BODIPY photosensitizer composition for photodynamic therapy

Abstract

The invention belongs to the technical field of dermatological disease treatment medicines, and relates to a BODIPY photosensitizer composition for photodynamic therapy, which comprises a BODIPY photosensitizer or an aza-BODIPY photosensitizer and a greasy matrix. The device has the beneficial effects that the device has relatively high singlet oxygen generation efficiency; the fat-soluble BODIPY compound is directly used, modification and modification are not needed, and nanocrystallization or micellization is not needed. The composition and the preparation thereof are simple in preparation process, do not need special equipment, and are convenient for mass production and clinical transformation. The traditional Chinese medicine composition can be conveniently prepared into various external preparations, can be smeared like cosmetics, has strong affinity to skin, and is convenient to meet the treatment requirements of different skin diseases. And the comfort and the compliance of the patient are improved. The composition has the advantages of high efficiency, broad spectrum, no toxicity and no drug resistance, and effectively widens the indication range of PDT.

Description

Technical Field

[0001] The present invention belongs to the technical field of drugs for treating dermatological diseases and relates to a BODIPY photosensitizer composition for photodynamic therapy. Background Art

[0002] Photodynamic therapy, abbreviated as PDT (Photodynamic therapy), involves three elements: a photosensitizer, light irradiation, and molecular oxygen. Among them, the role of the photosensitizer is to interact with molecular oxygen under light excitation to generate singlet oxygen ( 1 O 2 ). 1 O 2 is an excited-state molecular oxygen with extremely strong oxidation ability, which easily reacts with various biological components (proteins, amino acids, nucleic acids, etc.), leading to lipid peroxidation, damage to cell membranes and organelles, thereby killing pathogenic microorganisms or diseased cells to achieve the purpose of treatment. Therefore, a highly efficient and safe photosensitizer is the key and core of PDT. The basic requirements for it are: ① single component and clear structure; ② high singlet oxygen generation efficiency; ③ fast excretion, low toxicity and side effects, and short light avoidance time. ④ Convenient for formulation and administration.

[0003] Boron-dipyrromethene (BODIPY) compounds are photosensitizers with application potential. BODIPY fixes two pyrrole rings on a plane through a boron bridge bond and a methine bridge bond to form a rigid coplanar molecular structure. When the C atom at the 8th position of BODIPY is replaced by N, it is aza-BODIPY. The basic skeleton structure is as follows:

[0004] BODIPY photosensitizers: aza~BODIPY photosensitizers:

[0005]

[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 taken: (1) Modify water - soluble groups on the BODIPY molecule or attach PEG. This chemical modification increases the amphiphilicity of the product, but it is not yet water - soluble. (2) Adopt methods of encapsulation, micellization, and microencapsulation to achieve the dispersion of BODIPY in an organic matrix, forming micelles or microcapsules at the nanoscale, and then dispersing or suspending them in water. (3) Adopt the method of nano - self - assembly to directly prepare BODIPY nanocrystals or nanoparticles to achieve solubilization in an aqueous system. The improvement methods reported in the above - mentioned literature and patents, some require ingenious molecular structure design and complex and cumbersome chemical synthesis, and some rely on special photophysical mechanisms, such as specific intra - molecular and inter - molecular charge and energy transfer, aggregation - induced emission or quenching of photosensitizer molecules, etc. Although these improvements have certain effects, the difficulty of industrial production is very high and it is inconvenient for clinical transformation. Chinese Patent 201910794184.6 discloses a method for solubilizing the BODIPY photosensitizer reported in the literature without chemical modification and photophysical modification. The process is relatively simple, but the upper limit of the concentration that can be achieved is not high enough. Moreover, the most critical point is that the singlet oxygen generation efficiency is relatively low, seriously affecting its photodynamic efficacy. So, so far, although a lot of papers have been published and many patents have been applied, there has been no report on the use of BODIPY as a new drug in PDT clinical practice.

[0007] And the photosensitizers used in PDT clinical practice so far are mainly 5 - aminolevulinic acid hydrochloride (5 - ALA, "Aila"). It is a precursor compound of protoporphyrin - IX, with good biocompatibility and water solubility. It can be converted into protoporphyrin - IX under physiological conditions and play the role of a photosensitizer, but it needs to go through a complex physiological process to play its role. Therefore, the concentration used is as high as 20%, and the light intensity is as high as 100 - 120 J / cm 2 , so the cost is very high, the patient compliance is poor, the curative effect is limited, and the indication range is relatively narrow. Therefore, there is an urgent need for a new variety of photosensitizer in clinical PDT treatment that can replace or partially replace "Aila".

[0008] In the experiment, the inventors unexpectedly found that if the lipophilic BODIPY - type photosensitizer is dispersed in a variety of oily matrices to form a BODIPY - type photosensitizer composition, it has an extremely high singlet oxygen generation efficiency. Based on this discovery, the inventors carried out a clinical study on the treatment of skin diseases using such a composition and obtained gratifying results. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the problems that the BODIPY photosensitizers reported in the literature have poor water solubility, the nanometerization process is difficult to industrialize, and the singlet oxygen efficiency of the new solubilized products is relatively low. The "BODIPY photosensitizer composition" is the main means and technical approach to solve this problem.

[0010] The present invention discloses a BODIPY photosensitizer composition, comprising a BODIPY compound and an oily matrix.

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

[0012] Furthermore, the BODIPY photosensitizer compound is a compound having the structures shown in general formulas (I) and (II):

[0013]

[0014] or its derivatives; wherein:

[0015] X is selected from I, Br;

[0016] R 1 is selected from H, CH 3 , C 6 H 5 , C 6 H 4 OCH 3 , CH=CH~C 6 H 5 ,

[0017] CH=CH~C 6 H 4 OCH 3 ;

[0018] R 2 is selected from H, CH 3 , C 6 H 5 , C 6 H 4 OCH 3 , CH=CH~C 6 H 5 ,

[0019] CH=CH~C 6 H 5～n (OCH 3 ) n , where n = 1 - 3;

[0020] R 3 is selected from

[0021] R 4 selected from H, C n H 2n+1 , where n = 1 to 40, C 6 F 5 , C 6 H 5～n (CH 3 ) n , where n = 1 to 3, C 6 H 4 OH, C 6 H 5～n (OCH 3 ) n , where n = 1 to 3, C 6 H 4 CN, C 6 H 4 CF 3 , C 6 H 4 NO 2 , C 6 H 4 NH 2 , C 6 H 4 N(CH 3 ) 2 , C 5 H 4 N, C 5 H 4 NCH 3 I, CH=CH~C 6 H 5 , CH=CH~C 6 H 4 OCH 3 .

[0022] Furthermore, the derivative is at least one of a hydrate, a salt, a complex, a chelate, and an ester.

[0023] Preferably, the BODIPY-based photosensitizer compound is at least one of the compounds represented by Formulas A1 to A28:

[0024]

[0025]

[0026]

[0027] Furthermore, the oily base includes sesame oil, soybean oil, peanut oil, olive oil; hydrocarbons such as petrolatum, liquid paraffin, paraffin wax, microcrystalline wax, ozokerite; lipids such as lanolin, beeswax, spermaceti; synthetic or semi-synthetic oily bases such as squalane, silicone, fatty acids, fatty alcohols, lanolin derivatives.

[0028] The beneficial effects of the present invention are as follows:

[0029] 1. The BODIPY photosensitizer composition of the present invention has a high singlet oxygen generation efficiency, which is much higher than that of the solubilized BODIPY photosensitizer disclosed in Chinese Patent No. 201910794184.6.

[0030] 2. By directly using a lipophilic BODIPY compound without modification, nanosizing or micellization, the preparation process of the composition and its preparation is simple and does not require special equipment, so the manufacturing cost is low, there is no pollution, and it is convenient for mass production and clinical transformation.

[0031] 3. The composition can be conveniently made into various topical preparations, which can be applied like cosmetics, have a strong affinity for the skin, and are convenient for meeting the treatment needs of different skin diseases.

[0032] 4. Due to the high singlet oxygen generation efficiency, only a very low concentration of photosensitizer (0.01 - 0.5%) is required in the preparation, and only a relatively low light energy (10 - 60 J / cm 2 ) is needed during treatment to achieve the therapeutic effect, thereby improving the comfort and compliance of patients.

[0033] 5. Due to the high efficiency, broad spectrum, non-toxicity and non-drug resistance of the BODIPY photosensitizer, the composition and its preparation of the present invention are not only applicable to general infectious skin diseases, but also suitable for special skin diseases such as large-area burns and skin cancer, thus effectively broadening the indication range of PDT. Description of the Drawings

[0034] Figure 1 Efficacy diagram of BODIPY composition cream on a mouse skin wound Staphylococcus aureus infection model

[0035] Figure 2 Efficacy diagram of BODIPY solubilized gel on a mouse skin wound Staphylococcus aureus infection model

[0036] Figure 3 Photodynamic therapy diagram of BODIPY composition cream and BODIPY solubilized gel on a mouse skin wound Staphylococcus aureus infection model (relative wound area on the 6th and 12th days after surgery. C = cream, G = gel)

[0037] Figure 4 Efficacy diagram of BODIPY composition cream A9 on multiple verruca plantaris (Case 1)

[0038] Figure 5 Efficacy diagram of BODIPY composition cream A10 on periungual warts (Case 2)

[0039] Figure 6 Efficacy diagram of BODIPY composition cream A13 on periungual warts (Case 3)

[0040] Figure 7 Efficacy diagram of BODIPY composition cream A15 on verruca plantaris (Case 4)

[0041] Figure 8 Efficacy diagram of BODIPY composition cream A10 on verruca plantaris (Case 5)

[0042] Figure 9 Efficacy diagram of BODIPY composition cream A13 on verruca plantaris (Case 6)

[0043] Figure 10 Efficacy diagram of BODIPY composition cream A9 on verruca plantaris (Case 7)

[0044] Figure 11 Efficacy diagram of BODIPY composition cream A9 on acne (Case 8)

[0045] Figure 12 Efficacy diagram of BODIPY composition cream A10 on acne (Case 9)

[0046] Figure 13 Efficacy diagram of BODIPY composition cream A9 on acne (Case 10)

[0047] Figure 14 Efficacy diagram of BODIPY composition cream A9 on acne (Case 11)

[0048] Figure 15 Efficacy diagram of BODIPY composition cream A13 on acne (Case 12)

[0049] Figure 16 Efficacy diagram of BODIPY composition cream A10 on acne (Case 13) Detailed implementation manners

[0050] The following further describes the detailed implementation manners of the present invention in combination with embodiments. The following embodiments are only used to more clearly illustrate the technical embodiments of the present invention and cannot be used to limit the protection scope of the present invention.

[0051] Embodiments 1 to 56

[0052] Preparation of Cream Using BODIPY Composition

[0053] Prescription 1: 10 mg of BODIPY photosensitizer compound, 17 g of stearic acid, 2 g of lanolin, 10 ml of liquid paraffin, 2 g of triethanolamine, 5 ml of glycerol, 0.1 g of ethylparaben, and distilled water q.s. to 100 g.

[0054] Preparation process: Mix the BODIPY photosensitizer compound, stearic acid, lanolin, and liquid paraffin together, heat to 70 °C in a water bath to uniformly disperse the BODIPY photosensitizer compound in the oily matrix to obtain the drug-loaded oil phase; dissolve ethylparaben in water, then mix it with glycerol and triethanolamine, heat to the same temperature as the oil phase, and then slowly add it to the oil phase while stirring. After adding, let it stand and condense to obtain the product.

[0055] Among them, the BODIPY photosensitizer compound is selected from A1 - A28, corresponding to Examples 1 - 28 respectively.

[0056] Prescription 2: 100 mg of BODIPY photosensitizer compound, 25 g of stearyl alcohol, 25 g of petrolatum, 1 g of sodium lauryl sulfate, 12 g of propylene glycol, 0.025 g of methylparaben, and distilled water q.s. to 100 g.

[0057] Preparation process: Mix the BODIPY photosensitizer compound, stearic acid, and petrolatum together, heat to 70 °C in a water bath to uniformly disperse the BODIPY photosensitizer compound in the oily matrix to obtain the drug-loaded oil phase; dissolve methylparaben, sodium lauryl sulfate, and propylene glycol in water, heat to the same temperature as the oil phase, and then slowly add it to the oil phase while stirring. After adding, let it stand and condense to obtain the product.

[0058] Among them, the BODIPY photosensitizer compound is selected from A1 - A28, corresponding to Examples 29 - 56 respectively.

[0059] Examples 57 - 84

[0060] Preparation of Ointment Using BODIPY Composition

[0061] Prescription: 50 mg of BODIPY photosensitizer compound, 30 g of lanolin, 70 g of petrolatum.

[0062] Heat the BODIPY photosensitizer compound, lanolin, and petrolatum to 70 °C in a water bath, stir to uniformly disperse the BODIPY photosensitizer compound in the oily matrix, and condense to obtain the product.

[0063] Among them, the BODIPY photosensitizer compound is selected from A1 - A28, corresponding to Examples 57 - 84 respectively.

[0064] To further illustrate the beneficial effects of the present invention, the following comparative examples are specifically set up:

[0065] Comparative Example 1

[0066] Comparison of the singlet oxygen generation efficiency of BODIPY compositions and solubilized BODIPY

[0067] 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 from the interaction between the unpaired electrons and the externally applied magnetic field, and it is the most direct technical means for measuring free radicals. The detectable sample states include liquids, solids, powders, etc., and it is very suitable for detecting the singlet oxygen generation efficiency of BODIPY-based photosensitizer compositions in a semi-solid form.

[0068] Specific experimental method: Weigh different types of BODIPY precisely, mix and dissolve them with different types of representative oily matrices to obtain compositions with a BODIPY content of 0.1 mg / g. Among them, petrolatum, paraffin wax, stearic acid, lanolin, etc. need to be pre-heated and then mixed and dissolved with BODIPY. Use the ESR method to detect the singlet oxygen generation efficiency of each sample. Select TMP (2,2,6,6-tetramethyl-1-piperidine) as 1 O 2 the scavenger, uniformly mix it in the sample to be tested, and perform an ESR test after irradiating the sample cell with 300 W xenon lamp light for 10 minutes. TMP captures 1 O 2 and generates the nitroxide radical NO·, producing an ESR signal, as shown in the appendix Figure 2 . The peak height of the ESR is proportional to the amount of 1 O 2 captured. Therefore, take the average value of the positive and negative peak top distances of three peaks as the semi-quantitative index of the singlet oxygen generation efficiency.

[0069] Solubilized BODIPY was selected as the control sample, and the test concentration was also 0.1 mg / g. In order to make the physical forms of the BODIPY composition and solubilized BODIPY as consistent as possible and reduce measurement errors, solubilized BODIPY was in the form of a gel preparation and also in a semi-solid form. The preparation method of the solubilized BODIPY gel refers to Chinese Patent 201910794184.6. Specifically, 1 mg of BODIPY with different molecular formulas was accurately weighed and dissolved in 0.5 - 2 ml of acetone. Then the acetone solution was dropped into 10 - 100 ml of ultrapure water under stirring, and the mixture was continuously stirred at room temperature for 6 - 8 hours to volatilize acetone, obtaining an aqueous solution of solubilized BODIPY. After adding the freeze-drying protectant mannitol, it was freeze-dried to obtain a freeze-dried powder of solubilized BODIPY. After re-dissolving with ultrapure water, carbomer 943 with a mass percentage of 0.5% was added, and after sufficient swelling, an appropriate amount of triethanolamine was added during stirring, finally obtaining a solubilized BODIPY gel with a BODIPY content of 0.1 mg / g.

[0070] The production of singlet oxygen depends not only on the type and dose of photosensitizer, light dose, but also on the oxygen content of the sample. Therefore, when comparing the production of singlet oxygen, it is necessary to exclude the influence of the oxygen content in different samples on the results. The oxygen content of pure water at 20 °C is about 8.5 μg / g. The water content of the solubilized BODIPY gel used in this experiment is as high as 99.4%, and it can be estimated that the oxygen content of the gel is about 8.45 μg / g. There is currently no report on the oxygen content of vaseline-like semi-solid oily matrices. Oily matrices cannot form hydrogen bonds with oxygen like water to increase solubility. Moreover, vaseline is semi-solid, and the solubility of gas in solids is much lower than that in liquids. Vaseline is a mixture of alkane series hydrocarbons or saturated hydrocarbons and does not contain oxygen elements itself. We tried to use an elemental analyzer to detect the oxygen element content in vaseline and thus calculate the oxygen content. The method was to pyrolyze the sample at 850 °C in a pure helium atmosphere and react with platinum carbon to generate CO, and then through the detection of a thermal conductivity cell, finally calculate the content of oxygen elements. As a result, due to the too low oxygen content, no oxygen elements were detected. Therefore, for the convenience of comparison, we estimated that the oxygen content of vaseline is about 0.1 μg / g. Since the molecular formula of stearic acid is C 18 H 36 O 2 , the main components of lanolin are esters formed by sterols, fatty alcohols and triterpenyl alcohols and approximately equal amounts of fatty acids. The molecular formula of stearyl alcohol is C 18 H 38 O. These three oily matrices themselves contain oxygen elements, so they were not tested by elemental analysis method. We estimated that they are similar to the oxygen content of vaseline and were also assumed to be 0.1 μg / g.

[0071] The ratio of the average peak height of ESR to the oxygen content was used as the final evaluation index. The results showed that the singlet oxygen / oxygen content ratios of the compositions formed by various BODIPYs and various oily matrices were significantly higher than those of the corresponding solubilized BODIPY gels, generally being dozens of times higher, thus proving that BODIPY compositions are more suitable for use in photodynamic therapy than solubilized BODIPYs.

[0072] ESR average peak height / oxygen content

[0073]

[0074]

[0075] Comparative Example 2

[0076] Comparison of the curative effects of BODIPY composition cream and solubilized BODIPY gel in the treatment of Staphylococcus aureus infection in mouse skin wounds

[0077] 1. In this experiment, the curative effects of BODIPY composition cream and solubilized BODIPY gel on the Staphylococcus aureus infection model in mouse skin wounds were investigated and compared.

[0078] Therapeutic drug: The preparation method of the solubilized BODIPY gel was referred to Comparative Example 1. The corresponding types of BODIPY composition creams (A9, A10, A13, A14, A15, A16, A27, A28) were used directly. The drug content of both the gel and the cream was 0.1 mg / g.

[0079] 2. Therapeutic light source: An LED light source was used, and the corresponding wavelength was selected in the visible to near-infrared range (480 - 650 nm) according to the compound type.

[0080] 3. Animal model: KM female mice (12 - 14 weeks old), the back was depilated, and after anesthesia, a wound with an area of about 1 cm 2 was cut on the back with surgical scissors until the depth reached the muscle layer. The overnight-cultured Staphylococcus aureus S. aureus was adjusted to a concentration of 10 8 CFU / ml with physiological saline, and 20 μl of the bacterial solution was dropped onto the wound.

[0081] 4. Treatment method: One day after the animals were infected with bacteria, the experimental animals were divided into 17 groups, with 4 animals in each group. Groups 1 - 8 were the BODIPY composition cream groups (A9, A10, A13, A14, A15, A16, A27, A28). About 0.2 g of the cream was applied to the wound and wrapped with plastic wrap in the dark for 1 hour. Subsequently, photodynamic therapy was carried out, with a light energy density of 120 J / cm 2 , and a power density of 20 mW / cm 2Groups 9 - 16 were the solubilized BODIPY gel groups (A9, A10, A13, A14, A15, A16, A27, A28). Approximately 0.2 g of the gel was applied to the wound, and the remaining treatment methods and light parameters were the same as those in Group 1. Group 17 was the control group, without any treatment.

[0082] 5. Efficacy evaluation: Starting from the day when the skin wound infection model was prepared, the wound was photographed on the 0th, 6th, and 12th days, and the wound area was calculated using measurement software to calculate the relative wound area.

[0083] Relative wound area = wound area on the measurement day / wound area on the 0th day × 100%

[0084] 6. Experimental results: As can be seen from the appendix Figure 1 、 2 On the 6th day after surgery, 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 the 12th day after surgery, the wounds of the mice in the BODIPY composition cream groups had all healed completely, 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 (appendix Figure 3 ).

[0085] 7. Conclusion: The BODIPY composition cream has a more excellent photodynamic effect due to its higher singlet oxygen efficiency, and has higher antibacterial efficacy and skin healing rate compared with the solubilized BODIPY gel.

[0086] To further prove the practical application value of the present invention, the following examples are provided:

[0087] Example 85

[0088] Treatment of periungual warts / flat warts / plantar warts with BODIPY composition cream

[0089] 1. Treatment drug: The preparation methods of the BODIPY composition creams (A9, A10, A13, A15) refer to Examples 9, 10, 13, and 15. The content of the BODIPY photosensitizer in the cream is 0.5%.

[0090] 2. Recruit cases of periungual warts / flat warts / plantar warts aged 18 - 70 years: Gender is not limited, and the size and number of warts are not limited.

[0091] Inclusion criteria: Patients need to meet all of the following inclusion criteria to be included:

[0092] (1) Sign an informed consent form before the clinical study, and fully understand the content, process, and possible adverse reactions of the clinical study;

[0093] (2) Patients with periungual warts / flat warts / plantar warts who are clinically diagnosed and have undergone HPV genotyping detection;

[0094] (3) Patients with HPV viral warts who have not received local or systemic treatment within 3 months.

[0095] 3. Experimental method:

[0096] After removing the main visible warts by combined laser treatment, the BODIPY composition cream (concentration 0.5%) was applied to the affected area and within a 1-cm range around it, with a coating thickness of 1 mm and a dosage of (0.5 FTU). The LED lamp (wavelength 530 nm) had an energy density of 120 J / cm 2 , and a power density of 100 mW / cm 2 .

[0097] The evaluation method was to take photos of the affected area with a camera or dermatoscope before the first treatment, before each subsequent treatment, and during the follow-up period. Pain scores were recorded during each treatment, and the treatment effect and side effects were evaluated before each subsequent treatment.

[0098] 4. Results

[0099] A total of 7 subjects were actually completed.

[0100] Case 1: Female, multiple plantar warts. After removing the main warts by laser on day 0, photodynamic therapy was performed three times with BODIPY composition cream A9 on days 0, 8, and 17. There was no recurrence during the follow-up on day 184. See attachment Figure 4 .

[0101] Case 2: Female, periungual wart. After removing the main wart by laser on day 0, photodynamic therapy was performed four times with BODIPY composition cream A10 on days 0, 4, 8, and 13. There was no recurrence during the follow-up on day 103. See attachment Figure 5 .

[0102] Case 3: Female, periungual wart. After removing the main wart by laser on day 0, photodynamic therapy was performed six times with BODIPY composition cream A13 on days 0, 1, 2, 3, 6, and 7. There was no recurrence during the follow-up on day 104. See attachment Figure 6 .

[0103] Case 4: Male, plantar wart. It was not obvious to the naked eye, but keratinized substances and black bleeding points (caused by long-term compression after rupture of small blood vessels in the dermal papilla) were visible under dermatoscopy. After removing the main wart by laser on day 0, photodynamic therapy was performed six times with BODIPY composition cream A15 on days 0, 1, 2, 3, 6, and 7. There was no recurrence during the follow-up on day 64. See attachment Figure 7 .

[0104] Case 5: Female, verruca plantaris. Not obvious under naked eye observation, horny substances and bleeding points can be seen under dermoscopic observation. After the main verruca was removed by laser on the 0th day, photodynamic therapy was performed six times with BODIPY composition cream A15 on the 0th, 1st, 3rd, 4th, 5th, and 8th days respectively. Follow-up on the 95th day showed no recurrence, see appendix Figure 8 。

[0105] Case 6: Female, verruca plantaris. Not obvious under naked eye observation, bleeding points can be seen under dermoscopic observation. Photodynamic therapy was performed four times with BODIPY composition cream A13 on the 0th, 1st, 2nd, and 3rd days respectively. Follow-up on the 110th day showed no recurrence, see appendix Figure 9 。

[0106] Case 7: Female, verruca plantaris. Not obvious under naked eye observation, bleeding points can be seen under dermoscopic observation. Photodynamic therapy was performed three times with BODIPY composition cream A9 on the 0th, 1st, and 2nd days respectively. Follow-up on the 86th day showed no recurrence, see appendix Figure 10 。

[0107] 5. Conclusion Photodynamic therapy mediated by BODIPY composition cream can effectively treat periungual warts / flat warts / verruca plantaris. During the photodynamic therapy with ALA commonly used clinically, the pain of patients can reach grade 7, and the compliance is poor. While the pain of photodynamic therapy with BODIPY composition cream does not exceed grade 3 at most, greatly reducing the pain of patients. ALA photodynamic therapy often causes side effects such as redness and swelling at the affected area, so it can only be treated once a week, resulting in a whole treatment course that can be as long as 3 - 6 weeks. While BODIPY composition cream photodynamic therapy has no side effects, so the treatment course can be flexibly formulated, greatly shortening the treatment cycle to 3 - 6 days, with great potential for clinical application.

[0108] Example 86

[0109] Treatment of acne with BODIPY composition cream

[0110] 1. Treatment drug: The preparation methods of BODIPY composition creams (A9, A10, A13) refer to Examples 9, 10, and 13. The content of BODIPY photosensitizer in the cream is 0.5%.

[0111] 2. Recruit cases aged 18 - 70 years old: Gender is not limited.

[0112] Inclusion criteria: Patients need to meet all the following inclusion criteria to be included:

[0113] (1) Sign an informed consent form before the clinical study, and fully understand the content, process and possible adverse reactions of the clinical study;

[0114] (2) For acne, patients who have not received local or systemic treatment within 3 months.

[0115] 3. Experimental method:

[0116] After cleaning the entire face, use a fire needle to puncture the acne nodules, apply BODIPY cream, and seal it for 1 hour in the dark. Irradiate with an LED lamp (wavelength 530 nm) for 0.5 hours, with an energy density of 36 J / cm 2 , and a power density of 20 mW / cm 2 . The treatment is carried out five times, once a week.

[0117] 4. Results: A total of 6 subjects (cases 8 - 13) were actually completed. After five times of photodynamic therapy with BODIPY composition cream (three cases of A9, two cases of A10, and one case of A13), the acne nodules of the patients basically disappeared, as shown in the appendix Figures 11 - 16 .

[0118] 5. Conclusion: The photodynamic therapy mediated by BODIPY composition cream can effectively treat acne, especially suitable for severe acne. During the illumination of ALA-PDT, patients generally have a burning sensation, electric shock sensation, and acupuncture-like sensation, and about 16 - 20% of the patients may experience severe pain. The pain is the main factor hindering the treatment of acne by ALA-PDT, and after the treatment, the patients' faces are often swollen and red, and they need to avoid light for a long time. In contrast, according to the feedback of the patients, the photodynamic therapy mediated by BODIPY composition cream has basically no pain and no side effects, so it has great potential for clinical application.

[0119] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A BODIPY photosensitizer composition for photodynamic therapy, characterized in that: It includes a BODIPY type photosensitizer or an aza-BODIPY type photosensitizer, and an oily base.

2. The BODIPY photosensitizer composition for photodynamic therapy according to claim 1, characterized in that: Calculated by mass fraction, the composition comprises 0.001-10 parts of BODIPY photosensitizer compounds and 90-99.999 parts of oily matrix.

3. The BODIPY photosensitizer composition for photodynamic therapy according to claim 1, It is characterized in that The BODIPY type photosensitizer compound is a compound having a structure as shown in general formula (I) and (II): or its derivatives; wherein: X is selected from I, 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, 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 to 3, C6H4CN, C6H4CF3, C6H4NO2, C6H4NH2, C6H4N(CH3)2, C5H4N, C5H4NCH3I, CH=CH~C6H5, CH=CH~C6H4OCH3.

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

5. The BODIPY photosensitizer composition for photodynamic therapy according to claim 1, characterized in that: The BODIPY photosensitizer compound is a compound of formula A1 to A28: At least one of them.

6. The BODIPY 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 vaseline, liquid paraffin, solid paraffin, microcrystalline wax, ozokerite; lipids such as lanolin, beeswax, spermaceti; synthetic or semi-synthetic oily matrix such as squalane, silicone, fatty acid, fatty alcohol, lanolin derivatives.

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