Bodipy photosensitizer composition for photodynamic therapy

Abstract

Provided is a BODIPY photosensitizer composition for photodynamic therapy, comprising a BODIPY photosensitizer or an aza-BODIPY photosensitizer, and an oily matrix. The composition has relatively high singlet oxygen generation efficiency. The composition directly uses a fat-soluble BODIPY compound and can be made into various topical formulations.

Description

BODIPY-type photosensitizer compositions for photodynamic therapy

[0001] This application claims priority to Chinese Patent Application No. 202510346851.X, filed on March 24, 2025, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention belongs to the field of dermatological disease treatment drug technology, and relates to BODIPY-type photosensitizer compositions for photodynamic therapy. Background Technology

[0003] Photodynamic therapy (PDT) comprises three elements: photosensitizer, light exposure, and molecular oxygen. The photosensitizer's role is to interact with molecular oxygen under light excitation to produce singlet oxygen (…). 1 O2). 1 O2 is molecular oxygen in an excited state with extremely strong oxidizing power. It readily reacts with various biological components (proteins, amino acids, nucleic acids, etc.), leading to lipid peroxidation, cell membrane and organelle damage, thereby killing pathogenic microorganisms or diseased cells to achieve therapeutic purposes. Therefore, highly efficient and safe photosensitizers are the key and core of PDT (phototherapy), and their basic requirements are: ① single component and well-defined structure; ② high singlet oxygen generation efficiency; ③ rapid excretion, low toxicity and side effects, and short light avoidance time; ④ convenient formulation and administration.

[0004] Boron-dipyrromethene (BODIPY) is a photosensitizer with promising applications. BODIPY anchors two pyrrole rings in a single plane via boron and methanogenic bonds, forming a rigid coplanar molecular structure. When the carbon atom at position 8 of BODIPY is replaced by nitrogen, it becomes aza-BODIPY. The basic framework structure is as follows:

[0005] BODIPY-type photosensitizers: aza-BODIPY type photosensitizers:

[0006] The skeletons of BODIPY and aza-BODIPY, as well as most of their derivatives, are lipophilic, insoluble in water, and cannot be directly used in the human body. To improve their water solubility, the following technical measures have been adopted: (1) Modifying the BODIPY molecule with water-soluble groups or attaching it with PEG. This chemical modification increases the amphiphilicity of the product, but it is not water-soluble. (2) Using encapsulation, micellization, and microencapsulation methods to disperse BODIPY in an organic matrix, forming nanoscale micelles or microcapsules, which are then dispersed or suspended in water. (3) Using nano-self-assembly methods to directly prepare BODIPY nanocrystals or nanoparticles, thereby achieving solubilization in aqueous systems. Some of the improvement methods reported in the literature and patents above require ingenious molecular structure design and complex chemical synthesis, while others rely on special photophysical mechanisms, such as specific intramolecular and intermolecular charge and energy transfer, aggregation-induced emission or quenching of photosensitizer molecules, etc. Although these improvements have certain effects, industrial production is very difficult and inconvenient for clinical translation. Chinese patent 201910794184.6 discloses a method for directly solubilizing the reported BODIPY photosensitizer without chemical or photophysical modification. While the process is relatively simple, the achievable upper concentration limit is not high enough. More importantly, the singlet oxygen generation efficiency is low, severely impacting its photodynamic efficacy. Therefore, despite numerous published papers and patent applications, there are currently no reports of BODIPY being used as a new drug in PDT clinical trials.

[0007] The photosensitizer currently used in clinical PDT is primarily 5-aminolevulinic acid hydrochloride (5-ALA, "ALA"). It is a precursor compound of protoporphyrin-IX, exhibiting good biocompatibility and water solubility. Under physiological conditions, it can be converted to protoporphyrin-IX to exert its photosensitizing effect. However, this conversion requires a complex physiological process, necessitating a concentration as high as 20% and a light intensity as high as 100-120 J / cm². 2 Therefore, the cost is high, patient compliance is poor, the efficacy is limited, and the scope of indications is narrow. Thus, clinical PDT treatment urgently needs a new photosensitizer that can replace or partially replace "ALA".

[0008] During the experiments, the inventors unexpectedly discovered that dispersing lipid-soluble BODIPY-type photosensitizers in various oily matrices to form BODIPY-type photosensitizer compositions resulted in extremely high singlet oxygen generation efficiency. Based on this discovery, the inventors conducted clinical research using such compositions to treat skin diseases, obtaining promising results. Summary of the Invention

[0009] The technical problem this invention aims to solve is to overcome the issues of poor water solubility, difficulty in industrial production of BODIPY-type photosensitizers due to nano-sizing processes, and low singlet oxygen efficiency of novel solubilization products, as reported in the literature. "BODIPY-type photosensitizer compositions" represent the main means and technical approach to solving this problem.

[0010] This invention discloses a BODIPY-based photosensitizer composition comprising a BODIPY-based compound and an oily matrix.

[0011] Preferably, the BODIPY-type photosensitizer composition comprises, by mass fraction, 0.001-10 parts of BODIPY-type photosensitizer compound and 90-99.999 parts of oily matrix.

[0012] Furthermore, the BODIPY-type photosensitizer compounds are compounds with structures as shown in general formulas (I) and (II):

[0013] or its derivatives; wherein:

[0014] X is selected from I and Br;

[0015] R1 is selected from H, CH3, C6H5, C6H4OCH3, CH=CH~C6H5, CH=CH~C6H4OCH3;

[0016] R2 is selected from H, CH3, C6H5, C6H4OCH3, CH=CH~C6H5, CH=CH~C6H 5～n (OCH3) n Where n = 1 to 3;

[0017] R3 is selected from

[0018] R4 is selected from H and C. n H 2n+1 Where n = 1 to 40, C6F5, C6H 5～n (CH3) n Where n = 1 to 3, C6H4OH, C6H 5～n (OCH3) n , where n=1~3, C6H4CN, C6H4CF3, C6H4NO2, C6H4NH2, C6H4N(CH3)2, C5H4N, C5H4NCH3I, CH=CH~C6H5, CH=CH~C6H4OCH3.

[0019] Furthermore, the derivative is at least one of hydrate, salt, complex, chelate, and ester.

[0020] Preferably, the BODIPY-type photosensitizer compound is at least one of the compounds with molecular formulas A1 to A28:

[0021] Furthermore, the oily matrix includes sesame oil, soybean oil, peanut oil, olive oil; hydrocarbons such as petrolatum, liquid paraffin, solid paraffin, microcrystalline wax, and ceresin; lipids such as lanolin, beeswax, and cetearyl wax; and synthetic or semi-synthetic oily matrices such as squalane, silicone, fatty acids, fatty alcohols, and lanolin derivatives.

[0022] The beneficial effects of this invention are as follows:

[0023] 1. The BODIPY-type photosensitizer composition of the present invention has a high singlet oxygen generation efficiency, which is much higher than that of the solubilized BODIPY-type photosensitizer disclosed in Chinese Patent 201910794184.6.

[0024] 2. Direct use of lipid-soluble BODIPY compounds, without modification or alteration, and without nano- or micellarization, results in simple composition and formulation preparation processes that do not require special equipment, thus leading to low manufacturing costs, no pollution, and easy mass production and clinical translation.

[0025] 3. The composition can be easily formulated into a variety of topical preparations, which can be applied like cosmetics. It has strong affinity to the skin and can easily meet the treatment needs of different skin diseases.

[0026] 4. Due to the high efficiency of singlet oxygen generation, only a very low photosensitizer concentration (0.01-0.5%) is required in the formulation, and only a low light energy (10-60 J / cm²) is needed during treatment. 2 This can achieve therapeutic effects, thereby improving patient comfort and compliance.

[0027] 5. Due to the high efficiency, broad spectrum, non-toxicity, and lack of drug resistance of BODIPY-type photosensitizers, the compositions and formulations of the present invention are not only suitable for general infectious skin diseases, but also for special skin diseases such as large-area burns and skin cancer, thereby effectively broadening the indications for PDT. Attached Figure Description

[0028] Figure 1 shows the efficacy of BODIPY composition cream in a mouse model of Staphylococcus aureus infection in skin wounds;

[0029] Figure 2 shows the therapeutic effect of BODIPY solubilizing gel on a mouse model of Staphylococcus aureus infection in skin wounds;

[0030] Figure 3 shows the photodynamic therapy of BODIPY combination cream and BODIPY solubilizing gel on a mouse model of Staphylococcus aureus infection in skin wounds (relative wound area on day 6 and day 12 post-surgery, respectively. C = cream, G = gel).

[0031] Figure 4 shows the efficacy of BODIPY composition cream A9 in treating multiple plantar warts (Case 1);

[0032] Figure 5 shows the efficacy of BODIPY composition cream A10 on periungual warts (Case 2);

[0033] Figure 6 shows the efficacy of BODIPY composition cream A13 on periungual warts (Case 3);

[0034] Figure 7 shows the efficacy of BODIPY composition cream A15 in treating plantar warts (Case 4);

[0035] Figure 8 shows the efficacy of BODIPY composition cream A10 in treating plantar warts (Case 5);

[0036] Figure 9 shows the efficacy of BODIPY composition cream A13 in treating plantar warts (Case 6);

[0037] Figure 10 shows the efficacy of BODIPY composition cream A9 in treating plantar warts (Case 7);

[0038] Figure 11 shows the therapeutic effect of BODIPY composition cream A9 on acne (Case 8);

[0039] Figure 12 shows the therapeutic effect of BODIPY composition cream A10 on acne (Case 9);

[0040] Figure 13 shows the therapeutic effect of BODIPY composition cream A9 on acne (Case 10);

[0041] Figure 14 shows the therapeutic effect of BODIPY composition cream A9 on acne (Case 11);

[0042] Figure 15 shows the efficacy of BODIPY composition cream A13 in treating acne (Case 12);

[0043] Figure 16 shows the efficacy of BODIPY composition cream A10 in treating acne (Case 13). Detailed Implementation

[0044] The specific embodiments of the present invention will be further described below with reference to the examples. The following examples are only used to illustrate the technical embodiments of the present invention more clearly, and should not be used to limit the scope of protection of the present invention.

[0045] Examples 1-56. Preparation of creams using BODIPY compositions

[0046] Prescription 1: 10mg of BODIPY photosensitizer compound, 17g of stearic acid, 2g of lanolin, 10ml of liquid paraffin, 2g of triethanolamine, 5ml of glycerin, 0.1g of ethylparaben, and distilled water to 100g.

[0047] Preparation process: BODIPY-type photosensitizer compounds, stearic acid, lanolin, and liquid paraffin are mixed together and heated to 70°C in a water bath to uniformly disperse the BODIPY-type photosensitizer compounds in an oily matrix, thus obtaining a drug-loaded oil phase; ethylparaben is dissolved in water and then mixed with glycerol and triethanolamine, heated to the same temperature as the oil phase, and then slowly added to the oil phase while stirring. After the addition is complete, the mixture is allowed to stand and condense to obtain the final product.

[0048] Among them, the BODIPY-type photosensitizer compounds are selected from A1 to A28, corresponding to Examples 1 to 28 respectively.

[0049] Prescription 2: 100mg of BODIPY photosensitizer compound, 25g of stearyl alcohol, 25g of petrolatum, 1g of sodium dodecyl sulfate, 12g of propylene glycol, 0.025g of methylparaben, and distilled water to 100g.

[0050] Preparation process: BODIPY-type photosensitizer compounds, stearic acid, and petrolatum are mixed together and heated to 70°C in a water bath to uniformly disperse the BODIPY-type photosensitizer compounds in an oily matrix, thus obtaining a drug-loaded oil phase; methylparaben, sodium dodecyl sulfate, and propylene glycol are dissolved in water and heated to the same temperature as the oil phase, then slowly added to the oil phase while stirring. After the addition is complete, the mixture is allowed to stand and condense to obtain the final product.

[0051] Among them, the BODIPY-type photosensitizer compounds are selected from A1 to A28, corresponding to Examples 29 to 56 respectively.

[0052] Examples 57-84. Preparation of ointments using BODIPY compositions

[0053] Prescription: 50mg of BODIPY photosensitizer compound, 30g of lanolin, and 70g of petrolatum.

[0054] The BODIPY photosensitizer compound, lanolin, and petrolatum are heated to 70°C in a water bath and stirred to uniformly disperse the BODIPY photosensitizer compound in the oily matrix. The mixture is then cooled to obtain the final product.

[0055] Among them, the BODIPY-type photosensitizer compounds are selected from A1 to A28, corresponding to Examples 57 to 84 respectively.

[0056] To further illustrate the beneficial effects of the present invention, the following comparative examples are provided:

[0057] Comparative Example 1. Comparison of singlet oxygen generation efficiency between BODIPY composition and solubilized BODIPY

[0058] Electron spin resonance (ESR), also known as electron paramagnetic resonance (EPR), is a magnetic resonance technique used to detect substances containing unpaired electrons (including free radicals and transition metal ions). The signal is generated by the interaction between unpaired electrons and an applied magnetic field, making it the most direct technique for measuring free radicals. Detectable sample states include liquids, solids, and powders, making it ideal for detecting the singlet oxygen generation efficiency of semi-solid BODIPY-type photosensitizer compositions.

[0059] Specific experimental methods: Different types of BODIPY were accurately weighed and mixed and dissolved with representative oily matrices of different types to obtain compositions with a BODIPY content of 0.1 mg / g. Petrolatum, solid paraffin, stearic acid, lanolin, etc., required pre-heating treatment before being mixed and dissolved with BODIPY. The singlet oxygen generation efficiency of each sample was detected using the ESR method. TMP (2,2,6,6-tetramethyl-1-piperidine) was selected as the base. 1 O2 scavenger was uniformly mixed with the sample to be tested. The sample cell was irradiated with a 300W xenon lamp for 10 minutes before ESR testing. TMP capture... 1 O2 reacts to generate nitric oxide radicals (NO·), producing an ESR signal (see Figure 2). The peak height of the ESR is proportional to the amount of oxygen captured. 1 The amount of O2 is used as a semi-quantitative indicator of singlet oxygen generation efficiency, so the average distance between the positive and negative peaks of the three peaks is taken as the average distance between the positive and negative peaks.

[0060] Solubilized BODIPY was selected as the control sample, and the test concentration was also 0.1 mg / g. To ensure that the physical form of the BODIPY composition was as consistent as possible with that of the solubilized BODIPY and to reduce measurement errors, the solubilized BODIPY was prepared in the form of a gel, which is also in a semi-solid state. The preparation method of the solubilized BODIPY gel is based on Chinese Patent 201910794184.6. Specifically, 1 mg of different molecular formulas of BODIPY was accurately weighed, dissolved in 0.5-2 ml of acetone, and then the acetone solution was added dropwise to 10-100 ml of ultrapure water under stirring. The mixture was stirred at room temperature for 6-8 hours to evaporate the acetone, resulting in an aqueous solution of solubilized BODIPY. After adding mannitol as a lyophilization protectant, the mixture was freeze-dried to obtain lyophilized powder of solubilized BODIPY. After redissolving in ultrapure water, 0.5% by mass of carbomer 943 was added. After full swelling, an appropriate amount of triethanolamine was added while stirring to finally obtain a solubilized BODIPY gel with a BODIPY content of 0.1 mg / g.

[0061] The yield of singlet oxygen depends not only on the type and dosage of the photosensitizer and the light dose, but also on the oxygen content of the sample. Therefore, when comparing singlet oxygen yields, it is necessary to eliminate the influence of oxygen content in different samples on the results. Pure water at 20°C contains approximately 8.5 μg / g of oxygen. The water content of the solubilized BODIPY gel used in this experiment was as high as 99.4%, suggesting an oxygen content of approximately 8.45 μg / g. Currently, there are no reports on the oxygen content of petrolatum-like semi-solid oily matrices. Oily matrices cannot form hydrogen bonds with oxygen like water, thus increasing solubility. Moreover, petrolatum is a semi-solid, and the solubility of gases in solids is much lower than in liquids. Petrolatum is a mixture of alkane hydrocarbons or saturated hydrocarbons and does not contain oxygen itself. We attempted to use an elemental analyzer to detect the oxygen content in petrolatum to calculate its oxygen content. The method involved pyrolyzing the sample in a pure helium atmosphere (850℃) and reacting it with platinum carbon to generate CO. The oxygen content was then calculated using a thermal conductivity cell. The results showed that no oxygen was detected due to the extremely low oxygen content. Therefore, for ease of comparison, we estimate the oxygen content of petrolatum to be approximately 0.1 μg / g. Since the molecular formula of stearic acid is C... 18 H 36 O2, the main components of lanolin are esters formed from sterols, fatty alcohols, and triterpenoids with approximately equal amounts of fatty acids. The molecular formula of octadecyl alcohol is C. 18 H 38 O. All three of these oily matrices contain oxygen, so elemental analysis was not used to test them. We speculate that their oxygen content is similar to that of petrolatum, and therefore assume it to be 0.1 μg / g.

[0062] The ratio of average ESR peak height to oxygen content was used as the final evaluation index. The results showed that the singlet oxygen / oxygen content ratio of compositions formed by various BODIPYs and various oily matrices was significantly higher than that of the corresponding solubilized BODIPY gels, generally by tens of times, thus proving that BODIPY compositions are more suitable for photodynamic therapy than solubilized BODIPYs.

[0063] ESR average peak height / oxygen content

[0064] Comparative Example 2. Efficacy comparison of BODIPY composition cream and solubilized BODIPY gel in treating Staphylococcus aureus infection in mouse skin wounds.

[0065] 1. In this experiment, the efficacy of BODIPY composition cream and solubilized BODIPY gel in treating a mouse model of Staphylococcus aureus infection in skin wounds was investigated and compared.

[0066] Therapeutic drugs: The preparation method of the solubilized BODIPY gel is the same as that of Comparative Example 1. The corresponding types of BODIPY composition creams (A9, A10, A13, A14, A15, A16, A27, A28) are used directly. The drug content of both the gel and cream is 0.1 mg / g.

[0067] 2. Treatment light source: LED light source is used, and the appropriate wavelength is selected in the visible light to near-infrared range (480-650nm) according to the type of compound.

[0068] 3. Animal model: KM female mice (12-14 weeks old), with hair removed from their backs, and after anesthesia, a surgical scalpel cut an area of ​​approximately 1 cm² on their backs. 2 The wound extends to the muscle layer. The overnight culture of Staphylococcus aureus was adjusted to a concentration of 10 using physiological saline. 8 CFU / ml, add 20μl of bacterial solution to the wound.

[0069] 4. Treatment Method: One day after infection, the experimental animals were divided into 17 groups of 4 animals each. Groups 1-8 were treated with the BODIPY compound cream (A9, A10, A13, A14, A15, A16, A27, A28). Approximately 0.2g of the cream was applied to the wound, and the wound was sealed with plastic wrap to protect it from light for 1 hour. Photodynamic therapy was then administered with a light energy density of 120J / cm². 2 Power density 20mW / cm³ 2Groups 9-16 were the solubilizing BODIPY gel groups (A9, A10, A13, A14, A15, A16, A27, A28), where approximately 0.2g of gel was applied to the wound. Other treatment methods and light exposure parameters were the same as in Group 1. Group 17 was the control group and received no treatment.

[0070] 5. Evaluation of therapeutic effect: From the date of preparation of the skin wound infection model, the wound was photographed on days 0, 6 and 12. The wound area was calculated using measurement software, and the relative wound area was calculated.

[0071] Relative wound area = Wound area on the day of measurement / Wound area on day 0 × 100%

[0072] 6. Experimental Results: As shown in Figures 1 and 2, on postoperative day 6, the wound areas of all BODIPY composition cream groups (A9, A10, A13, A14, A15, A16, A27, A28) were significantly smaller than those of the corresponding solubilized BODIPY gel groups and the blank control group. By postoperative day 12, the wounds of mice in the BODIPY composition cream group had completely healed, and the wound healing rate was much faster than that of the corresponding solubilized BODIPY gel groups and the blank control group. The relative wound area data also verified this result (Figure 3).

[0073] 7. Conclusion: The BODIPY composition cream, with its higher singlet oxygen efficiency, has a better photodynamic effect and exhibits higher antibacterial efficacy and skin healing rate than the solubilized BODIPY gel.

[0074] To further demonstrate the practical application value of the present invention, the following embodiments are provided:

[0075] Example 85. BODIPY Composition Cream for the Treatment of Periungual Warts / Flat Warts / Plane Warts

[0076] 1. Therapeutic drugs: The preparation methods of BODIPY composition creams (A9, A10, A13, A15) are as described in Examples 9, 10, 13, and 15. The content of BODIPY photosensitizer in the cream is 0.5%.

[0077] 2. Seeking patients aged 18-70 with periungual warts / flat warts / plantar warts: gender not limited, size and number of warts not limited.

[0078] Inclusion criteria: Patients must meet all of the following inclusion criteria to be eligible for enrollment:

[0079] (1) Sign an informed consent form before the clinical study and fully understand the content, process and possible adverse reactions of the clinical study;

[0080] (2) Patients with periungual warts / flat warts / plantar warts who have been clinically diagnosed and have undergone HPV genotyping;

[0081] (3) Patients who have not received local or systemic treatment within 3 months for HPV-related warts.

[0082] 3. Experimental methods:

[0083] After removing the main visible warts with combined laser treatment, BODIPY compound cream (concentration 0.5%) was applied to the affected area and a 1cm radius around it, with a thickness of 1mm and a dosage of 0.5 FTU. The LED lamp (wavelength 530nm) had an energy density of 120 J / cm³. 2 Power density 100mW / cm³ 2 .

[0084] The evaluation method involved taking photos of the affected area with a camera or dermoscope before the first treatment, before each subsequent treatment, and during the follow-up period. Pain scores were calculated during each treatment, and the treatment effect and side effects were assessed before each subsequent treatment.

[0085] 4. Results:

[0086] Seven subjects actually completed the task.

[0087] Case 1: Female, multiple plantar warts on the sole of the foot. After laser removal of the main warts on day 0, photodynamic therapy was performed three times on days 0, 8, and 17 using BODIPY combination cream A9. No recurrence was observed at the 184-day follow-up (see Figure 4).

[0088] Case 2: Female, periungual warts. After laser removal of the main warts on day 0, she underwent four photodynamic therapy sessions on days 0, 4, 8, and 13 using BODIPY combination cream A10. No recurrence was observed on day 103 (see attached Figure 5).

[0089] Case 3: Female, periungual warts. After laser removal of the main warts on day 0, she underwent six photodynamic therapy sessions using BODIPY cream A13 on days 0, 1, 2, 3, 6, and 7. No recurrence was observed on day 104 (see attached Figure 6).

[0090] Case 4: Male, plantar warts. Not obvious to the naked eye, but keratinized material and black hemorrhages were visible under a dermoscope (caused by prolonged pressure after rupture of small blood vessels in the dermal papillae). After laser removal of the main warts on day 0, six photodynamic therapy sessions were performed on days 0, 1, 2, 3, 6, and 7 using the BODIPY combination cream A15. No recurrence was observed at day 64 (see attached Figure 7).

[0091] Case 5: Female, plantar warts. Not obvious to the naked eye, but keratinized tissue and bleeding points were visible under a dermoscope. After laser removal of the main warts on day 0, six photodynamic therapy sessions were performed on days 0, 1, 3, 4, 5, and 8 using BODIPY combination cream A15. No recurrence was observed at day 95 (see attached Figure 8).

[0092] Case 6: Female, plantar warts. Not obvious to the naked eye, but bleeding points were visible under a dermoscope. She received four photodynamic therapy sessions using BODIPY combination cream A13 on days 0, 1, 2, and 3. No recurrence was observed at day 110 (see Figure 9).

[0093] Case 7: Female, plantar warts. Not obvious to the naked eye, but bleeding points were visible under a dermoscope. She received three photodynamic therapy sessions using BODIPY combination cream A9 on days 0, 1, and 2 respectively. No recurrence was observed at day 86 (see Figure 10).

[0094] 5. Conclusion: BODIPY composition cream-mediated photodynamic therapy is an effective treatment for periungual warts / flat warts / plantar warts. In clinical practice, ALA photodynamic therapy commonly used can cause pain levels reaching level seven, resulting in poor patient compliance. In contrast, BODIPY composition cream-mediated photodynamic therapy causes pain levels no higher than level three, significantly reducing patient suffering. ALA photodynamic therapy often causes side effects such as redness and swelling at the affected area, thus limiting treatment to once a week and resulting in a treatment course of 3-6 weeks. BODIPY composition cream-mediated photodynamic therapy has no side effects, allowing for flexible treatment plans and significantly shortening the treatment cycle to 3-6 days, demonstrating great potential for clinical application.

[0095] Example 86. BODIPY Composition Cream for the Treatment of Acne

[0096] 1. Therapeutic drugs: The preparation methods of BODIPY composition creams (A9, A10, A13) are as described in Examples 9, 10, and 13. The content of BODIPY photosensitizer in the cream is 0.5%.

[0097] 2. Recruitment of patients aged 18-70: gender not limited.

[0098] Inclusion criteria: Patients must meet all of the following inclusion criteria to be eligible for enrollment:

[0099] (1) Sign an informed consent form before the clinical study and fully understand the content, process and possible adverse reactions of the clinical study;

[0100] (2) Patients who have not received local or systemic treatment for acne within the past 3 months.

[0101] 3. Experimental methods:

[0102] After cleansing the entire face, use a fire needle to prick the acne nodules, apply BODIPY cream, and occlude the area in the dark for 1 hour. Irradiate with an LED lamp (wavelength 530nm) for 0.5 hours, with an energy density of 36J / cm³. 2 Power density 20mW / cm³ 2 The patient received five treatments in total, once a week.

[0103] 4. Results: Six subjects actually completed the treatment (cases 8-13). After five photodynamic therapy sessions with BODIPY combination cream (three cases A9, two cases A10, and one case A13), the patients' acne nodules basically disappeared, as shown in Figures 11-16.

[0104] 5. Conclusion: BODIPY composition cream-mediated photodynamic therapy is highly effective in treating acne, especially severe acne. During ALA photodynamic therapy, patients commonly experience burning, electric shock, and tingling sensations, with approximately 16-20% experiencing severe pain. Pain is a major factor hindering ALA photodynamic therapy for acne, and patients often experience facial redness and swelling after treatment, requiring prolonged sun avoidance. In contrast, according to patient feedback, BODIPY composition cream-mediated photodynamic therapy is virtually painless and has no side effects, thus possessing significant clinical application potential.

[0105] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A BODIPY-type photosensitizer composition for photodynamic therapy, characterized in that, This includes BODIPY-type photosensitizers or aza-BODIPY-type photosensitizers, as well as oily matrices.

2. The BODIPY-type photosensitizer composition for photodynamic therapy according to claim 1, characterized in that, By mass fraction, it includes 0.001-10 parts of BODIPY-type photosensitizer compounds and 90-99.999 parts of oily matrix.

3. The BODIPY-type photosensitizer composition for photodynamic therapy according to claim 1, characterized in that, The BODIPY-type photosensitizer compounds are compounds with structures as shown in general formulas (I) and (II): or its derivatives; wherein: X is selected from I and Br; R1 is selected from H, CH3, C6H5, C6H4OCH3, CH=CH~C6H5, CH=CH~C6H4OCH3; R2 is selected from H, CH3, C6H5, C6H4OCH3, CH=CH~C6H5, CH=CH~C6H 5～n (OCH3) n Where n = 1 to 3; R3 is selected from R4 is selected from H and C. n H 2n+1 Where n = 1 to 40, C6F5, C6H 5～n (CH3) n Where n = 1 to 3, C6H4OH, C6H 5～n (OCH3) n , where n=1~3, C6H4CN, C6H4CF3, C6H4NO2, C6H4NH2, C6H4N(CH3)2, C5H4N, C5H4NCH3I, CH=CH~C6H5, CH=CH~C6H4OCH3.

4. The BODIPY-type photosensitizer compound for photodynamic therapy according to claim 3, characterized in that, The derivative is at least one of hydrate, salt, complex, chelate, and ester.

5. The BODIPY-type photosensitizer composition for photodynamic therapy according to claim 1, characterized in that, The BODIPY-type photosensitizer compounds are those with molecular formulas A1 to A28: At least one of them.

6. The BODIPY-type photosensitizer composition for photodynamic therapy according to claim 1, characterized in that, The oily matrix includes sesame oil, soybean oil, peanut oil, olive oil; hydrocarbons such as petrolatum, liquid paraffin, solid paraffin, microcrystalline wax, and ceresin; lipids such as lanolin, beeswax, and cetearyl wax; and synthetic or semi-synthetic oily matrices such as squalane, silicone, fatty acids, fatty alcohols, and lanolin derivatives.

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