dosage is reduced, indicating that topical tadalafil preparations have significant clinical advantages and a wide range of applications.

[0141] Example 3: Topical tadalafil nanoformulation reduces erectile latency in castrated ED rats

[0142] This study evaluated the efficacy of topical tadalafil nanoparticles in treating erectile dysfunction (ED) using a castrated rat model. The castrated ED rat model was established as follows: Quarantined rats were pre-emptively fasted for approximately 12 hours (water allowed), subcutaneously injected with 1 mg / kg meloxicam for analgesia, and intramuscularly injected with a mixture of melatonin II and acetaminophen (1:10 volume ratio). The rats were restrained in a prone position on a warming pad. The scrotal skin was incised, and the left and right testes and epididymis were separated in the model group. The spermatic cord was ligated at the head of the epididymis, the testes were removed, and the wounds were sutured layer by layer. The wounds were disinfected with iodine, and penicillin was administered intramuscularly for 3 consecutive days at a dose of 80,000 units per rat. The rats underwent a one-week recovery period. After one week of recovery, an erectile function test was performed. A successful model was defined as an erection frequency ≤ 50% of the normal control group's mean. In the sham-operated group, only the left and right testes and epididymis were separated; ligation and removal were not performed. Mice in the surgical group with successfully induced erectile dysfunction (ED) were treated with pure water, administered oral medication by gavage (2 mg / kg body weight), and treated with topical application of a 14-B-prepared formulation to the penis (100 μL applied topically, equivalent to 0.24 mg / kg body weight). The erectile latency of the rats was measured as follows: 20 min after administration, the rats were placed in individual cages for 10 min to acclimatize. Subsequently, an apomorphine (APO) solution prepared with 0.2 g / L vitamin C in physiological saline was subcutaneously injected into the neck and back. Videos were recorded within 30 min after injection. Erection was defined as penile engorgement and the appearance of the distal penile shaft. The time to the first erection was recorded, and the erectile latency was calculated as: first erection time - APO injection time. The results of the topical tadalafil nano-formulation effectively promoting erection in castrated ED rats are shown in the figure below. Figure 9 As shown, Figure 9 Image A shows the erection latency in castrated ED rats after different drug treatments. Erectile latency = time to first erection - APO injection time; Image B shows the penile erection effect in castrated ED rats after different drug treatments. Figure 9 The results showed that the pure water treatment group had the longest erection latency, while oral medication and topical preparations significantly shortened the erection latency in castrated ED rats. With the same effect as oral medication, the dosage of topical preparation was reduced by 8 times. These results indicate that topical tadalafil nanoparticles can promote erection in castrated ED rats, reduce the erection latency, and require a dosage 8 times lower than that of clinical oral medication.

[0143] Example 4: Topical tadalafil nano-formulation effectively promotes penile erection in monkeys

[0144] The effect of topical tadalafil nanoformulation on penile length enhancement was evaluated using rhesus macaques. The topical tadalafil nanoformulation prepared under 14-B conditions was topically applied to the penises of rhesus macaques, and changes in penile length were measured. The results are shown in the figure below. Figure 10 As shown, Figure 10Image A shows the curve of penile length increase in monkeys after treatment with topical tadalafil nanoparticles; image B shows the erectile effect of the monkeys after treatment with topical tadalafil nanoparticles. Figure 10 It was observed that penile enlargement occurred 5 minutes after application, reaching its maximum effect after 30 minutes, and then returning to the initial level after 180 minutes. These results indicate that topical tadalafil nanoparticle formulations promote penile erection in monkeys.

[0145] Example 5

[0146] 5.1 Based on previous experiments, the preparation conditions of the topical tadalafil nano-formulation were further optimized to simplify the preparation method and increase the tadalafil concentration. First, the dispersed phase (oil phase) was prepared according to the following mass ratio: polyoxyethylene castor oil 30%–80%, medium-chain triglycerides 10%–70%, anhydrous ethanol 5%–50%, menthol 0.1%–2%, and tadalafil 0.1%–2%. The continuous phase (aqueous phase) solution included, but was not limited to, water, PBS, physiological saline, glucose solution, or other buffer solutions. After the oil phase was prepared, it was mixed with the aqueous phase solution at a mass ratio of 20%–80% by stirring, vortexing, or sonication.

[0147] The oil phase formulation in this embodiment is as follows: 13 g of polyoxyethylene castor oil, 9 g of medium-chain triglycerides, 4 g of anhydrous ethanol, 0.2 g of menthol, and 0.15 g of tadalafil. The prepared oil phase is mixed with 30 g of water and stirred thoroughly using a high-speed shear mixer (model: HR-25D) to obtain a topical tadalafil nano-formulation.

[0148] The topical tadalafil nanoformulation was tested, and the characteristic image of the topical tadalafil nanoformulation was obtained as follows. Figure 11 As shown. Figure 11 In the figure, A represents the concentration of tadalafil in the topical tadalafil nano-formulation prepared under these conditions after being stored for different times. Figure 11 B represents the average particle size of the topical tadalafil nanoformulation prepared under these conditions after being stored for different times. Figure 11 C represents the PDI (post-exposure dispersibility) of the topical tadalafil nanoformulation prepared under these conditions after being stored for different times. Figure 11 It is known that the concentration of tadalafil nanoformulation is 1.7 mg / mL, the average particle size is about 200 nm, the PDI is less than 0.3, and the concentration and particle size remain stable over time.

[0149] 5.2 Topical tadalafil nano-formulation effectively increases the number of erections in castrated ED rabbits

[0150] The effect of the topical tadalafil preparation prepared in Example 5 on increasing the number of erections in castrated ED rabbits was evaluated. New Zealand rabbits that passed quarantine were selected and fasted for approximately 12 hours (water allowed). They were anesthetized with a subcutaneous injection of meloxicam (1 mg / kg) and an intramuscular injection of 0.2-0.3 ml / kg of a mixture of meloxicam and acetaminophen (volume ratio 1:2). The rabbits were restrained in a supine position, and the scrotum was prepared by incising the skin. The left and right testes and epididymis were separated in the model group animals. The spermatic cord was ligated at the head of the epididymis, the testes were removed, and the wounds were sutured layer by layer and disinfected with iodine. The animals were allowed one week of postoperative recovery. One week after recovery, an erectile function test was performed. A successful model was defined as an erection count ≤ 50% of the normal control group's mean. Mice in the surgical group whose model was successfully established were treated with pure water (model control group), administered commercially available oral tadalafil tablets by gavage (oral drug group, administered orally according to body weight, dosage 0.4 mg / kg body weight), and had tadalafil preparation applied topically to the penis (topical preparation group, 100 μL applied topically, equivalent to 0.05 mg / kg body weight). Immediately after treatment, a subcutaneous injection of 50 µg / kg of APO (apomorphine) solution prepared with 0.2 g / L vitamin C in physiological saline was administered into the back of the neck, with an injection volume of 1 ml / kg. Erection was observed within 30 minutes after injection, with penile engorgement and the appearance of the penile shaft constituting one erection. The number of erections was recorded, and the results of increasing the number of erections in castrated ED rabbits using topical tadalafil nanoparticle preparation were obtained. Figure 12 As shown, A represents the number of erections in castrated ED rabbits within 30 minutes under different conditions; B represents photographs of penile erections in castrated ED rabbits after treatment under different conditions. Figure 12 The results showed that, compared with the model control group, the topical preparation group significantly increased the number of erections in castrated ED rabbits. With the same effect as oral medication, the dosage of the topical preparation was reduced by 8 times.

[0151] 5.3 Topical application of tadalafil nanoparticles significantly reduced erectile latency in castrated ED rabbits.

[0152] The effect of the topical tadalafil formulation prepared in Example 5 on reducing the erectile latency in castrated ED rabbits was evaluated. Mice in the successfully modeled surgical group were treated with pure water (model control group), administered commercially available oral tadalafil tablets by gavage (oral medication group, dosage 0.4 mg / kg body weight), and had topical tadalafil formulation applied topically to the penis (topical formulation group, 100 μL applied topically, equivalent to 0.05 mg / kg body weight). Immediately after treatment, a subcutaneous injection of 50 µg / kg of APO solution prepared with 0.2 g / L vitamin C in physiological saline was administered into the back of the neck, at a volume of 1 ml / kg. The erectile latency was recorded after administration, defined as penile engorgement and the appearance of the distal penile shaft. Erectile latency = time to first erection - APO injection time. The results of the topical tadalafil nano-formulation reducing the erectile latency in castrated ED rabbits are shown in the figure below. Figure 13 As shown. Figure 13 The results showed that, compared with the model control group, the topical preparation group significantly reduced the erection latency in castrated ED rabbits, while the oral medication group showed no significant difference from the model control group. Furthermore, the dosage of the topical preparation was reduced by 8 times. This indicates that the topical preparation has advantages over the oral medication in terms of dosage and rapid erection promotion.

[0153] 5.4 Topical application of tadalafil nanoformulation significantly increased the number of matings in castrated ED rabbits.

[0154] The effect of the topical tadalafil formulation prepared in Example 5 on increasing the mating frequency of castrated ED rabbits was evaluated. Mice in the successfully modeled surgical group were treated with pure water (model control group), administered commercially available oral tadalafil tablets by gavage (oral medication group, dosage 0.4 mg / kg body weight), and had topical tadalafil formulation applied topically to the penis (topical formulation group, 100 μL applied topically, equivalent to 0.05 mg / kg body weight). Immediately after treatment, male New Zealand rabbits were placed in the mating area, followed by one female New Zealand rabbit in each mating area. The number of matings in the male rabbits within 30 minutes of the female rabbit's introduction was observed. Mating frequency: Male rabbits exhibited piston-like movements during intercourse, which were very brief. Those not ejaculating showed only brief licking of the penis and continued to chase and mate with the female rabbits. The results of the topical tadalafil nano-formulation increasing the mating frequency of castrated ED rabbits were obtained as shown in the figure. Figure 14 As shown. Figure 14 The results showed that, compared with the model control group, the topical preparation group significantly increased the number of matings in castrated ED rabbits. With the same effect as the oral medication, the dosage of the topical preparation was reduced by 8 times.

[0155] 5.5 Topical application of tadalafil nanoformulation significantly increased ICP / MCP in castrated ED rabbits.

[0156] The effect of the topical tadalafil preparation prepared in Example 5 on increasing the ICP (intraperitoneal pressure) / MCP (mean arterial pressure) ratio in castrated ED rabbits was evaluated. Mice in the successfully modeled surgical group were treated with pure water (model control group), administered commercially available oral tadalafil tablets by gavage (oral drug group, dosage 0.4 mg / kg body weight), and had topical tadalafil preparation applied topically to the penis (topical preparation group, 200 μL applied topically, equivalent to 0.1 mg / kg body weight). After 30 min of treatment, the animals were anesthetized by intramuscular injection of 0.2–0.3 ml / kg of a mixture of sedative-Ibuprofen II and styrax 50 (volume ratio 1:2). The abdomen was opened, exposing the bladder, prostate, ureter, and pelvic ganglion. The cavernous nerves of the penis were isolated and connected to stimulation electrodes; the base of the penis was exposed and connected to a pressure sensor; the neck vessels were exposed, and a carotid artery cannula was inserted and connected to a pressure sensor. Electrical stimulation was applied, and the intracavernosal pressure and mean arterial pressure were measured, and their ratio was calculated. The electrical stimulation parameters were: voltage 5V, pulse width 5ms, duration 50s, pulse rate 15 times / s. The results of increasing ICP / MCP in castrated ED rabbits using topical tadalafil nanoparticle formulation were obtained, as shown in the graph. Figure 15 As shown. Figure 15 The results showed that, compared with the model control group, the topical preparation group significantly increased the ICP / MCP of castrated ED rabbits. With the same effect as the oral drug, the dosage of the topical preparation was reduced by 4 times.

[0157] 5.6 Topical tadalafil nano-formulation has no skin irritation.

[0158] The skin irritation of the topical tadalafil formulation prepared in Example 5 was evaluated. The back hair of a New Zealand rabbit was shaved, and two skin patches (approximately 2 × 2 cm) were selected for testing. Using the same rabbit, one area was treated with water, and the other with the topical formulation. Each area received 400 μL of the formulation. The patches were then covered with a semi-occlusive dressing and secured with non-irritating adhesive tape to prevent licking or wiping off the test substance. The treatment duration was 4 hours. After the treatment period, the dressing was removed, and any remaining test substance was gently removed with warm water or a suitable solvent. Skin reactions were observed 1 h, 24 h, 48 h, and 72 h after removal of the test substance. The degree of erythema and edema was scored, and photographs were taken at the corresponding time points. The skin irritation results of the topical tadalafil nanoformulation are shown in the figure below. Figure 16 As shown. Specific scoring details are shown in Table 4. The average of four scores is used for determination: No irritation: average score <0.5; Mild irritation: average score ≥0.5 and <2.0; Moderate irritation: average score ≥2.0 and <5.0; Severe irritation: average score ≥5.0. Figure 16 The results showed that, similar to the blank control group, the skin irritation score of the topical preparation group was 0, indicating that the topical preparation had no skin irritation.

[0159] Table 4 Skin Reaction Scoring Details

[0160]

[0161] In summary, the topical tadalafil formulation provided by this invention has significant advantages in addressing the side effects of existing oral medications, increasing drug efficacy, and improving ease of use. It also effectively meets the needs of ED patients in China and around the world, and has broad market prospects.

[0162] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A topical tadalafil formulation, characterized in that, It includes a dispersed phase and a continuous phase; the dispersed phase includes tadalafil and a nonionic solubilizing emulsifier; The continuous phase includes an aqueous matrix.

2. The topical tadalafil preparation according to claim 1, characterized in that, The tadalafil in the dispersed phase is 0.01% to 5% of the mass of a nonionic solubilizing emulsifier.

3. The topical tadalafil preparation according to claim 1, characterized in that, The nonionic solubilizing emulsifier is selected from polyoxyethylene solubilizing emulsifiers and / or polyoxyethylene hydrogenated castor oil; The polyoxyethylene solubilizing emulsifier is selected from one or more of polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene copolymer, and poloxamer.

4. The topical tadalafil preparation according to claim 1, characterized in that, The dispersed phase further includes an oil phase matrix; the oil phase matrix is ​​selected from glycerides.

5. The topical tadalafil formulation according to claim 4, characterized in that, The glycerides are selected from one or more of medium-chain triglycerides, long-chain triglycerides, natural glycerides, glyceryl stearate, and polyglycerol fatty acid esters.

6. The topical tadalafil nanoformulation according to claim 4, characterized in that, The mass of the nonionic solubilizing emulsifier is 10% to 80% of the mass of the dispersed phase; The mass of tadalafil is 0.1% to 2% of the mass of the dispersed phase; The mass of the glyceride is 10% to 70% of the mass of the dispersed phase.

7. The topical tadalafil formulation according to claim 4, characterized in that, The dispersed phase further includes a co-emulsifier; the mass of the co-emulsifier is 5% to 50% of the mass of the dispersed phase.

8. The topical tadalafil formulation according to claim 7, characterized in that, The co-emulsifier is selected from one or more of alcohol co-emulsifiers, polyol co-emulsifiers, phospholipid co-emulsifiers, and surfactant co-emulsifiers; The alcohol-based co-emulsifier is selected from one or more of ethanol, propanol, n-butanol and cetyl alcohol; The polyol co-emulsifier is selected from one or more of glycerin, propylene glycol, polyethylene glycol and sorbitol; The phospholipid co-emulsifier is selected from one or more of lecithin, soybean lecithin, and hydrogenated phospholipids; The surfactant-type co-emulsifier is selected from one or more of high HLB Span co-emulsifiers, polyglycerol fatty acid esters, and sucrose fatty acid esters; the high HLB Span co-emulsifier has an HBL value greater than or equal to 5.

9. The topical tadalafil formulation according to claim 1, characterized in that, The dispersed phase further includes a penetration enhancer; the mass of the penetration enhancer is 0.1% to 5% of the mass of the dispersant.

10. The topical tadalafil formulation according to claim 9, characterized in that, The penetration enhancer is selected from one or more of the following: lipid disruptors, solvent-based penetration enhancers, surfactant-based penetration enhancers, hydration enhancers, biotransformation-based penetration enhancers, and physical penetration enhancers. The lipid-disrupting agent is selected from one or more of laurocapram, menthol, carvone, and limonene; The solvent-based penetration enhancer is selected from one or more of propylene glycol, glycerol, dimethyl sulfoxide, and ethanol; The surface-active penetration enhancer is selected from one or more of Tween, Span and sodium lauryl sulfate; The hydration enhancer is selected from hyaluronic acid and / or polyethylene glycol; The biotransformation-type penetration enhancer is selected from one or more of ethyl oleate, trioleic acid glyceride, monolaurate glyceride and dicetyl phosphate. The physical penetration enhancer is selected from one or more of the following: natural polymer viscosity agents, synthetic polymer viscosity agents, nonionic wetting agents, polyol wetting agents, siloxane wetting agents, natural film-forming agents, synthetic film-forming agents, siloxane film-forming agents, hair follicle targeting aids, charge-type aids, and hydrophilicity / hydrophobicity regulating aids.

11. The topical tadalafil formulation according to any one of claims 1 to 10, characterized in that, The aqueous matrix is ​​selected from one or more of water, physiological saline, glucose solution and buffer solution.

12. The topical tadalafil formulation according to any one of claims 1 to 10, characterized in that, The continuous phase further includes a water-soluble polymeric thickener; the mass of the water-soluble polymeric thickener is 0.01% to 5% of the mass of the continuous phase. And / or, the continuous phase further includes a pH adjuster; the mass of the pH adjuster is 0.001% to 0.05% of the mass of the continuous phase.

13. The topical tadalafil formulation according to claim 12, characterized in that, The water-soluble polymeric thickener is selected from one or more of polypropylene, polysaccharides and their derivatives, and cellulose derivatives; The pH adjuster is selected from alkaline pH adjusters.

14. The topical tadalafil formulation according to claim 1, characterized in that, The average particle size of the topical tadalafil formulation is 10 nm to 10 μm.

15. The topical tadalafil formulation according to claim 14, characterized in that, The average particle size of the topical tadalafil formulation is 50 nm to 500 nm; the PDI of the topical tadalafil formulation is 0.1 to 0.

4.

16. The topical tadalafil formulation according to claim 1, characterized in that, It also includes pharmaceutically acceptable excipients; said pharmaceutically acceptable excipients include one or more of humectants, preservatives and antioxidants.

17. A method for preparing the topical tadalafil formulation according to claim 1, characterized in that, Includes the following steps: S1) Provides a dispersion phase containing tadalafil and a nonionic solubilizing emulsifier; Provides a continuous phase containing an aqueous matrix; S2) The dispersed phase and the continuous phase are mixed to obtain a topical tadalafil formulation.

18. The preparation method according to claim 17, characterized in that, The mixing method includes one or more of the following: ultrasonication, vortexing, stirring, high-speed dispersion, high-pressure homogenization, vacuum homogenization, and static mixer.

19. The preparation method according to claim 17, characterized in that, The power of the ultrasound is 10~800 W; And / or, the ultrasound is continuous ultrasound or intermittent ultrasound; the duty cycle of the intermittent ultrasound is 50%~90%; the duration of the ultrasound is 5~30 min; And / or, the rotational speed of the vortex is 300~3500 rpm; the duration of the vortex is 5~60 min; And / or, the stirring speed is 100~3500 rpm; the stirring time is 5~60 min; And / or, the high-speed dispersion rotation speed is 1000~8000 rpm; the high-speed dispersion time is 5~60 min; And / or, the pressure of the high-pressure homogenizer is 50~150 MPa; And / or, the rotational speed of the vacuum homogenizer is 10,000 to 28,000 rpm.

20. The use of the topical tadalafil preparation according to any one of claims 1 to 16 or the topical tadalafil preparation prepared by any one of claims 17 to 19 in the preparation of a product for treating erectile dysfunction.

21. A product characterized in that, The preparation includes the topical tadalafil formulation according to any one of claims 1 to 16 or the topical tadalafil formulation prepared by any one of the preparation methods of claims 17 to 19.

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