Finasteride spray and method of making same

Abstract

This invention relates to a finasteride spray and its preparation method, belonging to the field of drug synthesis technology. The preparation method includes the following steps: (1) dissolving finasteride, soybean lecithin, and an antioxidant in anhydrous ethanol to form an alcohol phase; (2) injecting the alcohol phase into phosphate buffer solution under stirring, and continuing stirring to form a pre-emulsion; (3) subjecting the pre-emulsion to ultrasonic treatment under an ice bath to obtain an olprosome suspension; (4) adding a transdermal penetration enhancer and a solubilizer to the olprosome suspension, mixing, sterilizing and filtering, and filling into a spray bottle to obtain the finasteride spray. The finasteride spray provided by this invention utilizes olprosome technology to efficiently target and enrich the drug in hair follicles, significantly improving efficacy while greatly reducing the risk of systemic side effects. It also shortens the preparation steps, reduces the use of toxic reagents, and achieves both safety and high efficiency, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a finasteride spray and its preparation method. Background Technology

[0002] Finasteride is a type II 5α-reductase inhibitor widely used clinically to treat benign prostatic hyperplasia and androgenetic alopecia. Currently, finasteride is mainly administered orally in tablet form, but long-term use carries the risk of systemic side effects such as decreased libido and erectile dysfunction. Topical sprays can act directly on the hair follicles of the scalp, reducing systemic absorption and offering significant clinical advantages. However, commercially available finasteride sprays are generally ordinary alcoholic-aqueous solutions, resulting in a short drug retention time on the scalp and low efficiency of transdermal absorption into the hair follicle target, leading to low bioavailability, frequent dosing, and poor patient compliance. Therefore, there is an urgent need to develop a topical formulation that can significantly improve the amount of drug retained in the hair follicle target.

[0003] Furthermore, the synthesis of finasteride currently generally uses steroidal compounds as raw materials. Chinese patent CN109467584A discloses a method for preparing finasteride. This method uses 3-keto-4-aza-5-androstene-17β-acyl chloride as the starting material. It first undergoes an amidation reaction with tert-butylamine to generate 17β-tert-butylformamide-4-aza-5-androstene-3-one. Then, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used as a dehydrogenating agent to carry out 1,2-dehydrogenation in the presence of bis(trimethylsilyl)trifluoroacetamide to obtain finasteride.

[0004] However, this technical route has significant drawbacks: (1) DDQ used in this preparation method is a highly toxic chemical, and after the reaction, it produces an equimolar amount of cyanoquinone-containing byproducts. The waste liquid needs to be specially treated before it can be discharged, and the treatment cost is high. If not treated properly, it will pose a serious threat to the environment and the health of operators. (2) This method adopts a stepwise strategy of "amylation first, then dehydrogenation". Starting from the advanced intermediate 3-keto-4-aza-5-androstene-17β-acyl chloride, it still requires two independent operations of amidation and dehydrogenation. The intermediate needs to be separated and purified, resulting in a long production cycle, large solvent consumption, and large loss of total yield. (3) The starting material 3-keto-4-aza-5-androstene-17β-acyl chloride used in this method is not a bulk industrial raw material. It needs to be specially prepared from more basic steroids (such as 4-androstene-3,17-dione) through multiple steps. This does not actually reduce the production steps as a whole, and the stability and economy of the supply chain are constrained. The existing production process for finasteride active pharmaceutical ingredient is cumbersome and commonly uses highly toxic DDQ or selenium dioxide for 1,2-dehydrogenation, generating large amounts of toxic waste liquid, which does not meet the requirements of green chemistry. Therefore, providing a finasteride preparation method that is simple in steps and environmentally friendly, and compatible with high-efficiency formulations, is of significant practical importance. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a finasteride spray and its preparation method. The finasteride spray provided by this invention utilizes liposome technology to efficiently target and enrich the drug in hair follicles, significantly improving efficacy while greatly reducing the risk of systemic side effects. It also shortens the preparation steps, reduces the use of toxic reagents, and achieves both safety and high efficiency, making it suitable for industrial production.

[0006] In a first aspect, the present invention provides a method for preparing a finasteride spray, the method comprising the following steps: (1) Finasteride, soybean lecithin and antioxidants are dissolved in anhydrous ethanol to form an alcohol phase; (2) While stirring, the alcohol phase is injected into the phosphate buffer solution, and stirring is continued to form the primary emulsion; (3) The colostrum was subjected to ultrasonic treatment with a probe under an ice bath to obtain an alcohol suspension with an average particle size of 120-180 nm; (4) Add transdermal penetration enhancer and solubilizer to the alcohol suspension, mix well, filter sterile, and fill into spray bottles to obtain the finasteride spray. The spray comprises, by weight-volume percentage: 0.1-0.5% finasteride, 1.5-3.0% soybean lecithin, 25-40% anhydrous ethanol, 3-10% solubilizer, 0.5-2.0% transdermal penetration enhancer, 0.02-0.1% antioxidant, with the balance being phosphate buffer.

[0007] In the above technical solution, in step (1), the membrane material, drug and antioxidant are completely dissolved in ethanol to ensure that each component is uniformly dispersed in molecular form.

[0008] In step (2), the alcohol phase is injected into the aqueous phosphate buffer solution under stirring. Using the principle of solvent-nonsolvent method, the ethanol is rapidly diluted, and the phospholipid molecules form multilayered and polydisperse promulgated vesicles due to the hydrophobic ends being exposed in the water.

[0009] In step (3), the vesicles in colostrum are uneven in size and mostly multilayered. The ultrasound probe generates a strong cavitation effect and shear force, breaking down the multilayered large vesicles and reshaping them into uniform, structurally intact single-chambered small vesicles. Ice bath temperature control prevents local overheating during ultrasound from causing degradation of phospholipids and drugs.

[0010] In step (4), after granulation, a transdermal penetration enhancer and a solubilizer are added to ensure that they are completely miscible in the formulation.

[0011] Optionally, the cosolvent is propylene glycol, the transdermal penetration enhancer is azone, and the antioxidant is vitamin E acetate; the ultrasonic treatment power is 150-250W, and the time is 10-20min.

[0012] In the above technical solution, soybean phospholipids are amphiphilic molecules. A high proportion of ethanol can significantly reduce the interfacial tension of the phospholipid bilayer and increase its fluidity, forming a more deformable ethanol body, which can efficiently penetrate the stratum corneum and penetrate deep into the hair follicle channel. If the ethanol content is too low, the high deformability of the ethanol body will be lost; if it is too high, it may damage the stability of the vesicles.

[0013] Azone acts on the intercellular lipids of the stratum corneum, disrupting their highly ordered arrangement and increasing the fluidity of the lipid bilayer, thereby reducing the skin barrier's resistance to the diffusion of liposomes. Propylene glycol, as a solubilizer, can penetrate the stratum corneum and solubilize keratin, while also acting as a moisturizer to increase skin hydration, synergistically promoting drug penetration. The combined effect of these two agents significantly enhances the transdermal efficiency of liposomes.

[0014] Vitamin E acetate is used to protect the unsaturated fatty acid chains in soybean phospholipids and the finasteride molecules themselves, preventing them from being oxidized and degraded during preparation and storage.

[0015] Phosphate buffer, as an aqueous medium, provides an isotonic environment with a pH (approximately 5.5) close to the physiological pH of the skin surface, resulting in low irritation. During the infusion of the alcohol phase into the aqueous phase, phospholipid molecules spontaneously arrange themselves into vesicle structures due to hydrophobic interactions.

[0016] Optionally, the finasteride is prepared by a method comprising the following steps: reacting compound I with tert-butylamine in an organic solvent in the presence of a high-valent iodine oxidant to obtain finasteride; the amount of tert-butylamine used is 1.0-1.5 equivalents of compound I, and the amount of the high-valent iodine oxidant is 2.0-2.5 equivalents of compound I; compound I is 3-keto-4-aza-5a-androstan-17b-carboxylic acid, with the structural formula shown in Formula I: .

[0017] In the above technical solution, the 17β-carboxyl group of compound I is first activated by a hypervalent iodine reagent to form a highly reactive mixed anhydride intermediate. This intermediate is then nucleophilically attacked by tert-butylamine in the system, forming an amide bond. The hypervalent iodine reagent also acts as an oxidant, selectively removing hydrogen atoms at the C1 and C2 positions of ring A. Through a carbocation rearrangement process, a 1,2-double bond is formed, which then forms a stable conjugated system with the ketone carbonyl group at the C3 position. The reaction is a one-step cascade reaction, eliminating the need to separate intermediates and exhibiting extremely high step economy.

[0018] The oxidizing agent needs to be slightly more than 2 equivalents because the oxidation from the C1-C2 single bond to the double bond requires 2 electrons, and the activation of the carboxyl group consumes the reagent. A slight excess of tert-butylamine ensures complete amidation and also acts as an acid-binding agent to neutralize the acid generated in the reaction.

[0019] Optionally, the high-valent iodine oxidant is any one or more of di(trifluoroacetic acid)iodobenzene, diacetic acid iodobenzene, and iodobenzoylbenzene; the organic solvent is any one of acetonitrile, dichloromethane, tetrahydrofuran, or N,N-dimethylformamide.

[0020] Optionally, the reaction temperature is (-5) to (30) °C.

[0021] In the above technical solution, the reaction of the high-valent iodine oxidant with carboxylic acids to form anhydrides and the subsequent oxidative dehydrogenation is an exothermic process. Low-temperature operation can control the initial reaction rate and suppress side reactions such as excessive oxidation and polymerization caused by local overheating. Gradually raising the temperature to room temperature may increase the viscosity of the system and decrease the concentration of active species in the later stages of the reaction; appropriate heating can ensure complete reaction and shorten the production cycle. This temperature range does not require special low-temperature or high-temperature equipment and has strong industrial applicability.

[0022] Optionally, the preparation steps of compound I are as follows: (a) The androst-4-ene-3,17-dione was subjected to ozone oxidation for ring opening and ammonium acetate for ring closing to obtain a reaction mixture; (b) The reaction mixture was hydrogenated under palladium-carbon catalysis. After filtering out the catalyst, it was directly cyano-treated with trimethylcyanosylsilane, followed by dehydration, hydrogenation reduction, and alkaline hydrolysis to obtain compound I; the structural formula of the androst-4-ene-3,17-dione is shown in formula II: .

[0023] In the above technical solution, ozone selectively cleaves the C4-C5 double bond with the highest electron cloud density in androst-4-en-3,17-dione, generating ozonides, which, after post-treatment, yield 5,17-dioxo-3,5-open-ring androstonic acid. This intermediate has high reactivity and requires no purification. The carboxylic acid at C3 and the carbonyl group at C4 of the open-ring dione undergo condensation, dehydration, and cyclization with ammonia provided by ammonium acetate at high temperature, reforming the A ring to form a 4-aza-5-en-3,17-dione structure.

[0024] After filtering out any solid impurities that may be present in the previous step, palladium on carbon is added to selectively hydrogenate the sterically less hindered and more reactive 5,6-double bond, yielding saturated A and B trans-fused rings. After filtering out the catalyst, trimethylcyanosilane and a Lewis acid catalyst are directly added to perform stereoselective nucleophilic addition to the ketone group at position 17, generating β-cyanosilyl ether. Subsequently, a dehydrating agent (such as methanesulfonyl chloride / pyridine) is added sequentially to generate an olefinic nitrile, followed by the addition of palladium on carbon to reduce the cyano group and the double bond. Finally, under alkaline conditions, the cyano group is hydrolyzed to a carboxylate, and acidification yields compound I. The entire process, through sequential feeding, avoids the separation of toxic and unstable intermediates.

[0025] Optionally, the alkaline hydrolysis described in step (b) is carried out in the presence of lithium hydroxide and hydrogen peroxide.

[0026] In the above technical solution, during the hydrolysis of nitrile to carboxylic acid, hydrogen peroxide can form a lithium peroxide-lithium hydroxide complex with lithium hydroxide. This substance is a nucleophilic catalyst for nitrile hydrolysis, which can rapidly convert nitrile into amide intermediates under mild conditions (relatively low temperature and low alkali concentration), and further hydrolyze them into carboxylic acid. H2O2 can also suppress side reactions (such as over-reduction) that may occur during the palladium carbon hydrogenation reduction stage and are harmful to subsequent reactions, thus improving the robustness of the process.

[0027] Secondly, the present invention provides a finasteride spray, which is prepared by the above-described preparation method.

[0028] In summary, the present invention has at least one of the following beneficial technical effects: 1. This invention uses organic high-valent iodine reagent to replace the traditional 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or selenium dioxide to complete 1,2-dehydrogenation. The reagent itself is a non-toxic or low-toxic compound, and the reaction byproduct iodobenzene can be recycled and reused. This fundamentally eliminates the highly toxic cyanoquinone-containing waste liquid generated by the DDQ process and the heavy metal pollution problems caused by the selenium process, making the entire production process fully compliant with the requirements of green chemistry and sustainable development.

[0029] 2. The present invention creatively discovers that, under specific conditions, high-valent iodine oxidant can simultaneously drive the amidation activation of 17β-carboxylic acid and the 1,2-dehydrogenation of ring A, integrating two independent reactions that must be carried out in separate steps in the traditional process into a one-step operation, reducing the synthesis steps of finasteride, shortening the production cycle, and making it suitable for industrial production.

[0030] 3. The finasteride protoplast spray prepared by this invention utilizes flexible vesicles formed by a specific ratio of ethanol and phospholipids, which can efficiently penetrate the stratum corneum and accumulate along the hair follicle channel. This can ensure the local therapeutic effect while minimizing the transdermal entry of the drug into the systemic circulation, thereby reducing the risk of systemic side effects such as sexual dysfunction commonly seen in oral preparations and significantly improving the safety of medication.

[0031] 4. The overall preparation method starts from low-cost raw materials and uses a one-pot series reaction to directly reach the key intermediate. The entire process does not require separation and purification and eliminates the use of highly toxic cyanide. The total yield exceeds 40%, achieving a balance between safety, efficiency and economy. Attached Figure Description

[0032] Figure 1 The image shows the HPLC chromatogram of finasteride prepared in Example 1. Detailed Implementation

[0033] The present invention will be further described in detail below with reference to the embodiments.

[0034] All materials used in the following examples are available for purchase on the market.

[0035] Example 1: This example provides a method for preparing finasteride raw material.

[0036] This embodiment provides a method for preparing finasteride, and the reaction formula is as follows: The preparation method includes the following steps: S1. Preparation of Compound I: 20.0 g (69.8 mmol) of androstenedione-4-ene-3,17-dione was dissolved in 300 mL of dichloromethane. The solution was cooled to -15 °C, and ozone was introduced. The reaction was monitored by TLC until the reactants were completely reacted. After purging with nitrogen, the mixture was quenched with 10% sodium bisulfite solution. The mixture was separated into liquid and liquid phases, and the organic phase was concentrated to dryness. 200 mL of glacial acetic acid and 30.0 g of ammonium acetate were added to the residue, and the mixture was refluxed for 5 hours. The acetic acid was removed by vacuum distillation, and the residue was dissolved in 400 mL of tetrahydrofuran. 2.0 g of 5% palladium on carbon was added, and the mixture was hydrogenated at atmospheric pressure until no more hydrogen was absorbed. The catalyst was filtered off, and 10.4 g (104.7 mmol) of trimethylcyanosilane was added to the filtrate. 1.5 mmol (1.5 eq) and 1.1 g of zinc iodide were reacted at 45 °C for 2 h. Then, 8.0 g of methanesulfonyl chloride and 8.3 g of pyridine were added, and the reaction was carried out at 60 °C for 1 h for dehydration. 2.0 g of 5% palladium on carbon was added again, and hydrogen was passed through for reduction. After filtering off the catalyst, 4.4 g of lithium hydroxide dissolved in 60 mL of water and 20 mL of 30% hydrogen peroxide were added. The mixture was hydrolyzed at 80 °C for 2 h. After cooling, the pH was adjusted to 3 with dilute hydrochloric acid, extracted with ethyl acetate, concentrated, slurried with n-hexane, filtered and dried to give 15.8 g of white solid compound I (4-aza-5α-androst-3-one-17β-carboxylic acid), with a yield of 70.5% and an HPLC purity of 98.2%.

[0037] S2. Preparation of finasteride: Under nitrogen protection, 5.0 g (15.7 mmol) of compound I obtained in step S1 and 80 mL of anhydrous acetonitrile were added to a dry reaction flask and stirred to suspend the mixture. 1.4 g (18.8 mmol, 1.2 eq) of tert-butylamine was added, and the mixture was cooled to 0 °C in an ice-salt bath. 14.9 g (34.5 mmol, 2.2 eq) of di(trifluoroacetic acid)iodobenzene was added in batches over approximately 30 min. The ice bath was removed, and the mixture was stirred at room temperature for 14 h. TLC monitoring showed that compound I had essentially disappeared. The reaction solution was slowly poured into 100 mL of icy dilute hydrochloric acid (1 M) to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized from ethanol and water in a volume ratio of 6:4 to obtain 4.7 g of white crystalline powder finasteride, with a yield of 80.2%. Figure 1 The HPLC purity is 99.6%, and the melting point is 253-255℃.

[0038] Example 2: This example provides a method for preparing finasteride raw material.

[0039] The preparation method of finasteride in this embodiment is the same as that in Example 1, except that: S2, preparation of finasteride: under nitrogen protection, 5.0 g (15.7 mmol) of compound I and 80 mL of anhydrous acetonitrile were added to a dry reaction flask and stirred to suspend. 1.4 g (18.8 mmol, 1.2 eq) of tert-butylamine was added, and the mixture was cooled to 0 °C in an ice-salt bath. 13.1 g (2.2 eq) of diacetic acid iodobenzene was added in batches, and the addition was completed in about 30 min. The ice bath was removed, and the mixture was stirred at room temperature for 18 h. TLC monitoring showed that compound I had basically disappeared. The reaction solution was slowly poured into 100 mL of ice-cold dilute hydrochloric acid (1 M) to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined. The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized with ethanol and water in a volume ratio of 6:4 to obtain 4.3 g of white crystalline powder finasteride, with a yield of 73.5%, HPLC purity of 99.2%, and melting point of 253-255 °C.

[0040] Example 3: This example provides a finasteride spray and its preparation method.

[0041] The preparation method includes the following steps: S1. Dissolve 0.25g of finasteride, 2.0g of soybean lecithin and 0.05g of vitamin E acetate obtained in Example 1 in 35.0mL of anhydrous ethanol and stir magnetically until completely dissolved to form a clear alcohol phase.

[0042] S2. Under magnetic stirring at 500 rpm, the alcohol phase is slowly injected into about 55 mL of phosphate buffer (pH 5.5) at a rate of about 2 mL / min using a syringe. After injection, stirring is continued for 30 min to form a milky proembryo.

[0043] S3. Place the colostrum in an ice bath and process it using a probe sonicator. Set the power to 200W and the working mode to sonicate for 2 seconds followed by 3 seconds of interval, for a total sonication time of 15 minutes. A semi-transparent, bluish-white opalescent alcohol suspension is obtained. The average particle size is 152 nm, as determined by dynamic light scattering.

[0044] S4. Add 5.0 mL of propylene glycol and 1.0 mL of azone to the liposome suspension in sequence, stir well, add phosphate buffer to make up to 100 mL, filter through a 0.22 μm microporous membrane for sterilization, and fill into a metering spray pump bottle to obtain finasteride spray.

[0045] Example 4: This example provides a finasteride spray and its preparation method.

[0046] The preparation method includes the following steps: S1. Dissolve 0.10g of finasteride, 1.5g of soybean lecithin and 0.02g of vitamin E acetate obtained in Example 1 in 25.0mL of anhydrous ethanol and stir magnetically until completely dissolved to form a clear alcohol phase.

[0047] S2. Under magnetic stirring at 500 rpm, the alcohol phase is slowly injected into about 50 mL of phosphate buffer (pH 5.5) at a rate of about 2 mL / min using a syringe. After injection, stirring is continued for 30 min to form a milky promulgated emulsion.

[0048] S3. Place the colostrum in an ice bath and process it using a probe sonicator. Set the power to 150W and the working mode to 2 seconds of sonication followed by 3 seconds of intermittent sonication, for a total sonication time of 10 minutes. A semi-transparent, bluish-white opalescent alcohol suspension is obtained. The average particle size is 178 nm as determined by dynamic light scattering.

[0049] S4. Add 3.0 mL of propylene glycol and 0.5 mL of azone to the alcohol suspension in sequence, stir well, add phosphate buffer to make up to 100 mL, filter through a 0.22 μm microporous membrane for sterilization, and fill into a metering spray pump bottle to obtain finasteride spray.

[0050] Example 5: This example provides a finasteride spray and its preparation method.

[0051] The preparation method includes the following steps: S1. Dissolve 0.5g of finasteride, 3.0g of soybean lecithin and 0.10g of vitamin E acetate obtained in Example 1 in 40.0mL of anhydrous ethanol and stir magnetically until completely dissolved to form a clear alcohol phase.

[0052] S2. Under magnetic stirring at 500 rpm, the alcohol phase is slowly injected into about 65 mL of phosphate buffer (pH 5.5) at a rate of about 2 mL / min using a syringe. After injection, stirring is continued for 30 min to form a milky promulgated emulsion.

[0053] S3. Place the colostrum in an ice bath and process it using a probe sonicator. Set the power to 250W and the working mode to 2 seconds of sonication followed by 3 seconds of intermittent sonication, for a total sonication time of 20 minutes. A semi-transparent, bluish-white opalescent alcohol suspension is obtained. The average particle size is 138 nm as determined by dynamic light scattering.

[0054] S4. Add 10.0 mL of propylene glycol and 2.0 mL of azone to the alcohol suspension in sequence, stir well, add phosphate buffer to make up to 100 mL, filter through a 0.22 μm microporous membrane for sterilization, and fill into a metering spray pump bottle to obtain finasteride spray.

[0055] Comparative Example 1: This comparative example provides a control of finasteride, prepared as follows: S1. Preparation of Compound I: 20.0 g (69.8 mmol) of androstenedione-4-ene-3,17-dione was dissolved in 300 mL of dichloromethane. The solution was cooled to -15 °C, and ozone was introduced. The reaction was monitored by TLC until the reactants were completely reacted. After purging with nitrogen, the mixture was quenched with 10% sodium bisulfite solution. The mixture was separated into liquid and liquid phases, and the organic phase was concentrated to dryness. 200 mL of glacial acetic acid and 30.0 g of ammonium acetate were added to the residue, and the mixture was refluxed for 5 hours. The acetic acid was removed by vacuum distillation, and the residue was dissolved in 400 mL of tetrahydrofuran. 2.0 g of 5% palladium on carbon was added, and the mixture was hydrogenated at atmospheric pressure until no more hydrogen was absorbed. The catalyst was filtered off, and 10.4 g (104.7 mmol) of trimethylcyanosilane was added to the filtrate. 1.5 mmol (1.5 eq) and 1.1 g of zinc iodide were reacted at 45 °C for 2 h. Then, 8.0 g of methanesulfonyl chloride and 8.3 g of pyridine were added, and the reaction was carried out at 60 °C for 1 h for dehydration. 2.0 g of 5% palladium on carbon was added again, and hydrogen was passed through for reduction. After filtering off the catalyst, 4.4 g of lithium hydroxide dissolved in 60 mL of water and 20 mL of 30% hydrogen peroxide were added. The mixture was hydrolyzed at 80 °C for 2 h. After cooling, the pH was adjusted to 3 with dilute hydrochloric acid, extracted with ethyl acetate, concentrated, slurried with n-hexane, filtered and dried to give 15.8 g of white solid compound I (4-aza-5α-androst-3-one-17β-carboxylic acid), with a yield of 70.5% and an HPLC purity of 98.2%.

[0056] S2. 5.0 g of the compound I prepared above was reacted with oxalyl chloride to form an acyl chloride, which was then condensed with tert-butylamine to obtain 5.2 g of 17β-tert-butylformamide-4-aza-5α-androst-3-one (i.e., the 5,6-saturated finasteride precursor). 5.0 g of this precursor was dissolved in 80 mL of anhydrous dioxane, and 4.5 g (19.8 mmol, approximately 1.5 eq) of 2,3-dichloro-5,6-dicyano-p-benzoquinone and 10.2 g of bis(trimethylsilyl)trifluoroacetamide were added. The mixture was refluxed under nitrogen protection for 8 h. After cooling, the precipitate was removed by filtration, the filtrate was concentrated, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether) to obtain 3.5 g of white solid finasteride. The combined yield of the two steps was approximately 61.3%, and the HPLC purity was 98.0%.

[0057] Comparative Example 2: This comparative example provides a finasteride spray prepared in the same way as in Example 3, except that: the finasteride prepared in Comparative Example 1 is used, wherein the average particle size of the alcohol suspension is 163 nm.

[0058] Comparative Example 3: This comparative example provides a comparative finasteride spray. The preparation steps are as follows: 0.25 g of finasteride obtained in Example 1 was dissolved in 35.0 mL of anhydrous ethanol. 5.0 mL of propylene glycol, 1.0 mL of azone, and phosphate buffer were added sequentially to make up to 100 mL. The mixture was stirred evenly, filtered through a 0.22 μm microporous membrane for sterilization, and filled into a metering spray pump bottle to obtain a clear, vesicle-free ordinary alcohol-water solution spray.

[0059] A transdermal retention comparison experiment was conducted on the finasteride spray prepared in Example 3 and the comparative finasteride spray prepared in Comparative Examples 2-3. The experimental method was as follows: Fresh detached pig ear skin was taken, trimmed to an appropriate size, and fixed on a Franz diffusion cell with the stratum corneum facing upwards. The receiving chamber was filled with pH 7.4 phosphate buffer, the temperature was controlled at 32±1℃, and the diffusion area was 1.77 cm². 2 200 μL each of the sprays prepared in Examples 3-5 and Comparative Examples 2-3 (containing approximately 0.5 mg of finasteride) were added to the drug supply chamber. After 24 hours, the skin was removed, and the stratum corneum was repeatedly peeled off using cyanoacrylate tape. Hair follicle units were extracted using micro-forceps and weighed. Methanol was added for homogenization and extraction, and the drug concentration was determined by HPLC. Each group was tested in six replicates, and the results are expressed as mean ± standard deviation. The test results are shown in Tables 1 and 2.

[0060] Table 1. Drug concentration within hair follicles As shown in Table 1, Example 3 used the finasteride prepared in Example 1 of this invention, Comparative Example 2 used the comparative finasteride prepared in Comparative Example 1, and although Comparative Example 3 also used the finasteride prepared in Example 1 of this invention, the preparation method of the spray was different. Comparative Example 2 showed a 2.2-fold increase compared to Comparative Example 3, indicating that even using raw materials with slightly lower purity from traditional processes, the liposome formulation alone can achieve a significant increase in follicular drug concentration. This directly demonstrates the important role of liposome vesicle structure in follicular targeting. Example 3 further improved by 18.8% compared to Comparative Example 2 and by 284% compared to Comparative Example 3. This indicates that the finasteride obtained by the high-valent iodine one-step method of this invention provides a better drug loading basis for the liposome system compared to the traditional DDQ method, and the combination of the two produces a synergistic effect of 1+1>2.

[0061] Table 2. Drug distribution in different skin layers over 24 hours According to the data in Table 2, in Comparative Example 3, the drug was mainly concentrated in the active epidermal layer (42.8%) and the stratum corneum (35.2%), with only 12.5% ​​entering the hair follicle. In contrast, the hair follicle distribution ratio in Example 3 and Comparative Example 2 was significantly increased, and the retention rate in the active epidermal layer was significantly reduced. This demonstrates that the protoplasts actively accumulate in the hair follicle channels through their deformability, guiding the drug from the epidermis and superficial dermis to the hair follicle target. The drug content in the receiving solution in Example 3 was 8.5%, while in Comparative Example 2 it was 11.0%, a reduction of 22.7% compared to Comparative Example 2. This indicates that the protoplasts in Example 3 have better structural integrity and drug retention capacity within the skin, resulting in a lower risk of formulation leakage into the systemic circulation and higher safety. Furthermore, the active epidermal layer retention rate in Example 3 (24.3%) was lower than that in Comparative Example 2 (26.5%), indicating that the high-purity active pharmaceutical ingredient provides the protoplasts with better encapsulation efficiency and in vivo stability, preventing premature drug release in superficial tissues.

[0062] In summary, the high-purity finasteride prepared by this invention, due to the absence of quinone impurities remaining from the DDQ process, can form denser and more stable liposome vesicles, thereby more efficiently delivering the drug to the hair follicle and retaining it at the target site. Simultaneously, the liposome formulation itself actively bypasses the stratum corneum barrier, transferring the drug from ineffective retention in the epidermis to the effective site in the hair follicle. The synergistic effect of these two factors ultimately achieves a high drug concentration in the hair follicle while also possessing superior safety.

[0063] The above are all preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, all equivalent changes made in accordance with the structure, shape and principle of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing a finasteride spray, characterized in that, The preparation method includes the following steps: (1) Finasteride, soybean lecithin and antioxidants are dissolved in anhydrous ethanol to form an alcohol phase; (2) While stirring, the alcohol phase is injected into the phosphate buffer solution, and stirring is continued to form the primary emulsion; (3) The colostrum was subjected to ultrasonic treatment with a probe under an ice bath to obtain an alcohol suspension with an average particle size of 120-180 nm; (4) Add transdermal penetration enhancer and solubilizer to the alcohol suspension, mix well, filter sterile, and fill into spray bottles to obtain the finasteride spray. The spray comprises, by weight-volume percentage: 0.1-0.5% finasteride, 1.5-3.0% soybean lecithin, 25-40% anhydrous ethanol, 3-10% solubilizer, 0.5-2.0% transdermal penetration enhancer, 0.02-0.1% antioxidant, with the balance being phosphate buffer.

2. The method for preparing a finasteride spray according to claim 1, characterized in that, The cosolvent is propylene glycol, the transdermal penetration enhancer is azone, and the antioxidant is vitamin E acetate; the ultrasonic treatment power is 150-250W, and the time is 10-20min.

3. The method for preparing a finasteride spray according to claim 1, characterized in that, The finasteride was prepared by a method comprising the following steps: reacting compound I with tert-butylamine in an organic solvent in the presence of a high-valent iodine oxidant to obtain finasteride; the amount of tert-butylamine used was 1.0-1.5 equivalents of compound I, and the amount of the high-valent iodine oxidant was 2.0-2.5 equivalents of compound I; compound I was 3-keto-4-aza-5a-androstan-17b-carboxylic acid, with the structural formula shown in Formula I: 。 4. The method for preparing a finasteride spray according to claim 3, characterized in that, The high-valent iodine oxidant is any one or more of di(trifluoroacetic acid)iodobenzene, diacetic acid iodobenzene, and iodophenylene; the organic solvent is any one of acetonitrile, dichloromethane, tetrahydrofuran, or N,N-dimethylformamide.

5. The method for preparing a finasteride spray according to claim 3, characterized in that, The reaction temperature is (-5) - (30)℃.

6. The method for preparing a finasteride spray according to claim 3, characterized in that, The preparation steps of compound I are as follows: (a) The androst-4-ene-3,17-dione was subjected to ozone oxidation for ring opening and ammonium acetate for ring closing to obtain a reaction mixture; (b) The reaction mixture was hydrogenated under palladium-carbon catalysis. After filtering out the catalyst, it was directly cyano-treated with trimethylcyanosylsilane, followed by dehydration, hydrogenation reduction, and alkaline hydrolysis to obtain compound I; the structural formula of the androst-4-ene-3,17-dione is shown in formula II: 。 7. The method for preparing a finasteride spray according to claim 6, characterized in that, The alkaline hydrolysis described in step (b) is carried out in the presence of lithium hydroxide and hydrogen peroxide.

8. A finasteride spray, characterized in that, The finasteride spray is prepared using the preparation method described in any one of claims 1-7.

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