Aminolevulinic acid composition

Abstract

The present invention provides a composition comprising 5-aminolevulinic acid or a salt or ester thereof, comprising: (a) an active ingredient selected from 5-aminolevulinic acid or a salt or ester thereof; and (b) an aqueous carrier comprising an analgesic. The 5-aminolevulinic acid or the salt or ester thereof can be used for photodynamic therapy analgesia for more than 20 minutes, so that the clinical treatment cycle can be covered, the pain feeling after photodynamic therapy can be obviously relieved, the photodynamic therapy receiving time of a patient is prolonged, and the medication compliance of the patient is improved. Moreover, the composition provided by the invention can also improve the condition of tissue edema after photodynamic therapy, improve the skin smoothness after photodynamic therapy and shorten the pigmentation time, and meanwhile, compared with a marketed preparation, the composition has a better effect in the aspect of photodynamic therapy of inflammatory diseases (such as psoriasis or contact dermatitis) or acne and the like, and has a good application prospect. The acceptability of the patient to the photodynamic therapy is further improved; and the application scene of the photodynamic therapy is widened.

Description

Technical Field

[0001] This invention belongs to the fields of human and veterinary drugs or cosmetics, and specifically relates to a composition with 5-aminolevulinic acid or its salt or ester as the active ingredient. Background Technology

[0002] Photodynamic therapy (PDT) is a treatment based on photochemical reactions, consisting of three elements: light at a specific wavelength, oxygen, and a photosensitizer. Since its successful clinical application in 1978, it has received widespread attention. Under photoexcitation, photosensitizer molecules absorb light energy and transfer it to surrounding oxygen, converting it into highly cytotoxic reactive oxygen species, namely singlet oxygen. 1 When the above process occurs within cancer cells, the generated singlet oxygen can oxidize and damage biomolecules such as nucleic acids and proteins within the cancer cells, thereby causing apoptosis and necrosis of the cancer cells.

[0003] Aminolevulinic acid (5-ALA) is a photosensitizing drug currently approved for use in dermatology. It is an intermediate substance produced during the synthesis of heme and does not possess photosensitizing activity itself. ALA-PDT treatment first uses 5-ALA to act on the skin, penetrating into cells and causing the accumulation of the endogenous photosensitizer protoporphyrin IX (PpIX) within the cells. Then, PpIX is excited by light with a wavelength of 600-700 nm, and the energy is transferred to oxygen molecules to form cytotoxic singlet oxygen. Through photochemical and photobiological effects, it causes irreversible photodamage to cells.

[0004] In 1990, Canadian scholar Kennedy first successfully used 5-ALA to treat malignant skin tumors. Currently, 5-ALA is widely used in photodynamic therapy (PDT) for the control and treatment of superficial basal cell carcinoma, superficial squamous cell carcinoma, Bowen's disease, and other malignant tumors. It can also be used to treat actinic keratosis, condyloma acuminata, acne, and other diseases. Clinical trials have found that 5-ALA in PDT can also be used to treat freckles, rough skin, sallow complexion, psoriasis, and scarring. There are even reports that photodynamic therapy is applicable to veterinary applications, such as treating squamous cell carcinoma, transitional cell carcinoma, prostate cancer, cutaneous hemangiomas and angiosarcomas, as well as superficial skin tumors.

[0005] Photodynamic therapy requires frequent administration, and patients with decades of UV damage require repeated treatments to achieve complete clearance. However, the most common adverse reaction to photodynamic therapy is pain during treatment, generally caused by the sudden release of PPIX accumulated under light after photosensitizer encapsulation. Therefore, improving tolerability is crucial, as it improves the patient experience and increases the likelihood of treatment adherence. For example, according to the EU review data (Summary of Product Characteristics) for aminolevulinic acid gel (AMELUZ), which was marketed in the EU in 2011, headaches are common (≥1 / 100 to <1 / 10) when using AMELUZ, while pain (including burning pain) is very common (≥1 / 10).

[0006] Unfortunately, current technology has not effectively solved the problem of severe pain during ALA-PDT treatment.

[0007] According to the FDA drug information leaflet, the marketed AMELUZ gel involves an aqueous carrier containing 5-aminolevulinic acid. Its aqueous carrier BF200 is composed of soybean lecithin, polysorbate 80, caprylic / capric triglyceride, isopropanol, and phosphate buffer.

[0008] The ALA drug (ALA) approved for marketing in my country is a powder form, which requires immediate preparation for clinical administration. This means it must be prepared into three different dosage forms—a solution, cream, and gel—using slightly acidic water for injection, a base cream, and a thermosensitive gel, respectively, making the process inconvenient. Furthermore, the drug's instructions also indicate that adverse reactions during treatment may include pain, burning pain, erythema, swelling, erosion, bleeding, ulceration, and pigmentation.

[0009] In summary, existing technologies have not adequately addressed the severe pain associated with 5-aminolevulinic acid in photodynamic therapy. Summary of the Invention

[0010] To address the severe pain associated with 5-aminolevulinic acid (5-ALA) in photodynamic therapy (PDT), this invention provides a composition containing 5-ALA or its salts or esters. This composition provides pain relief for over 20 minutes during PDT, significantly alleviating pain and improving patient adherence to the treatment. Furthermore, the composition improves post-PDT tissue edema, skin smoothness, and reduces pigmentation time. Compared to commercially available formulations, it demonstrates superior efficacy in treating inflammatory diseases (such as psoriasis or contact dermatitis) and acne, further enhancing patient acceptance and expanding the application scenarios of PDT.

[0011] Therefore, a first aspect of the present invention is to provide a composition comprising:

[0012] (a) An active ingredient selected from 5-aminolevulinic acid or its salts or esters; said salts and esters are selected from hydrochloride, sulfate, nitrate, phosphate, borate, lactate, acetate, succinate, citrate, tartrate, formate, propionate, butyrate, hexanoate, caprylate, ethyl acetate, dodecyl ester, myristate, palmitate, oleate; and

[0013] (b) An aqueous carrier containing an analgesic, wherein the analgesic is a terpene compound, preferably a monoterpene compound, more preferably menthol and its derivatives.

[0014] In a preferred embodiment of the invention, the content of the active ingredient is 0.1% to 20% by weight, or 0.1% to 15% or 0.5% to 15% based on the total weight of the composition;

[0015] In a preferred embodiment of the invention, the analgesic content is 0.1% to 10%, or 0.1% to 5%, or 0.1% to 2%, or 0.1% to 1% based on the total weight of the composition;

[0016] In a preferred embodiment of the invention, the aqueous carrier content is 10% to 90%, or 10% to 80%, or 10% to 70%, or 10% to 60%, or 20% to 90%, or 20% to 80%, or 20% to 70%, or 20% to 60%, or 10% to 50%, or 20% to 50% based on the total weight of the composition.

[0017] In a preferred embodiment of the present invention, the aqueous carrier is nanoparticles with an average diameter ≤300nm, preferably ≤200nm, and more preferably ≤100nm.

[0018] In a preferred embodiment of the present invention, the instrument used for measuring the average diameter of the aqueous carrier can be a Litesizer dynamic light scattering nanoparticle size analyzer. TM The 500 can determine particle size, zeta potential, and molecular weight by measuring dynamic light scattering (DLS), electrophoretic light scattering (ELS), and static light scattering (SLS). The specific method of use is to pipette 1 mL of the test solution into a cuvette, place it in the device, repeat the measurement three times, and calculate the average particle size and PDI value.

[0019] The PDI value is the Polydispersity Index, an important parameter characterizing the uniformity of particle size distribution. It measures the deviation between the actual particle size distribution and the ideal monodisperse system (i.e., all particles are the same size). The PDI value is usually measured by dynamic light scattering (DLS) and reflects the breadth and uniformity of the particle size distribution.

[0020] In a preferred embodiment of the present invention, the analgesic is a terpenoid compound, preferably a monoterpenoid compound, and more preferably menthol and its derivatives.

[0021] Menthol (MT), also known as peppermint, is chemically named 5-methyl-2-isopropyl-cyclohexanol and is the main component of peppermint oil. MT (C 10 H 20 O, MW 156.27) has a cyclic terpene structure with three chiral carbon atoms on the cyclohexanol, so it has four pairs of optical isomers, including: (+)- and (-)-menthol, (+)- and (-)-neomenthol, (+)- and (-)-isomenthol, and (+)- and (-)-isoneomenthol.

[0022] In a preferred embodiment of the invention, the menthol is preferably L-menthol; the menthol derivative is preferably an L-menthol derivative, and particularly preferably a derivative of the general formula.

[0023] Specifically, the L-menthol derivative can be a menthol ester derivative formed by linking menthol with a saturated straight-chain fatty acid via ester bonds, such as at least one of the following: menthol acetate (M-ACE), menthol propionate (M-PRO), menthol butyrate (M-BUT), menthol valerate (M-PEN), menthol hexanoate (M-HEX), menthol heptanoate (M-HEP), menthol caprylate (M-OCT), menthol nonanoate (M-NON), menthol decanoate (M-DEC), menthol dodecanoate (M-DOD), menthol tetradecanoate (M-TET), menthol hexadecanoate (M-PAL), menthol stearate (M-STE), menthol oleate (M-OA), and menthol cinnamate (M-CA).

[0024] In a preferred embodiment of the present invention, the aqueous carrier further contains an emulsifier and a co-emulsifier.

[0025] In a preferred embodiment of the present invention, the emulsifier comprises phospholipid emulsifiers and non-phospholipid emulsifiers.

[0026] In a preferred embodiment of the present invention, the phospholipid emulsifier is selected from at least one of soybean phospholipid, egg lecithin, hydrogenated soybean lecithin, hydrogenated egg lecithin, soybean phosphatidylcholine, and egg lecithin, preferably soybean phospholipid.

[0027] In a preferred embodiment of the present invention, the nonphospholipid emulsifier is nonionic and is selected from at least one of vitamin E polyethylene glycol derivatives, polysorbate, and poloxamer, preferably at least one of vitamin E polyethylene glycol succinate, polysorbate 20 (Tween 20), and poloxamer 407.

[0028] In a preferred embodiment of the invention, the emulsifier content is 0.1% to 10%, or 0.5% to 10%, or 0.5% to 5%, or 1% to 5% based on the total weight of the composition.

[0029] In a preferred embodiment of the present invention, the co-emulsifier is selected from at least one of monohydric alcohols and polyhydric alcohols, wherein the monohydric alcohol is a lower alkanol selected from at least one of methanol, ethanol, n-propanol, and isopropanol, preferably at least one of ethanol and isopropanol; and the polyhydric alcohol is selected from at least one of ethylene glycol, propylene glycol, and glycerol, preferably propylene glycol.

[0030] The content of the co-emulsifier is 0.1% to 10%, or 0.5% to 10%, or 0.5% to 5%, or 1% to 5% based on the total weight of the composition.

[0031] In a preferred embodiment of the present invention, the aqueous carrier further contains pharmaceutically common excipients, including at least one selected from pH adjusters, solubilizers, antioxidants, chelating agents, preservatives, and viscosity modifiers.

[0032] In a preferred embodiment of the present invention, the pH adjuster is selected from at least one of acetic acid, adipic acid, ammonium carbonate, ammonium hydroxide, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium propionate, succinic acid, sulfuric acid, tartaric acid, triethylamine, triethanolamine, tromethamine, and meglumine; preferably at least one of acetic acid, citric acid, diethanolamine, fumaric acid, malic acid, propionic acid, potassium acetate, potassium citrate, sodium acetate, sodium citrate, sodium glycolate, sodium lactate, sodium propionate, succinic acid, tartaric acid, triethylamine, triethanolamine, tromethamine, and meglumine; more preferably at least one of acetic acid, citric acid, diethanolamine, potassium acetate, potassium citrate, sodium acetate, sodium citrate, sodium glycolate, triethylamine, triethanolamine, tromethamine, and meglumine.

[0033] In a preferred embodiment of the invention, the pH adjuster is present in an amount of 0.1% to 10% by weight, or 0.1% to 5%, or 0.1% to 2%, or 0.1% to 1%, more specifically preferably 1% or 0.6%, based on the total weight of the composition.

[0034] Alternatively, in a preferred embodiment of the invention, the content of the pH adjuster is limited to the final pH value of the composition, which is 2-7, or 2-6, or 3-7, or 3-6, or 2-5, or 3-5, or 2-4, or 3-4.

[0035] In a preferred embodiment of the present invention, the solubilizer is selected from at least one of povidone (preferably K30 or K15), dextran (40 or 70), cyclodextrin and its derivatives, hydroxypropyl-β-cyclodextrin, poloxamers, polysorbates, and Spans, preferably hydroxypropyl-β-cyclodextrin.

[0036] In a preferred embodiment of the present invention, the antioxidant may be at least one selected from α-tocopherol succinate, ascorbate palmitate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0037] In a preferred embodiment of the present invention, the preservative may be at least one of phenoxyethanol, chlorphenesin, methylparaben, and p-hydroxyacetophenone, preferably phenoxyethanol.

[0038] A second aspect of the present invention is to provide the use of any of the above compositions in the preparation of a pharmaceutical formulation, said pharmaceutical formulation being in liquid or semi-solid form, said liquid being selected from solutions, sprays, aerosols, emulsions or lotions; said semi-solid being selected from ointments, creams, gels, lotions, foams, pastes and / or suspensions.

[0039] A third aspect of the present invention is to provide a 5-aminolevulinic acid gelling agent comprising any of the above-described compositions and further comprising a gel matrix.

[0040] In a preferred embodiment of the present invention, the gel matrix is ​​selected from at least one of glycerol, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose and carbomer; preferably at least one of carbomer and xanthan gum; more preferably xanthan gum.

[0041] In a preferred embodiment of the invention, the gel matrix content is 0.1% to 5% by weight based on the total weight of the gelling agent.

[0042] In a preferred embodiment of the present invention, the method for preparing the 5-aminolevulinic acid gel agent includes the following steps:

[0043] Preparation of aqueous carrier: (1) Weigh the prescribed amount of monohydric alcohol, phospholipid emulsifier, and analgesic and stir and mix them evenly at 40℃-50℃; (2) Add polyhydric alcohol, non-phospholipid emulsifier, and solubilizer (if added) and continue to stir evenly while keeping warm; (3) Add solvent and stir, and cool to room temperature to obtain aqueous carrier.

[0044] Preparation of gel matrix: Heat pure water to 30°C, add xanthan gum in small batches, stir evenly, and cool to room temperature to obtain gel matrix;

[0045] Preparation of gel: Add the prescribed amount of 5-aminolevulinic acid or its salt or ester, aqueous carrier, and pH adjuster to the gel matrix, and stir evenly at room temperature to obtain the gel.

[0046] A fourth aspect of the present invention is to provide a 5-aminolevulinic acid foaming agent, which contains any of the above-described compositions, and further contains a gelling agent and a foam skeleton.

[0047] In a preferred embodiment of the present invention, the gelling agent is selected from at least one of glycerol, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose and carbomer; preferably at least one of carbomer and xanthan gum; more preferably xanthan gum;

[0048] In a preferred embodiment of the invention, the gelling agent content is 0.1% to 5% by weight based on the total weight of the foaming agent;

[0049] In a preferred embodiment of the present invention, the foam skeleton is selected from at least one of cetyl alcohol, stearyl alcohol, arachidyl alcohol, stearic acid, arachidic acid and oleyl alcohol, preferably cetyl alcohol and / or stearyl alcohol.

[0050] In a preferred embodiment of the invention, the foam skeleton content is 0.1% to 15% by weight based on the total weight of the foaming agent.

[0051] In a preferred embodiment of the invention, the foaming agent further contains a propellant, which is a hydrocarbon gas or a hydrofluoroalkane liquefied gas, wherein the hydrocarbon gas is selected from at least one of propane, butane, and isobutane and mixtures thereof, and the hydrofluoroalkane liquefied gas is selected from at least one of tetrafluoroethane, heptafluoropropane, and dimethyl ether.

[0052] In a preferred embodiment of the present invention, the propellant content is 1% to 15% of the total mass of the foaming agent.

[0053] The fifth aspect of the invention is the use of any of the above-described compositions, gels, or foams in the production of a medicament for photodynamic therapy.

[0054] The sixth aspect of the present invention is to provide any of the above-described compositions, gels, or foams for cosmetic use as an anti-aging agent.

[0055] A seventh aspect of the present invention is to provide the use of any of the above-described compositions, gels, or foams for the production of a medicament for the treatment of any one of viral diseases, dermatological diseases, or tumor diseases.

[0056] In a preferred embodiment of the present invention, the viral disease is caused by human papillomavirus.

[0057] In a preferred embodiment of the present invention, the viral disease is condyloma acuminata.

[0058] In a preferred embodiment of the present invention, the dermatological disease is any one of keratosis, acne, photoaging, psoriasis, scarring, or vitiligo.

[0059] In a preferred embodiment of the present invention, the tumor disease is any one of esophageal cancer, lung cancer, brain tumor, head and neck tumor, eye tumor, pharyngeal cancer, chest wall tumor, breast cancer, pleural mesothelioma, abdominal sarcoma, bladder cancer, gynecological tumor, rectal cancer, Kaposi's sarcoma, and skin cancer. Attached Figure Description

[0060] Figure 1 Effects of each group of drugs on the weight of rabbit ear tissue

[0061] Figure 2 Data on hair follicle area in each group of drugs

[0062] Figure 3 Data on papule reduction in each drug group Detailed Implementation

[0063] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0064] Experimental materials and equipment

[0065]

[0066] Equipment Name Equipment Model Manufacturer Electronic balance MS4002TS / 02 Mettler Electronic balance MS204TS / 02 Mettler pH meter FE28 Mettler Particle size analyzer LITES AntonPaar

[0067] Example 1: Screening of aqueous carrier emulsifiers

[0068] This embodiment explored different combinations of emulsifiers or co-emulsifiers, and suitable emulsifiers or co-emulsifiers were selected by testing average particle size, average PDI, and appearance. The information on the screened components is shown in Tables 1 and 2. The preparation process is as follows:

[0069] ① Weigh soybean lecithin, emulsifier, menthol, and hydroxypropyl β-cyclodextrin at 45℃, stir and mix, then add non-phospholipid emulsifier and phenoxyethanol, stir evenly, and slowly add pure water (keeping the temperature at 45℃) to obtain sample a.

[0070] ②Add API and sodium dihydrogen phosphate monohydrate to pure water and stir to dissolve. Then add to a to obtain the final product.

[0071] Table 1

[0072]

[0073] Table 2

[0074]

[0075]

[0076] The aqueous carriers prepared according to the components in Tables 1 and 2 were analyzed using a Littizer dynamic light scattering nanoparticle size analyzer. TM To measure particle size, use a pipette to transfer 1 mL of the test solution into a cuvette, place it in the device, and repeat the measurement three times. Calculate the average particle size and average PDI, and observe the appearance.

[0077] Table 3

[0078]

[0079] Table 4

[0080]

[0081]

[0082] The results are shown in Tables 3 and 4. When the non-phospholipid emulsifiers are selected from vitamin E polyethylene glycol succinate (TPGS), polysorbate 20 (Tween 20), and poloxamer 407, they can all form aqueous carriers well. The co-emulsifiers selected from ethanol + propylene glycol and ethanol + isopropanol can also form aqueous carriers.

[0083] Example 2: Preparation of an aqueous carrier containing menthyl acetate and menthyl lactate

[0084] Based on the S-241101 component in Example 1, an aqueous carrier containing menthyl acetate and menthyl lactate was prepared. The component information is shown in Table 5. The preparation method is the same as in Example 1.

[0085] Table 5

[0086]

[0087] Similarly, the aqueous carriers prepared according to the components in Table 5 were analyzed using a Litesizer dynamic light scattering nanoparticle size analyzer. TM To measure the particle size, use a pipette to transfer 1 mL of the test solution into a cuvette, place it in the device, and repeat the measurement three times. Calculate the average particle size and average PDI, and observe the appearance. The results are shown in Table 6.

[0088] Table 6

[0089]

[0090] Replacing L-menthol in the aqueous carrier of the present invention with menthol derivatives, such as menthol acetate and / or menthol lactate derivatives, can form an aqueous carrier with good particle size.

[0091] Example 3: Preparation of gelling agents with different components

[0092] Based on component S-241101 in Example 1, gelling agents with different components were prepared. The component information is shown in Table 7, and the preparation process is as follows:

[0093] ① Weigh anhydrous ethanol, soybean lecithin, and menthol in the prescribed proportions and mix them at 45°C. Then add propylene glycol, TPGS, and phenoxyethanol in sequence and continue to keep warm and mix until homogeneous. Add about 25% pure water and stir. Let it cool to room temperature to obtain an aqueous carrier.

[0094] ② Sodium benzoate is added to pure water, stirred and dissolved, heated to 30°C, xanthan gum is added in small batches, stirred evenly, and cooled to room temperature to form a gel matrix;

[0095] ③ Add the prescribed amount of API, aqueous carrier, and triethanolamine to the gel matrix and stir evenly at room temperature to obtain the final product.

[0096] ④ Nitrogen filling.

[0097] Table 7

[0098]

[0099]

[0100] Example 4: Preparation of foaming agents with different components

[0101] Based on component S-241101 in Example 1, foaming agents with different components were prepared. The component information is shown in Table 8. The preparation process is as follows:

[0102] ① Alcohol phase: Weigh the prescribed amounts of anhydrous ethanol, propylene glycol, soybean lecithin, TPGS, phenoxyethanol, octadecyl alcohol, and cetyl alcohol in sequence, stir and mix them evenly at 60℃ until clear, cool to room temperature and add menthol.

[0103] ② Aqueous phase: Weigh out pure water, sodium citrate, and xanthan gum, add the active ingredient, and stir well;

[0104] ③ Add the aqueous phase to the alcohol phase and stir until homogeneous to obtain the drug solution.

[0105] ④ Filling and filling: Fill the aerosol can with the liquid medicine, cap it, and fill it with propellant according to the weight ratio of liquid medicine to propellant of 100:8.

[0106] Table 8

[0107]

[0108] Example 5: Animal Experiment

[0109] I. Materials and Methods

[0110] New Zealand rabbit (weight: 2.0kg-2.5kg), manufacturer: Hunan Taiping Biotechnology Co., Ltd., license number: NO.43073231100288236, feeding conditions (ordinary maintenance feed, temperature 20℃~26℃, humidity 40%~70%).

[0111] Main experimental materials

[0112]

[0113] Main instruments and equipment

[0114] Experimental instruments model factory pipette 100-1000μl Eppendorf AG (Germany) pipette 20-200μl Eppendorf AG (Germany) pipette 5-50μl Eppendorf AG (Germany) Fully automated microplate reader WD-2102B Beijing Liuyi Biotechnology Co., Ltd. Refrigerated and frozen boxes BD / BC-415DKEM Midea Group Co., Ltd. Electric thermostatic incubator DHP-9054 Shandong Boke Biotechnology Co., Ltd. Medicine refrigeration cabinet BYC-310 Shandong Boke Biotechnology Co., Ltd. Upright white light photographic microscope CX43 Olympus Corporation of Japan slicer 2235 Leica Instruments GmbH, Germany Electric constant temperature drying oven HGZF-101-1 Shanghai Yuejin Medical Devices Co., Ltd. Infrared phototherapy device YCGL-6602 Xuzhou Yachuang Biotechnology Co., Ltd. Electronic balance WTC10002 Hangzhou Wante Weighing Instrument centrifuge TD4C Jiangsu High-Tech

[0115] Sample solution preparation

[0116] Preparation of 2% coal tar solution: Take 49 mL of corn oil and 1 mL of coal tar (manufacturer: Nanchang Kemakai Technology Co., Ltd., batch number: DW00575), and shake thoroughly to mix.

[0117] Columbia blood agar plates: Dissolve 3.9g of Columbia blood agar base in 100mL of distilled water, autoclave at 121℃ for 20min, cool to 50℃-55℃, add 5mL of sterile defibrinated sheep blood, mix well, and pour into plates for later use.

[0118] BHI liquid culture medium: Dissolve 3.85g BHI in 100mL distilled water, autoclave at 121℃ for 20min, cool and store in a refrigerator for later use.

[0119] Preparation of ALA Gel Emulsion: Due to the poor photostability of aminolevulinic acid, ALA gel emulsion must be prepared and used immediately to ensure its effectiveness. For each treatment, ALA gel should be freshly prepared and stored at 2℃-8℃, protected from light, for no more than 4 hours. Before use, dissolve 118mg / vial in 0.262g of purified water in the ALA topical cyclophosphamide vial, then add 0.800g of blank gel (xanthan gum 1.7%; sodium benzoate 0.2%; purified water 98.1%; batch number S-230901), and stir thoroughly. The resulting gel percentage is: 0.118g / (0.118+0.262+0.800)g = 10%.

[0120] Modeling (Preparation of animal models of acne):

[0121] The animals arrived on August 28, 2023. After 7 days of acclimatization, modeling of G1, G2, and G3 animals was carried out on September 4, 2023; modeling of G4 animals was carried out on September 6; modeling of G5 animals was carried out on September 8; modeling of G6 animals was carried out on September 10; modeling of G7 animals was carried out on September 18; and modeling of G8 animals was carried out on September 20.

[0122] Before modeling, the initial body weight was measured. Normal controls received no treatment. For other model animals, 0.5-1 ml of 2% coal tar was applied to the inner side of the right ear once daily. *Propionibacterium acnes* was directly inoculated onto *Clostridium perfringens* culture medium, placed in an anaerobic bag, and incubated at 37°C for 48 hours. The *Propionibacterium acnes* population was then adjusted to 6 × 10⁻⁶ using physiological saline. 8 / mL, for later use. Starting on day 8, inject Propionibacterium acnes (6×10⁶) intradermally into the ear skin of the model rabbits. 8 The injection is administered every other day (8 sites per injection, 30-40 μL per site), for a total of 6 injections.

[0123] Animal grouping

[0124] 1) Normal control group (no intervention) (N=8)

[0125] 2) Acne model (no intervention) (N=8)

[0126] 3) Acne model + phototherapy group (phototherapy only, single drug administration, observation for 1 week) (N=8)

[0127] 4) Acne model + blank preparation phototherapy group (blank preparation combined with photodynamic therapy, single dose: 0.4 mL / animal, topical application, single administration, observation for 1 week) (N=8 animals)

[0128] 5) Acne model + AMELUZ gel phototherapy group (AMELUZ gel combined with photodynamic therapy, dosage: 0.4 mL / animal, applied topically, single administration, observed for 1 week) (N=8 animals)

[0129] 6) Acne model + ALA phototherapy group (ALA topical powder combined with photodynamic therapy, dosage: 0.4 mL / animal topical application, single administration, observation for 1 week) (N=8 ani)

[0130] 7) Acne model + 10% gel phototherapy group (10% gel combined with photodynamic therapy, dosage: 0.4 mL / animal, applied topically, single administration, observed for 1 week) (N=8 ani)

[0131] 8) Acne model + 5% gel phototherapy group (5% gel combined with photodynamic therapy, dosage: 0.4 mL / animal, applied topically, single administration, observed for 1 week) (N=8 ani)

[0132] 9) Acne model + 5% foaming agent phototherapy group (5% foaming agent combined with photodynamic therapy, dosage: 0.4 mL / animal, applied topically, single administration, observed for 1 week) (N=8 ani)

[0133] 10) Acne model + 2.5% foaming agent phototherapy group (2.5% foaming agent combined with photodynamic therapy, dosage: 0.4 mL / animal, applied topically, single administration, observed for 1 week) (N=8 ani)

[0134] Animal drug administration

[0135] Experimental environment: Temperature 20℃-26℃, humidity 40%-70%.

[0136] On day 19 of modeling, the animals in each group were photographed with a day 0 score. According to the inclusion score criteria, 8 animals were selected from each group to start treatment. The corresponding drug was applied to the modeling site of the right ear, 0.4 mL / animal. After application, the drug application site was wrapped with a black plastic bag and kept in the dark for 4 hours. The black plastic bag was then removed, and the drug application site was irradiated with an infrared phototherapy device for 20 minutes.

[0137] 1. Observation of light conditions in rabbits after drug administration

[0138] The experiment observed whether the rabbits experienced pain and head retraction after receiving the corresponding medication during the 20-minute phototherapy period. The specific details are shown in Table 9.

[0139] Table 9

[0140]

[0141]

[0142] Note: × indicates no response, √ indicates a response.

[0143] As shown in the table, no pain response was observed in the normal control group, acne model group, acne model + phototherapy group, and acne model + blank preparation + phototherapy group during the 20-minute photodynamic therapy. The acne model + AMELUZ + phototherapy group showed significant pain symptoms, with only one animal showing no pain. The acne model + ALA + phototherapy group also showed relatively significant pain symptoms, with only two animals showing no pain. All four groups of animals using the gel and foam agent provided by this invention did not experience pain, significantly alleviating pain after photodynamic therapy and keeping the treated animals calm, allowing them to continue treatment without forced immobilization. Furthermore, the gel and foam agent provided by this invention are more convenient to use than ALA, which requires immediate preparation.

[0144] 2. Observation of general symptoms in rabbit ears

[0145] In the above-mentioned drug groups, the following groups were selected for observation of general symptoms in rabbit ears: normal control group, acne model group, acne model + phototherapy group, acne model + blank preparation + phototherapy group, acne model + AMELUZ + phototherapy group, acne model + ALA + phototherapy group, acne model + 10% gel + phototherapy group, and acne model + 5% gel + phototherapy group, in order to examine the effect of the gel provided by the present invention on improving general symptoms.

[0146] detection indicators

[0147] 1. Observation and weighing of general symptoms of rabbit ears: Before treatment (day 0), day 1 of treatment, day 4 of treatment, day 7 of treatment, take photos of the right ear of all animals and record the rabbit ear symptoms at different times and the animal's condition during treatment.

[0148] 2. Seven days after treatment, use a 2.8cm diameter punch to prepare ear pieces at the same application site and weigh and record the ear pieces.

[0149] 3. HE pathological examination.

[0150] Statistical methods

[0151] Quantitative data (ear weight, hair follicle area, and number of papules reduced) are expressed as mean ± standard error. Data were analyzed using one-way ANOVA.

[0152] result

[0153] The weight test results of rabbit ear tissue are as follows: Figure 1 As shown, the hair follicle area data is as follows: Figure 2 As shown, the data on papule reduction are as follows: Figure 3 As shown, the grouping of each color is as follows (see table below).

[0154] Table 10

[0155]

[0156]

[0157] The weight test results of rabbit ear tissue are as follows: Figure 1 As shown, compared with the normal control, the weight of rabbit ears in the acne model group was significantly increased (p<0.01), indicating that the tissues of acne-affected rabbits will have a certain degree of edema. Phototherapy, blank preparation + phototherapy, AMELUZ + phototherapy, and ALA + phototherapy all failed to reduce rabbit ear tissue edema; in fact, they increased it to varying degrees. However, the use of the 10% gel + phototherapy and 5% gel + phototherapy of this invention both reduced the weight of rabbit ear tissue and decreased tissue edema.

[0158] Hair follicle area data as follows Figure 2 As shown, compared with the normal control group, the hair follicle area in the model group was significantly increased, indicating that acne-affected tissues will experience pigmentation, leading to an enlarged hair follicle area, affecting skin smoothness or causing other adverse effects. Phototherapy, blank preparation + phototherapy, AMELUZ + phototherapy, and ALA + phototherapy did not reduce the hair follicle area; in fact, they increased it to varying degrees. However, the hair follicle area was significantly reduced after using the 10% gel + phototherapy and 5% gel + phototherapy of this invention, indicating that the gel provided by this invention can improve skin smoothness after photodynamic therapy and shorten the time of pigmentation.

[0159] Papule reduction data such as Figure 3 As shown, there was no data on papules in the normal control group, while the number of papules in the model group increased. Phototherapy, blank preparation + phototherapy, AMELUZ + phototherapy, ALA + phototherapy, and the 10% gel + phototherapy and 5% gel + phototherapy of the present invention can all reduce the number of papules to varying degrees. However, the reduction effect of the 10% gel + phototherapy and 5% gel + phototherapy of the present invention is significantly better than that of other groups, indicating that the 10% gel and 5% gel of the present invention are more effective in treating inflammatory diseases (such as psoriasis or contact dermatitis) or acne.

[0160] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and controls without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A composition, characterized in that, The composition comprises: (a) An active ingredient selected from 5-aminolevulinic acid or its salts or esters; said salts and esters are selected from hydrochloride, sulfate, nitrate, phosphate, borate, lactate, acetate, succinate, citrate, tartrate, formate, propionate, butyrate, hexanoate, caprylate, ethyl acetate, dodecyl ester, myristate, palmitate, oleate; and (b) An aqueous carrier containing an analgesic, wherein the analgesic is a terpene compound, preferably a monoterpene compound, more preferably menthol and its derivatives.

2. The composition according to claim 1, characterized in that, The content of the active ingredient is 0.1% to 20%, or 0.1% to 15%, or 0.5% to 15% based on the total weight of the composition; the content of the analgesic is 0.1% to 10%, or 0.1% to 5%, or 0.1% to 2%, or 0.1% to 1% based on the total weight of the composition; the content of the aqueous carrier is 10% to 90%, or 10% to 80%, or 10% to 70%, or 10% to 60%, or 20% to 90%, or 20% to 80%, or 20% to 70%, or 20% to 60%, or 10% to 50%, or 20% to 50% based on the total weight of the composition.

3. The composition according to claim 1, characterized in that, The aqueous carrier further contains emulsifiers and co-emulsifiers.

4. The composition according to claim 3, characterized in that, The emulsifier comprises phospholipid emulsifiers and non-phospholipid emulsifiers. The phospholipid emulsifiers are selected from at least one of soybean phospholipids, egg lecithin, hydrogenated soybean lecithin, hydrogenated egg lecithin, soybean phosphatidylcholine, and egg lecithin, preferably soybean phospholipids. The non-phospholipid emulsifiers are nonionic and are selected from at least one of vitamin E polyethylene glycol derivatives, polysorbate, and poloxamer, preferably at least one of vitamin E polyethylene glycol succinate, polysorbate 20, and poloxamer 407.

5. The composition according to claim 3, characterized in that, The emulsifier content is 0.1% to 10%, or 0.5% to 10%, or 0.5% to 5%, or 1% to 5% based on the total weight of the composition.

6. The composition according to claim 3, characterized in that, The co-emulsifier is selected from at least one monohydric alcohol and a polyhydric alcohol. The monohydric alcohol is a lower alkanol and is selected from at least one of methanol, ethanol, n-propanol, and isopropanol, preferably at least one of ethanol and isopropanol. The polyhydric alcohol is selected from at least one of ethylene glycol, propylene glycol, and glycerol, preferably propylene glycol.

7. The composition according to claim 3, characterized in that, The content of the co-emulsifier is 0.1% to 10%, or 0.5% to 10%, or 0.5% to 5%, or 1% to 5% based on the total weight of the composition.

8. The composition according to claim 3, characterized in that, The aqueous carrier further contains pharmaceutically common excipients, including at least one selected from pH adjusters, solubilizers, antioxidants, chelating agents, preservatives, and viscosity modifiers.

9. The composition according to claim 8, characterized in that, The pH adjuster is selected from at least one of acetic acid, adipic acid, ammonium carbonate, ammonium hydroxide, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium propionate, succinic acid, sulfuric acid, tartaric acid, triethylamine, triethanolamine, tromethamine, and meglumine; preferably at least one of acetic acid, citric acid, diethanolamine, fumaric acid, malic acid, propionic acid, potassium acetate, potassium citrate, sodium acetate, sodium citrate, sodium glycolate, sodium lactate, sodium propionate, succinic acid, tartaric acid, triethylamine, triethanolamine, tromethamine, and meglumine; more preferably at least one of acetic acid, citric acid, diethanolamine, potassium acetate, potassium citrate, sodium acetate, sodium citrate, sodium glycolate, triethylamine, triethanolamine, tromethamine, and meglumine.

10. The composition according to claim 8, characterized in that, The solubilizer is selected from at least one of povidone, dextran, cyclodextrin and its derivatives, hydroxypropyl-β-cyclodextrin, poloxamers, polysorbates, and Spans, with hydroxypropyl-β-cyclodextrin being preferred.

11. The composition according to claim 8, characterized in that, The antioxidant may be at least one selected from α-tocopherol succinate, ascorbate palmitate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

12. The composition of claim 8, characterized in that, The preservative may be at least one of phenoxyethanol, chlorphenesin, methylparaben, and p-hydroxyacetophenone, preferably phenoxyethanol.

13. Use of any one of the compositions of claims 1 to 12 for the preparation of a pharmaceutical formulation, said pharmaceutical formulation being in liquid or semi-solid form, said liquid being selected from solutions, sprays, aerosols, emulsions or lotions; said semi-solid being selected from ointments, creams, gels, lotions, foams, pastes and / or suspensions.

14. A 5-aminolevulinic acid gelling agent, characterized in that, The gelling agent contains the composition of any one of claims 1 to 12, and further contains a gel matrix.

15. The gelling agent as described in claim 14, characterized in that, The gel matrix is ​​selected from at least one of glycerol, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose and carbomer; preferably at least one of carbomer and xanthan gum; Xanthan gum is preferred; its content is 0.1% to 5% by weight based on the total weight of the gelling agent.

16. A method for preparing the gelling agent as described in claim 14 or 15, characterized in that, The method includes the following steps: Preparation of aqueous carrier: (1) Weigh the prescribed amount of monohydric alcohol, phospholipid emulsifier, and analgesic and stir and mix them evenly at 40℃-50℃; (2) Add polyhydric alcohol, non-phospholipid emulsifier, and solubilizer (if added) and continue to keep warm and stir evenly; (3) Add solvent and stir, and cool to room temperature to obtain aqueous carrier. Preparation of gel matrix: Heat pure water to 30°C, add xanthan gum in small batches, stir evenly, and cool to room temperature to obtain gel matrix; Preparation of gel: Add the prescribed amount of 5-aminolevulinic acid or its salt or ester, aqueous carrier, and pH adjuster to the gel matrix, and stir evenly at room temperature to obtain the gel.

17. A 5-aminolevulinic acid foaming agent, characterized in that, The foaming agent contains the composition of any one of claims 1 to 12, and further contains a gelling agent and a foam skeleton.

18. The foaming agent as described in claim 17, characterized in that, The gelling agent is selected from at least one of glycerol, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and carbomer; preferably at least one of carbomer and xanthan gum; more preferably xanthan gum, with a content of 0.1% to 5% by weight based on the total weight of the foaming agent; the foam skeleton is selected from at least one of cetyl alcohol, stearyl alcohol, arachidyl alcohol, stearic acid, arachidic acid, and oleyl alcohol, preferably cetyl alcohol and / or stearyl alcohol; with a content of 0.1% to 15% by weight based on the total weight of the foaming agent.

19. The foaming agent as described in claim 17, characterized in that, The foaming agent additionally contains a propellant, which is a hydrocarbon gas or a hydrofluoroalkane liquefied gas, wherein the hydrocarbon gas is selected from at least one of propane, butane, and isobutane and mixtures thereof, and the hydrofluoroalkane liquefied gas is selected from at least one of tetrafluoroethane, heptafluoropropane, and dimethyl ether; the ratio of its content to the total weight of the foaming agent by weight is 1 to 20:

100.

20. Use of any composition of claims 1 to 12, any gel of claims 14 to 15, or any foam of claims 17 to 19 in the production of a medicament for photodynamic therapy.

21. The cosmetic use of any composition of claims 1 to 12, any gel of claims 14 to 15, or any foam of claims 17 to 19 as an anti-aging agent.

22. Use of any composition of claims 1 to 12, any gel of claims 14 to 15, or any foam of claims 17 to 19 for the production of a medicament for the treatment of any one of a viral disease, a dermatological disease, or a tumor disease.

23. The use as described in claim 22, wherein the viral disease is caused by human papillomavirus.

24. The use as described in claim 23, wherein the viral disease is condyloma acuminata.

25. The use as described in claim 22, wherein the dermatological disease is any one of keratosis, acne, photoaging, psoriasis, scarring, or vitiligo.

26. The use as described in claim 22, wherein the tumor disease is any one of esophageal cancer, lung cancer, brain tumor, head and neck tumor, eye tumor, pharyngeal cancer, chest wall tumor, breast cancer, pleural mesothelioma, abdominal sarcoma, bladder cancer, gynecological tumor, rectal cancer, Kaposi's sarcoma, and skin cancer.

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