Composite hydrogel and use thereof

Abstract

A composite hydrogel and the use thereof in the preparation of a medicament for eliminating benign hyperpigmentation. The composite hydrogel comprises: 1-60% by weight of perfluorocarbon and / or a semi-fluorinated alkane relative to the total weight of the composite hydrogel, and a gel matrix, wherein the perfluorocarbon and / or the semi-fluorinated alkane are dispersed in the gel matrix in the form of droplets; and in the droplets, the ratio of the number of droplet particles having a diameter of greater than 100 μm to the number of droplet particles having a diameter of 1-100 μm is not higher than 0.1.

Description

Composite hydrogel and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medical cosmetology, and more particularly relates to a composite hydrogel and application thereof in removing benign pigmentation. BACKGROUND

[0002] With the development of science and the increasing improvement of the quality of life of the Chinese people, more and more new medical technologies and equipment are applied to a wider range of fields and diseases. Photoelectric treatment methods for the skin play a significant role in improving skin problems, and their audience is growing. Laser therapy is a method of treating diseases by using the special properties of laser, such as high monochromaticity, high directionality, high brightness, and high coherence. When laser irradiates biological tissue, it can produce photoeffect, heat effect, pressure effect, and electromagnetic field effect, and can be applied to medical cosmetology, blood coagulation, tumor treatment, laser scalpel, and other fields. For example, it is recorded in the "2022 Expert Consensus on Clinical Application of Picosecond Laser" (Practical Dermatology Journal, April 2022, Vol. 15, No. 2, 65-69) that picosecond laser can be applied to the treatment of pigment increase diseases, skin rejuvenation, scars, chloasma, tattoos, and other problems.

[0003] However, after the light emitted by photoelectric treatment equipment irradiates the human skin, it can cause damage to the skin tissue, resulting in redness, swelling, and even blisters, skin whitening, purpura, and exudation in the skin, and the person receiving the light irradiation has a burning and painful sensation. Further, in the field of strong laser irradiation treatment, such as pigmentation, scar fading, tattoo removal, and the like, the skin problems and discomfort caused by the human body after receiving laser irradiation will be more serious and difficult to tolerate.

[0004] In order to alleviate the discomfort caused by photoelectric treatment, the most widely used in the treatment process at present is light guide gel, i.e. photon cooling gel, which is safe and non-toxic in composition and does not cause damage and corrosion to the light treatment head, and is non-irritating to the human skin. The light guide gel mainly plays a moisturizing and hydrating role, and at the same time relieves the burning and pain during the treatment process.

[0005] However, the current light guide gel still has unmet clinical needs in the application process. In the treatment field that requires high-intensity and high-frequency laser irradiation, such as the laser treatment process of removing benign pigmentation lesions such as nevus of Ota, seborrheic keratosis, chloasma, cafe-au-lait spots, freckles, age spots, benign pigmented spots, tattoos, etc., the existing light guide gel on the market has limited auxiliary effect. Even in the case of applying light guide gel, after the patient receives high-intensity and high-frequency laser irradiation, the treated skin area often appears severe redness, skin whitening, itching, inflammation, etc., accompanied by strong burning and pain. For example, the patent document with the authorization announcement number CN115068368B discloses a light guide gel which, on the basis of the conventional light guide gel, adds nano silicon dioxide and hexagonal boron nitride to enhance the fluidity and thermal conductivity of the light guide gel accordingly, mainly playing the role of easy to apply and local heat conduction, but it has almost no more positive and effective effect on deep, high-frequency and high-energy laser treatment. For example, CN116271547A discloses a medical light guide gel with high light guide performance, which adds aminolevulinic acid propyl ester hydrochloride to enhance the light guide performance of the light guide gel on the basis of the conventional light guide gel. It does not provide an effective solution to the skin problems caused by laser treatment. The light guide gel in the prior art does not provide an effective solution to the skin problems caused by laser treatment.

[0006] During the laser treatment of removing benign pigmentation lesions such as tattoos, due to the rapid heating and energy transfer related to laser irradiation, the high temperature generated by the skin tissue instantaneously after laser irradiation causes the gas in the tissue to escape, forming bubbles in the dermis. These bubbles, on the one hand, will reduce the treatment effect, and on the other hand, will cause skin whitening. The prior art shows that perfluorocarbons or semi-fluorinated alkanes have good effect in removing skin whitening caused by laser treatment. However, the existing mature perfluorocarbon delivery method still has shortcomings in safety. For example, US patent document US9381167B2 discloses the use of perfluorodecalin to alleviate the problem of whitening, however, perfluorodecalin is hydrophobic and oleophobic, not skin-friendly, with poor skin adhesion, low utilization rate and limited treatment effect. In order to make the non-skin-friendly perfluorodecalin better and longer adhere to the skin area that needs laser irradiation, the patent document uses a patch to deliver perfluorodecalin to the treatment area to improve the problem of local skin whitening caused by laser removal of tattoos. However, the delivery method using the patch is prone to reflection during laser treatment, which poses a risk of blindness to the laser treatment operator, making the use of the patch to deliver perfluorodecalin a less safe solution. Therefore, in order to improve the safety of the process of removing benign pigmentation, there is an urgent need for a product that delivers perfluorocarbons or semi-fluorinated alkanes in a safe form. SUMMARY

[0007] In view of the fact that the light guide gel in the prior art does not provide an effective solution to the skin problems caused by the light treatment scheme, the present application provides, in a first aspect, a composite hydrogel containing perfluorocarbon or / and semi-fluorinated alkane, which, when applied in the auxiliary light treatment method, especially in the auxiliary laser removal of benign pigmentation, can effectively relieve the burning and pain of the skin of the subject during the light treatment process, and can effectively prevent the whitening reaction and problems such as redness and itching of the skin of the subject during the light treatment. In addition, in view of the safety problems of the perfluorocarbon patch product during use, the composite hydrogel does not need to be delivered / dosed by a patch, but can be directly coated on the skin surface, thereby avoiding the problems of low utilization rate of patch delivery / dosing and poor safety for the operator. On this basis, the present application further provides a composite hydrogel with improved storage stability.

[0008] The second aspect of the present application provides a preparation method of the composite hydrogel containing perfluorocarbon or / and semi-fluorinated alkane, which, by controlling the viscosity and rheology of the gel matrix, obtains a stable dispersion of the composite hydrogel containing perfluorocarbon or / and semi-fluorinated alkane.

[0009] The third aspect of the present application provides the application of the composite hydrogel containing perfluorocarbon or / and semi-fluorinated alkane in the auxiliary light treatment method, especially in the auxiliary laser removal of benign pigmentation.

[0010] Technical scheme

[0011] In order to solve the above problems, the technical scheme adopted by the present application is as follows:

[0012]

Composite hydrogel

[0013] The first aspect of the present application provides a composite hydrogel, which comprises:

[0014] Perfluorocarbon or / and semi-fluorinated alkane in a weight percentage of 1-60% relative to the total weight of the composite hydrogel; and

[0015] Gel matrix;

[0016] The perfluorocarbon or / and semi-fluorinated alkane is dispersed in the gel matrix in the form of droplets;

[0017] In the droplets, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1-100 μm is not higher than 0.1. It should be noted that the droplets are mainly micron-sized droplets. Specifically, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1-100 μm in the present application is determined by the following steps:

[0018] i. The composite hydrogel is observed and photographed using an optical microscope to obtain a microscopic photograph of the composite hydrogel; in order to ensure the accuracy of the statistics, the number of droplets in the microscopic photograph that are not less than 1 μm should not be less than 100; in order to make the statistics as close to the truth as possible, after each microscopic photograph is taken, the position of the slide is adjusted and the photograph is taken again; if the same sample has been counted at each position, a new sample is prepared for further counting, and a total of 20 microscopic fields are counted.

[0019] ii. The droplet size of the droplets in the microscopic photograph that are not less than 1 μm is measured;

[0020] iii. The number of droplet particles in the microscopic photograph that are greater than 100 μm in diameter, and the number of droplet particles in the microscopic photograph that are 1-100 μm in diameter, are determined;

[0021] iv. The ratio of the number of droplet particles in the microscopic photograph that are greater than 100 μm in diameter to the number of droplet particles in the microscopic photograph that are 1-100 μm in diameter is calculated.

[0022] In general, if it can be determined by the naked eye that there are no droplet particles in the microscopic photograph that are greater than 100 μm in diameter, steps i-iv above do not need to be performed, and it can be determined that the ratio of the number of droplet particles that are greater than 100 μm in diameter to the number of droplet particles that are 1-100 μm in diameter is not greater than 0.1.

[0023] In the clinical application of light therapy, especially laser therapy, to remove benign pigmentation, light therapy or high-intensity, high-frequency laser therapy can easily cause skin damage, whitening and other problems. The application of perfluorocarbons or / and semifluorinated alkanes before, during or after the irradiation of light, especially laser, from photoelectric treatment equipment to the skin can significantly improve the side effects of skin damage caused by light therapy, especially in high-intensity, high-frequency laser therapy. Delivering perfluorocarbons or / and semifluorinated alkanes in the form of a gel avoids the safety hazards of delivering perfluorodecalin in the form of a patch to laser therapy operators in the prior art, while improving the convenience of operators when in use. Specifically, when perfluorocarbons or / and semifluorinated alkanes in the form of droplets of a specific size range are dispersed in the gel matrix and applied to the skin before, during the irradiation of light, especially laser, the operator can more easily identify the area of light, especially laser, irradiation due to the scattering effect of particles mainly concentrated in the micron size range (1-100 μm), significantly increasing the visibility of the light spot, especially the laser spot. At the same time, since the presence of droplets of perfluorocarbons or / and semifluorinated alkanes that are too large in size will cause poor storage stability of the composite hydrogel, making it difficult to maintain a long shelf life, it is necessary to limit the proportion of large-sized perfluorocarbon or / and semifluorinated alkane droplets in the composite hydrogel.

[0024] According to a preferred embodiment of any of the first aspect of the present application, the perfluorocarbon includes one or more of perfluorotripropylamine, perfluorotributylamine, perfluorobromooctane, perfluoro-n-butyltetrahydrofuran, perfluorooctane, perfluorodecalin, perfluorophenanthrene, and the like. These perfluorocarbons have excellent gas solubility and can absorb or remove bubbles well, and thus can be used in the composite hydrogel of the present application for the improvement of skin whitening caused by laser treatment.

[0025] According to a preferred embodiment of any of the first aspect of the present application, the semifluorinated alkane has a molecular formula of C a H 2a+1 -C b F 2b+1 wherein a is selected from any integer value from 3 to 10, and b is selected from any integer value from 3 to 10; preferably, the semifluorinated alkane is selected from one or more of C5H 11 -C4F9, C6H 13 -C4F9, C6H 13 -C6F 13 , C8H 17 -C6F 13 , C9H 19 -C6F 13 , C 10 H 21 -C6F 13 .

[0026] According to a preferred embodiment of any of the first aspect of the present application, the perfluorocarbon and the semifluorinated alkane are added to the composite hydrogel in a specific ratio, wherein the mass ratio of the perfluorocarbon to the semifluorinated alkane is 0.01-100:1, preferably 1-100:1.

[0027] According to the first aspect of the present application, there is provided a composite hydrogel, comprising:

[0028] perfluorocarbon in an amount of 1-60% by weight relative to the total weight of the composite hydrogel, the perfluorocarbon being perfluorobromooctane; and

[0029] a gel matrix;

[0030] the perfluorobromooctane is dispersed in the gel matrix in the form of droplets;

[0031] in the droplets, the ratio of the number of droplet particles having a diameter greater than 100 μm to the number of droplet particles having a diameter of 1-100 μm is not higher than 0.1. It is to be noted that the droplets are mainly micrometer-sized droplets.

[0032] Perfluorooctyl bromide is a colorless and transparent high-boiling liquid, and has physical, chemical and biological stability. It has good light guiding property under light irradiation, especially does not change its physical and chemical properties under laser irradiation, and has laser stability, and can tolerate high-intensity and high-frequency laser irradiation. Meanwhile, perfluorooctyl bromide has excellent gas solubility. When perfluorooctyl bromide is used simultaneously with laser treatment of the skin, the escaped gas caused by laser irradiation can be captured, and the occurrence of skin whitening can be avoided. In addition, perfluorooctyl bromide has anti-inflammatory properties, and can be used to relieve inflammation after laser treatment.

[0033] Perfluorooctyl bromide is applied to the subject in the form of a gel before, during or after the skin is irradiated with laser in photoelectric treatment equipment, which can not only significantly improve the side effects of skin damage caused by light treatment, especially high-intensity and high-frequency laser treatment, but also avoid the safety hazard of delivering perfluorocarbon in the form of a patch to the laser treatment operator in the prior art. In the composite hydrogel of the present application, perfluorooctyl bromide mainly exists in the form of micrometer-sized droplets, and can adhere to the skin surface for a long time while guiding light and heat, and can relieve the skin for a long time after high-intensity and high-frequency laser irradiation, effectively reducing adverse reactions such as redness, inflammation and skin whitening. In addition, the composite hydrogel containing micrometer-sized perfluorooctyl bromide droplets can partially scatter the laser, enhancing the visibility of the laser spot and facilitating the observation of the operator during the actual treatment.

[0034] When the proportion of large-sized perfluorocarbon or / and semifluorinated alkane droplets in the composite hydrogel is too high, the composite hydrogel is prone to sedimentation and cannot be stored stably for a long time, and therefore the proportion of large-sized perfluorocarbon or / and semifluorinated alkane droplets in the composite hydrogel needs to be limited.

[0035] According to a preferred embodiment of the first aspect of the present application, in the droplets, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1-100 μm is not higher than 0.05, more preferably not higher than 0.02, and most preferably the ratio is 0.

[0036] According to a preferred embodiment of the first aspect of the present application, in the droplets, the ratio of the number of droplet particles with a diameter greater than 80 μm to the number of droplet particles with a diameter of 1-80 μm is not higher than 0.1, preferably not higher than 0.05, more preferably not higher than 0.02, and most preferably the ratio is 0.

[0037] According to a preferred embodiment of the first aspect of the present application, in the droplets, the ratio of the number of droplet particles with a diameter greater than 50 μm to the number of droplet particles with a diameter of 1-50 μm is not higher than 0.1, preferably not higher than 0.05, more preferably not higher than 0.02, and most preferably the ratio is 0.

[0038] According to a preferred embodiment of any of the first aspect of the application, the ratio of the number of droplet particles having a diameter greater than 30 μm to the number of droplet particles having a diameter between 1 and 30 μm in the droplets is not higher than 0.1, preferably not higher than 0.05, more preferably not higher than 0.02, and most preferably the ratio is 0.

[0039] According to a preferred embodiment of any of the first aspect of the application, the ratio of the number of droplet particles having a diameter greater than 20 μm to the number of droplet particles having a diameter between 1 and 20 μm in the droplets is not higher than 0.1, preferably not higher than 0.05, more preferably not higher than 0.02, and most preferably the ratio is 0.

[0040] According to a preferred embodiment of any of the first aspect of the application, the droplet size of the perfluorocarbon or / and semi-fluorinated alkane, in particular perfluorooctylbromide, is selected from the range of any of the following groups or values therein:

[0041] not higher than 90 μm; not higher than 80 μm; not higher than 70 μm; not higher than 60 μm; not higher than 50 μm; not higher than 40 μm; not higher than 30 μm; not higher than 20 μm; not higher than 10 μm; not higher than 5 μm.

[0042] According to a preferred embodiment of any of the first aspect of the application, the perfluorocarbon or / and semi-fluorinated alkane, in particular perfluorooctylbromide, is dispersed in the form of droplets having a size not higher than 50 μm in the gel matrix.

[0043] According to a preferred embodiment of any of the first aspect of the application, the weight percentage of the perfluorocarbon or / and semi-fluorinated alkane, in particular perfluorooctylbromide, relative to the total weight of the composite hydrogel is selected from the range of any of the following groups or values therein:

[0044] 1 to 55%, 1 to 50%, 1 to 45%, 1 to 40%, 1 to 35%, 1 to 30%, 1 to 25%, 1 to 20%, 1 to 18%, 1 to 15%, 1 to 14%, 1 to 13%, 1 to 12%, 1 to 11%, 1 to 10%, 1 to 9%, 1 to 8%, 1 to 7%, 1 to 6%, 1 to 5%, 1 to 4%, 1 to 3%, 1 to 2%;

[0045] 2 to 60%, 2 to 55%, 2 to 50%, 2 to 45%, 2 to 40%, 2 to 35%, 2 to 30%, 2 to 25%, 2 to 20%, 2 to 18%, 2 to 15%, 2 to 14%, 2 to 13%, 2 to 12%, 2 to 11%, 2 to 10%, 2 to 9%, 2 to 8%, 2 to 7%, 2 to 6%, 2 to 5%, 2 to 4%, 2 to 3%;

[0046] 3～60％，3～55％，3～50％，3～45％，3～40％，3～35％，3～30％，3～25％，3～20％，3～18％，3～15％，3～14％，3～13％，3～12％，3～11％，3～10％，3～9％，3～8％，3～7％，3～6％，3～5％，3～4％；

[0047] 4～60％，4～55％，4～50％，4～45％，4～40％，4～35％，4～30％，4～25％，4～20％，4～18％，4～15％，4～14％，4～13％，4～12％，4～11％，4～10％，4～9％，4～8％，4～7％，4～6％，4～5％；

[0048] 5～60％，5～55％，5～50％，5～45％，5～40％，5～35％，5～30％，5～25％，5～20％，5～18％，5～15％，5～14％，5～13％，5～12％，5～11％，5～10％，5～9％，5～8％，5～7％，5～6％；

[0049] 6～60％，6～55％，6～50％，6～45％，6～40％，6～35％，6～30％，6～25％，6～20％，6～18％，6～15％，6～14％，6～13％，6～12％，6～11％，6～10％，6～9％，6～8％，6～7％；

[0050] 7～60％，7～55％，7～50％，7～45％，7～40％，7～35％，7～30％，7～25％，7～20％，7～18％，7～15％，7～14％，7～13％，7～12％，7～11％，7～10％，7～9％，7～8％；

[0051] 8～60％，8～55％，8～50％，8～45％，8～40％，8～35％，8～30％，8～25％，8～20％，8～18％，8～15％，8～14％，8～13％，8～12％，8～11％，8～10％，8～9％；

[0052] 9～60％，9～55％，9～50％，9～45％，9～40％，9～35％，9～30％，9～25％，9～20％，9～18％，9～15％，9～14％，9～13％，9～12％，9～11％，9～10％；

[0053] 10～60％，10～55％，10～50％，10～45％，10～40％，10～35％，10～30％，10～25％，10～20％，10～18％，10～15％，10～14％，10～13％，10～12％，10～11％；

[0054] 11～60％，11～55％，11～50％，11～45％，11～40％，11～35％，11～30％，11～25％，11～20％，11～18％，11～15％，11～14％，11～13％，11～12％；

[0055] 12～60％，12～55％，12～50％，12～45％，12～40％，12～35％，12～30％，12～25％，12～20％，12～18％，12～15％，12～14％，12～13％；

[0056] 13～60％，13～55％，13～50％，13～45％，13～40％，13～35％，13～30％，13～25％，13～20％，13～18％，13～15％，13～14％；

[0057] 14～60％，14～55％，14～50％，14～45％，14～40％，14～35％，14～30％，14～25％，14～20％，14～18％，14～15％；

[0058] 15～60％，15～55％，15～50％，15～45％，15～40％，15～35％，15～30％，15～25％，15～20％，15～18％；

[0059] 18～60％，18～55％，18～50％，18～45％，18～40％，18～35％，18～30％，18～25％，18～20％

[0060] 20～60％，20～55％，20～50％，20～45％，20～40％，20～35％，20～30％，20～25％；

[0061] 25～60％，25～55％，25～50％，25～45％，25～40％，25～35％，25～30％；

[0062] 30～60％，30～55％，30～50％，30～45％，30～40％，30～35％；

[0063] 35-60%, 35-55%, 35-50%, 35-45%, 35-40%;

[0064] 40-60%, 40-55%, 40-50%, 40-45%;

[0065] 45-60%, 45-55%, 45-50%;

[0066] 50-60%, 50-55%;

[0067] 55-60%.

[0068] According to a preferred embodiment of any of the first aspect of the present application, the gel matrix comprises a gel thickening agent, and the gel thickening agent has a dynamic viscosity of not less than 20 Pa-s at 25°C. Preferably, the gel thickening agent has a dynamic viscosity of not less than 25 Pa-s at 25°C. There are many kinds of gel thickening agents in the prior art, but not all kinds of gel thickening agents can meet the requirements of the present application. Surprisingly, compared with gel thickening agents with good rheological properties, gel thickening agents with poor rheological properties can achieve better results in the present application, and although gel thickening agents with good rheological properties can also obtain composite hydrogels, the storage stability of the composite hydrogels is not ideal and it is difficult to store for a long time.

[0069] Under the combined action of factors such as the type of perfluorocarbon or / and semi-fluorinated alkane, the size of the droplets, the weight percentage relative to the total weight of the composite hydrogel, and the dynamic viscosity of the gel thickening agent at 25°C, a composite hydrogel with excellent storage stability can be ensured.

[0070] According to a preferred embodiment of any of the first aspect of the present application, the gel matrix comprises a gel thickening agent, a pH adjuster, a humectant, an emulsifier, and water.

[0071] According to a preferred embodiment of any of the first aspect of the present application, the gel thickening agent is selected from one or more of carbomer, hyaluronic acid, sodium hyaluronate, and sodium carboxymethyl cellulose.

[0072] According to a preferred embodiment of any of the first aspect of the present application, the carbomer is selected from one or both of a carbomer homopolymer of type B or a carbomer homopolymer of type C. The carbomer homopolymer of type B or the carbomer homopolymer of type C has a cross-linked structure and a high dynamic viscosity, and can well support the perfluorocarbon or / and semi-fluorinated alkane, especially the perfluorooctyl bromide droplets, within the required size range, so that the composite hydrogel prepared can be stored for a long time and is not prone to delamination or sedimentation.

[0073] According to a preferred embodiment of any of the first aspect of the present application, the pH adjusting agent is selected from one or more of triethanolamine, sodium hydroxide, potassium hydroxide. The pH adjusting agent functions to maintain the pH of the composite hydrogel between 5 and 8.

[0074] According to a preferred embodiment of any of the first aspect of the present application, the humectant is selected from one or both of glycerol, 1,2-pentanediol.

[0075] According to a preferred embodiment of any of the first aspect of the present application, the emulsifier is selected from one or more of poloxamer, tween, phospholipid.

[0076] According to a preferred embodiment of any of the first aspect of the present application, the gel base further comprises a bactericidal preservative.

[0077] According to a preferred embodiment of any of the first aspect of the present application, the bactericidal preservative is selected from one or more of hydroxybenzoate, benzoate, sorbic acid or its salts.

[0078] According to a preferred embodiment of any of the first aspect of the present application, the gel base comprises:

[0079] a gel thickener in a weight percentage of 0.5 to 2.5% relative to the total weight of the composite hydrogel;

[0080] a pH adjusting agent in a weight percentage of 0.5 to 4% relative to the total weight of the composite hydrogel;

[0081] a humectant in a weight percentage of 1 to 8% relative to the total weight of the composite hydrogel;

[0082] an emulsifier in a weight percentage of 1 to 6% relative to the total weight of the composite hydrogel;

[0083] a bactericidal preservative in a weight percentage of 0 to 0.2% relative to the total weight of the composite hydrogel; and

[0084] water.

[0085] According to a preferred embodiment of any of the first aspect of the present application, the gel base comprises:

[0086] a carbomer homopolymer in a weight percentage of 0.5 to 2.5% relative to the total weight of the composite hydrogel;

[0087] triethanolamine in a weight percentage of 0.5 to 4% relative to the total weight of the composite hydrogel;

[0088] glycerol in a weight percentage of 1 to 8% relative to the total weight of the composite hydrogel;

[0089] an emulsifier in a weight percentage of 1 to 6% relative to the total weight of the composite hydrogel;

[0090] a bacteriostatic preservative in an amount of 0-0.2% by weight relative to the total weight of the composite hydrogel; and

[0091] water.

[0092] According to a preferred embodiment of any one of the first aspect of the present application, there is provided a composite hydrogel comprising, by weight relative to the total weight, 1-10% perfluorooctyl bromide, 1-2.5% carbomer, 1-3% triethanolamine, 2-6% glycerol, 2-6% emulsifier, 0-0.2% bacteriostatic preservative, and the balance being water.

[0093] Further preferably, the composite hydrogel comprises, by weight relative to the total weight, 2-7% perfluorooctyl bromide, 1-2% carbomer, 1-2.5% triethanolamine, 3-6% glycerol, 2-5% emulsifier, 0-0.1% bacteriostatic preservative, and the balance being water.

[0094] Method for preparing the composite hydrogel

[0095] The second aspect of the present application provides a method for preparing the composite hydrogel as described in any one of the first aspect of the present application, comprising the following steps:

[0096] a) swelling the gel thickener; for example, specifically, the carbomer can be added in batches to heated water and stirred to obtain fully swollen carbomer;

[0097] b) adding a pH adjuster, such as triethanolamine, to the mixture obtained in step a), keeping stirring and heating until gel formation;

[0098] c) adding a humectant (such as glycerol), an emulsifier, and optionally a bacteriostatic preservative to the mixture obtained in step b), keeping stirring and heating; in order to enable long-term stable storage of the gel, a bacteriostatic preservative is generally added, but in some cases, the bacteriostatic preservative can also not be added, for example, when there is a sterilization step, then the bacteriostatic preservative can not be added, i.e. whether to add the bacteriostatic preservative can be arbitrarily selected by those skilled in the art according to the actual situation;

[0099] d) adding a perfluorocarbon such as perfluorooctyl bromide to the mixture obtained in step c), and when the composite hydrogel contains a semifluorinated alkane, the semifluorinated alkane is also added in step d); keeping stirring and heating to obtain the composite hydrogel.

[0100] According to a preferred embodiment of any one of the second aspect of the present application, the dynamic viscosity of the gel thickener at 25°C is not less than 20 Pa·s.

[0101] According to a preferred embodiment of any of the above-mentioned aspects of the present application, the stirring speed in steps a) to d) is in the range of 600 to 1500 rpm, preferably in the range of 800 to 1200 rpm.

[0102] According to a preferred embodiment of any of the above-mentioned aspects of the present application, the heating temperature in steps b) to d) is in the range of 25 to 90 °C, further preferred in the range of 60 to 90 °C, most preferred in the range of 70 to 80 °C.

[0103] It should be noted that the stirring speed and the heating temperature have an influence on the rheology of the composite hydrogel and the size of the perfluorocarbon (in particular perfluorooctyl bromide) or / and semifluorinated alkane. The higher the stirring speed and the heating temperature, the better the rheology of the composite hydrogel, which leads to an easy settling of the perfluorocarbon or / and semifluorinated alkane droplets during the subsequent storage of the composite hydrogel. The lower the stirring speed and the heating temperature, the incomplete dispersion of the perfluorocarbon or / and semifluorinated alkane droplets in the composite hydrogel, which leads to an increase of the size of the perfluorocarbon or / and semifluorinated alkane droplets, which in turn has an influence on the homogeneity, stability and visualization of the composite hydrogel.

[0104] According to a preferred embodiment of any of the above-mentioned aspects of the present application, the stirring time in step a) is in the range of 30 to 60 min, the stirring time in step c) is in the range of 10 to 20 min, and the stirring time in step d) is in the range of 20 to 720 min, further preferred in the range of 120 to 720 min, and most preferred in the range of 240 to 360 min.

[0105] It should be noted that the stirring time in the above-mentioned steps has an influence on the rheology of the composite hydrogel and the size of the perfluorocarbon or / and semifluorinated alkane. The longer the stirring time, the better the rheology of the composite hydrogel, which is not beneficial for the storage stability of the composite hydrogel. The shorter the stirring time, the size of the perfluorocarbon or / and semifluorinated alkane droplets in the composite hydrogel is too large, which in turn has an influence on the homogeneity, stability and visualization of the composite hydrogel.

[0106]

Application of the composite hydrogel

[0107] According to a preferred embodiment of any of the above-mentioned aspects of the present application, the composite hydrogel according to any of the above-mentioned aspects of the present application is used for the removal of benign pigmentation, in particular for the removal of benign pigmentation by laser.

[0108] According to a preferred embodiment of any of the above-mentioned aspects of the present application, the benign pigmentation is selected from one or more of the group consisting of nevus of Ota, seborrheic keratosis, chloasma, cafe-au-lait spots, freckles, age spots, benign lentigo, and tattoos.

[0109] According to a preferred embodiment of any of the third aspects of the present application, the composite hydrogel can be applied before, during or after the irradiation of light to the skin. More preferably, the composite hydrogel can be applied before or during the irradiation of laser to the skin. In particular, the composite hydrogel can be directly applied to the surface of the skin of the subject, and due to the good skin-friendliness of the composite hydrogel, there is no need to additionally use a patch for delivery / dosing. In particular, the composite hydrogel can be topically dosed to the surface of the skin.

[0110]

[0111] As used herein, the following terms have the following definitions, unless a different definition is expressly provided or is clear from the context.

[0112] In the present application, perfluorocarbon refers to a compound in which all hydrogen atoms in a hydrocarbon molecule are replaced by fluorine atoms, and a compound in which a perfluorinated alkyl or a perfluorinated cycloalkyl is replaced by one and only one halogen (chlorine, bromine, iodine) atom or oxygen atom or nitrogen atom or sulfur atom.

[0113] In the present application, semifluorinated alkane refers to a class of halogenated alkanes in which one end is a perfluorinated alkyl group and the other end is an alkyl group.

[0114] In the present application, gel refers to a special dispersion system in which colloidal particles or polymers in sol or solution are connected to each other under certain conditions to form a spatial network structure, and the structure voids are filled with liquid or gas as the dispersion medium.

[0115] In the present application, hydrogel refers to a gel system in which water is the main dispersion medium.

[0116] In the present application, gel matrix refers to other components in the gel except the main effective components. For example, in the present application, the main effective components are perfluorocarbon or / and semifluorinated alkane, and further perfluorooctyl bromide.

[0117] In the present application, emulsifier refers to a class of substances that can form stable emulsions of two or more mutually immiscible components.

[0118] In the present application, bactericidal preservative refers to a class of substances that can kill bacteria or make them lose the ability to grow and reproduce to ensure that the material does not deteriorate during use.

[0119] In the present application, pH regulator refers to a class of substances used to maintain or change the acidity or alkalinity of a system.

[0120] In the present application, humectant refers to a class of substances used to increase the water content and retain moisture of the skin or other objects.

[0121] In the present application, carbomer refers to a high molecular polymer of acrylate bonded allyl sucrose or pentaerythritol allyl ether.

[0122] ​The B-type carbomer homopolymer in the present invention refers to a high molecular polymer of acrylic acid bonded allyl sucrose or pentaerythritol allyl ether using a non-benzene solvent as a polymerization solvent, and the specified dynamic viscosity thereof should be 25-45 Pa-s (25°C).

[0123] The C-type carbomer homopolymer in the present invention refers to a high molecular polymer of acrylic acid bonded allyl sucrose or pentaerythritol allyl ether using a non-benzene solvent as a polymerization solvent, and the specified dynamic viscosity thereof should be 40-60 Pa-s (25°C).

[0124] The "accelerated healing" mentioned in the present invention refers to the accelerated speed of burn / trauma repair and healing compared to patients without auxiliary treatment.

[0125] The "applied to a subject" mentioned in the present invention refers to applying, coating or using a drug, medicine or rescue method to a subject to relieve and cure a pathological state.

[0126] The "alleviate", "relieve" state or situation mentioned in the present invention refers to reducing the symptoms of a certain state or situation.

[0127] The "topical administration" mentioned in the present invention refers to applying a test product to the skin of a subject.

[0128] The "weight percentage (wt%)" in the present invention, when referring to the percentage content of a component in a composite hydrogel, refers to the weight percentage of the component relative to the total weight of the composite hydrogel.

[0129] The "optionally selected" component in the present invention represents that the component can be selected or not selected.

[0130] 3. Beneficial effects

[0131] Compared with the prior art, the beneficial effects of the present invention are:

[0132] (1) The composite hydrogel provided by the present application disperses perfluorocarbon or / and semifluorinated alkane in the form of micron-sized droplets in the composite hydrogel system. Compared with the traditional light guide gel which uses water, carbomer and triethanolamine as main raw materials, the composite hydrogel containing micron-sized particles has the following advantages when used in the auxiliary light treatment method, especially in the auxiliary laser removal of benign pigmentation: on the one hand, it can effectively relieve the burning and pain of the skin of the subject during the light treatment process; on the other hand, it can effectively prevent the whitening reaction and problems such as redness and itching of the skin of the subject during the light treatment. In addition, the composite hydrogel containing micron-sized particles can slightly scatter the laser, thereby enhancing the visibility of the laser spot, facilitating the identification of the operator during the actual treatment process, enhancing the visibility of the laser spot and the operability of the operator. Compared with perfluorodecalin delivered in the form of a patch, the composite hydrogel avoids total reflection of the smooth patch surface to the laser, thereby further improving the safety of the laser treatment and protecting the operator. In addition, the composite hydrogel of the present application has wide application scenarios. In addition to the positive effect of heat absorption and cooling, it can also be applied to the treatment of laser removal of benign pigmentation with greater intensity and higher frequency, such as laser treatment of nevus of Ota, seborrheic keratosis, chloasma, cafe-au-lait spots, freckles, age spots, benign pigmented spots, tattoos, etc. The application of the composite hydrogel of the present application before, during or after treatment can effectively relieve, alleviate or accelerate the healing of the patient's burning, pain, skin redness, inflammation, skin whitening and other discomfort symptoms.

[0133] (2) The present application disperses perfluorooctyl bromide in the form of micron-sized droplets in the composite hydrogel system. Compared with other forms such as directly applying perfluorooctyl bromide to the skin, the composite hydrogel in the form of micron-sized droplets has better adhesion, so that perfluorooctyl bromide can act for a longer time and have better effect.

[0134] (3) In the composite hydrogel provided by the present application, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1-100 μm is not higher than 0.1, which will be beneficial to the storage stability of the composite hydrogel.

[0135] (4) In the composite hydrogel provided by the present application, the dynamic viscosity of the gel thickening agent used at 25℃ is not less than 20 Pa·s, which can effectively stabilize the micron-sized perfluorocarbon or / and semifluorinated alkane, especially perfluorooctyl bromide droplets, so that the composite hydrogel product can maintain good stability for a long time.

[0136] In summary, the composite hydrogel provided by the present application, when used for removing benign pigmentation, especially for assisting laser removal of benign pigmentation, has the functions of light and heat conduction, dissolved gas and anti-inflammatory, can effectively accelerate healing and reduce the discomfort symptoms of patients such as burning, pain, skin redness, inflammation, skin whitening, etc., enhance the visibility of light spots, improve the safety of laser treatment, solve the current clinical application deficiencies, and has extremely high clinical application value. BRIEF DESCRIPTION OF DRAWINGS

[0137] Fig. 1 is a morphological image of the composite hydrogel prepared in Examples 1-7 under an optical microscope.

[0138] Fig. 2 is a picture of the skin of the experimental group 1 after the end of the first cycle of treatment in the benign pigmentation model.

[0139] Fig. 3 is a picture of the skin of the experimental group 2 after the end of the first cycle of treatment in the benign pigmentation model.

[0140] Fig. 4 is a picture of the skin of the experimental group 3 after the end of the first cycle of treatment in the benign pigmentation model.

[0141] Fig. 5 is a picture of the skin of the experimental group 4 after the end of the first cycle of treatment in the benign pigmentation model.

[0142] Fig. 6 is a picture of the skin of the experimental group 4 after the end of the first cycle of treatment in the benign pigmentation model.

[0143] Fig. 7 is a picture of the skin of the experimental group 4 after the end of the first cycle of treatment in the benign pigmentation model.

[0144] Fig. 8 is a picture of the skin of the experimental group 4 after the end of the first cycle of treatment in the benign pigmentation model.

[0145] Fig. 9 is a picture of the skin of the experimental group 4 after the end of the first cycle of treatment in the benign pigmentation model.

[0146] Fig. 10 is a picture of the skin of the experimental group 4 after the end of the first cycle of treatment in the benign pigmentation model. DETAILED DESCRIPTION

[0147] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs; the term "or / and" used herein includes any and all combinations of one or more associated listed items.

[0148] When specific conditions are not specified in the examples, they are carried out under conventional conditions or according to the manufacturer's recommendations. When the manufacturer of a reagent or instrument is not named, conventional products available from commercial vendors are used.

[0149] As used herein, the term "about" is used to provide flexibility to a given term, measurement, or value. The degree of flexibility of a particular variable will be readily determined by one of skill in the art.

[0150] Concentrations, percentages, and other numerical data can be presented in this disclosure in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be construed as having been followed to following the principle of including and covering all the individual values of both the range extremes if it should contain various precision corrections and or measurement round off errors, and to include all the individual values within the range limits. For instance, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly recited values of 1 to about 4.5, but also include individual values and sub ranges within the indicated range, for example, 2, 3, 4, 1 to 3, 2 to 4, etc. The same principle applies to ranges reciting only one numerical value, such as "less than about 4.5", which should be interpreted to include all the values and ranges above. In addition, this interpretation should apply regardless of the breadth of the range or the characteristics being described.

[0151] The droplet size of perfluorocarbon or / and semifluorinated alkane or perfluorooctylbromide in the composite hydrogel in the present application is determined by the following method:

[0152] The composite hydrogel is spread on a hemocytometer, and after covering with a blood cover, the hemocytometer is directly observed using an optical microscope, and the light and magnification are adjusted, and a photo is taken for record, and the photo is measured using a drawing tool, and the droplet size in the photo range is obtained.

[0153] The ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1 to 100 μm is determined by the following steps:

[0154] i. The composite hydrogel is observed and photographed using an optical microscope, and a microscopic photo of the composite hydrogel is obtained; in order to ensure the accuracy of the statistics, the number of droplets not less than 1 μm in the microscopic photo should not be less than 100; in order to make the statistics as close to the fact as possible, after each photo is taken, the position of the slide is adjusted, and the photo is taken again, and if the same sample has been counted at each position, a new sample is prepared for continued counting, and a total of 20 microscopic view windows are taken for counting.

[0155] ii. The droplet size of the droplets not less than 1 μm in the microscopic photo is measured;

[0156] iii. determining the number of droplet particles with a diameter greater than 100 μm and the number of droplet particles with a diameter of 1-100 μm in the micrograph;

[0157] iv. calculating the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1-100 μm in the micrograph.

[0158] The present application uses an XSP-8CAV optical microscope to take pictures.

[0159] Generally, if it can be determined by naked eyes that there is no droplet particle with a diameter greater than 100 μm in the micrograph, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1-100 μm can be determined without performing steps i-iv.

[0160] In the present application, the degree of skin whitening is determined by the following method: using a camera to take pictures of the skin area treated by laser, measuring the pictures using a drawing tool, and calculating the proportion of whitened skin to obtain the size of the whitened skin area after laser treatment.

[0161] In the present application, the anti-inflammatory effect is determined by the following method: in the experiment of model animals, after the model animals are sacrificed, the skin tissue samples of the skin area treated by laser are taken for homogenization, and then the expression levels of inflammatory cytokines TNF-α, IL-6 and MMP-9 are detected by ELISA method, which can effectively obtain the basis for anti-inflammatory effect.

[0162] In the present application, the degree of visualization is determined by the following method: in the model of benign pigmented lesions of subcutaneous tattoos, a questionnaire survey is conducted on the experimental operator during each laser treatment, and the spot brightness, spot size and operation convenience are evaluated, with 0-5 points set from low to high, and the degree of visualization of each experimental group is judged by the scores of each item and the total score.

[0163] In the present application, the storage stability is determined by the following method: the experimental samples are stored under the conditions of temperature, humidity, illumination and sealing degree according to the specified time, and the appearance, particle size, pH value and other physical and chemical properties of the samples are investigated at the specified end of the experiment, and the storage stability of the samples is comprehensively evaluated.

[0164] In the present application, the degree of pigment removal is determined by the following method: in the model of benign pigmented lesions of subcutaneous tattoos, the skin area treated by laser is photographed at the end of the experiment, the area reduction and pigment lightening degree of the tattoo area of each picture are calculated by drawing software, and the degree of pigment removal is evaluated by comprehensively analyzing the data of each experimental group and drawing a bar chart.

[0165] The application will be further described in connection with specific examples.

[0166] Example 1

[0167] The composite hydrogel of this example comprises the following components by weight percentage of the total weight: 20% perfluorotributylamine, 1.8% carbomer homopolymer type B, 2.5% triethanolamine, 7% glycerol, 5% poloxamer, 0.2% hydroxyphenyl ethyl ester, and the balance water.

[0168] The preparation process of the composite hydrogel comprises the following steps:

[0169] a) After weighing the above components, the carbomer homopolymer type B is added in batches to water heated to 70°C, and stirred at a speed of 1100 rpm for 60 min;

[0170] b) Triethanolamine is added to the mixture obtained in step a), the stirring speed and temperature are kept unchanged, and stirring is continued for 20 min;

[0171] c) Glycerol, poloxamer, and hydroxyphenyl ethyl ester are added to the mixture obtained in step b), the stirring speed and temperature are kept unchanged, and stirring is continued for 15 min;

[0172] d) Perfluorotributylamine is added to the mixture obtained in step c), the stirring and heating are kept unchanged, stirring is continued for 6 h, and heating and stirring are stopped, to obtain the composite hydrogel. As shown in FIG. 1a, by optical microscope detection, the droplet size of perfluorotributylamine in the composite hydrogel obtained in this example is mainly concentrated in 10-20 μm, and there is no perfluorotributylamine droplet with a size larger than 100 μm in the photo range.

[0173] Example 2

[0174] The composite hydrogel of this example comprises the following components by weight percentage of the total weight: 10% perfluorotributylamine, 1.5% carbomer homopolymer type C, 2% triethanolamine, 4% glycerol, 5% phospholipid, 0.1% sorbic acid, and the balance water.

[0175] The preparation process of the composite hydrogel comprises the following steps:

[0176] a) After weighing the above components, the carbomer homopolymer type C is added in batches to water heated to 80°C, and stirred at a speed of 1000 rpm for 45 min;

[0177] b) Triethanolamine is added to the mixture obtained in step a), the stirring speed and temperature are kept unchanged, and stirring is continued for 10 min;

[0178] c) adding glycerol, phospholipid, sorbic acid into the mixture obtained in step b), keeping the stirring speed and temperature unchanged, continuing stirring for 20 min;

[0179] d) adding perfluorooctyl bromide into the mixture obtained in step c), keeping the stirring and heating unchanged, stirring for 4 h, stopping heating and stirring, to obtain the composite hydrogel. As shown in Fig. 1b, by light microscope detection, the droplet size of perfluorooctyl bromide in the composite hydrogel obtained in this example mainly concentrates in 10-20 μm, and there is no perfluorooctyl bromide droplet with size higher than 100 μm in the range of the photo.

[0180] Example 3

[0181] The composite hydrogel of this example contains the following components in percentage of the total weight: 7% perfluorohexyl n-octane, 1.5% C-type carbomer homopolymer, 2.5% triethanolamine, 7% glycerol, 4% Tween 80, 0.2% sodium benzoate and the balance of water.

[0182] The preparation process of the composite hydrogel comprises the following steps:

[0183] a) after weighing the above components, adding the C-type carbomer homopolymer into water heated to 60°C in batches, stirring at a speed of 1000 rpm for 45 min;

[0184] b) adding triethanolamine into the mixture obtained in step a), keeping the stirring speed and temperature unchanged, continuing stirring for 10 min;

[0185] c) adding glycerol, Tween 80 and sodium benzoate into the mixture obtained in step b), keeping the stirring speed and temperature unchanged, continuing stirring for 20 min;

[0186] d) adding perfluorohexyl n-octane into the mixture obtained in step c), keeping the stirring and heating unchanged, stirring for 5 h, stopping heating and stirring, to obtain the composite hydrogel.

[0187] As shown in Fig. 1c, by light microscope detection, the droplet size of perfluorohexyl n-octane in the composite hydrogel obtained in this example mainly concentrates in 10-20 μm, and there is no perfluorohexyl n-octane droplet with size higher than 100 μm in the range of the photo.

[0188] Example 4

[0189] The composite hydrogel of this example contains the following components in percentage of the total weight: 3% perfluorooctyl bromide, 1% C-type carbomer homopolymer, 1.5% triethanolamine, 4% glycerol, 3% Tween 80, 0.1% hydroxybenzoate and the balance of water.

[0190] The preparation of the composite hydrogel:

[0191] a) After weighing the above components, the C-type carbomer homopolymer was added in batches to water heated to 75°C, and stirred at a speed of 1000 rpm for 45 min;

[0192] b) To the mixture obtained in step a), triethanolamine was added, the stirring speed and temperature were kept unchanged, and stirring was continued for 20 min;

[0193] c) To the mixture obtained in step b), glycerol, Tween 80, and hydroxybenzyl ester were added, the stirring speed and temperature were kept unchanged, and stirring was continued for 15 min;

[0194] d) To the mixture obtained in step c), perfluorooctane bromide was added, the stirring and heating were kept unchanged, stirring was continued for 4 h, and then heating and stirring were stopped, to obtain the composite hydrogel.

[0195] As shown in FIG. 1d, by optical microscope detection, the droplet size of perfluorooctane bromide in the composite hydrogel obtained in this example was mainly concentrated in 15-30 μm, and there was no perfluorooctane bromide droplet with a size larger than 100 μm in the range of the photograph.

[0196] Comparative Example 1

[0197] The gel matrix of this comparative example contained the following components in terms of weight percentage of the total weight: 1% of C-type carbomer homopolymer, 1.5% of triethanolamine, 4% of glycerol, 3% of Tween 80, 0.1% of hydroxybenzyl ester, and the balance of water.

[0198] Preparation of the gel matrix:

[0199] a) After weighing the above components, the C-type carbomer homopolymer was added in batches to water heated to 75°C, and stirred at a speed of 1000 rpm for 45 min;

[0200] b) To the mixture obtained in step a), triethanolamine was added, the stirring speed and temperature were kept unchanged, and stirring was continued for 20 min;

[0201] c) To the mixture obtained in step b), glycerol, Tween 80, and hydroxybenzyl ester were added, the stirring speed and temperature were kept unchanged, and stirring was continued for 15 min, and then heating and stirring were stopped, to obtain the composite hydrogel control gel matrix.

[0202] Table 1. Prescription ratio of Example 4 and Comparative Example 1

[0203] Example 5

[0204] The composite hydrogel of this example had the same component composition as Example 2, except that in the preparation method:

[0205] The stirring temperature of steps a) to d) is 25℃.

[0206] As shown in Figure 1e, by optical microscope detection, the droplet size of perfluorooctyl bromide in the composite hydrogel obtained in this example is mainly concentrated in 40-70 μm, and there is no perfluorooctyl bromide droplet with a size greater than 100 μm in the range of the photo.

[0207] Example 6

[0208] The composite hydrogel of this example has the same component composition as that of Example 2, except that in the preparation method:

[0209] The stirring time of step d) is 20 min.

[0210] As shown in Figure 1f, by optical microscope detection, the droplet size of perfluorooctyl bromide in the composite hydrogel obtained in this example is mainly concentrated in 45-85 μm, and there is no perfluorooctyl bromide droplet with a size greater than 100 μm in the range of the photo.

[0211] Example 7

[0212] This example is a composite hydrogel, and other component compositions and preparation methods are the same as those of Example 4, except that perfluorooctyl bromide is replaced by perfluorooctyl bromide and perfluorohexyl-n-octane (weight ratio of 1:1).

[0213] As shown in Figure 1g, by optical microscope detection, the droplet size of perfluorooctyl bromide in the composite hydrogel obtained in this example is mainly concentrated in 10-30 μm, and there is no perfluorooctyl bromide droplet with a size greater than 100 μm in the range of the photo.

[0214] Comparative Example 2

[0215] The composite hydrogel of this example has the same component composition and preparation method as those of Example 1, except that:

[0216] The gel thickener B-type carbomer homopolymer is replaced by an equal amount of hyaluronic acid (molecular weight of three hundred to one million daltons, and the dynamic viscosity measured at 25℃ is 15-20 Pa·s), and the amount of triethanolamine is adjusted to make the pH value of the composite hydrogel of this example 5-8.

[0217] The composite hydrogel obtained in this comparative example is settled when the long stability test is carried out for two months.

[0218] Example 8

[0219] In the pig model of benign pigmented lesions with subcutaneous tattooing, the therapeutic effects of no laser treatment, laser treatment only, gel matrix (gel matrix prepared in Comparative Example 1) + laser treatment, and composite hydrogel (composite hydrogel prepared in Example 4) + laser treatment were tested and compared.

[0220] 1. Study design

[0221] Three male Bama pigs, about 2-3 months old, weighing about 10 kg. All Bama pigs were caged and fed in normal experimental rooms, exposed to a 12-hour dark 12-hour light cycle.

[0222] 2. Model of benign pigmented lesions with subcutaneous tattooing

[0223] The back skin of the Bama pig was tattooed to establish a model of benign pigmentation. Briefly, quarantine qualified Bama pigs were included in the study group and started to be fed, and anesthesia was performed after 7 days. The left and right sides of each animal were divided into 4 equal size square tattooing areas, a total of 12 tattoos, and the same pattern of tattooing was performed. After the model was established, the animals were continued to be fed for 4 weeks, and then laser treatment was started.

[0224] 3. Treatment regimen

[0225] This study included four experimental groups. Each group randomly corresponded to any tattooing of three Bama pigs (Table 2), and different treatment methods were performed every 4 weeks after the model was established, and a total of two treatments were performed.

[0226] Table 2. Detailed information of laser treatment on the body surface

[0227] 4. Clinical observation

[0228] After the modeling was successful (before treatment intervention), before the first cycle of treatment, 0 days, 3 days, and 10 days after treatment, before the second cycle of treatment, 0 days, 3 days, and 10 days after treatment, the modeling area was photographed at the observation endpoint to ensure uniformity of the field of view size, shooting angle, background, and light. The photographed area had obvious hair coverage and needed to be shaved. At the same time, blood and pathological examinations were performed at the observation endpoint.

[0229] 5. Sample collection

[0230] After the observation at the observation endpoint, all Bama pigs were sacrificed, and the benign pigmented lesion modeling site and surrounding skin were carefully removed. Part of the skin was paraffin-embedded and sectioned, and then the whole mount was further treated for staining.

[0231] 6. Clinical observation and photographing results

[0232] After the modeling is successful, the modeling area is photographed and observed before and after the first cycle of treatment (i.e., before and after the laser treatment), and different subcutaneous tattoo conditions in each group are checked.

[0233] Comparing the image of the blank control group (group 1) (Figure 2) with the images of the different treatment groups (Figures 3-5), it can be seen that the skin of group 2 has pits and is severely damaged, the application effect of the experimental group (group 4) is the best, and the protection effect on the skin is excellent. At the same time, when the laser treatment is performed on the body surface of the experimental animals in group 2, the heart rate of the experimental animals in group 2 is faster and fluctuates more than that in group 4. After comparison, it is found that the experimental animals in group 2 feel more severe pain during treatment.

[0234] 7. Data analysis

[0235] The different treatment groups are photographed after the first cycle of treatment, and the whitening of the treatment area after laser irradiation is calculated according to the obtained images. The whitening area ratio of the treatment area after laser irradiation is shown in Figure 6. It can be seen that the whitening area of the experimental group (group 4) is the smallest.

[0236] At the observation endpoint, the collected photos of the modeled and treated skin samples are analyzed, and the remaining tattoo area ratio of each group is obtained based on the tattooed area of the blank control group (group 1) as the standard, as shown in Figure 7. Among them, the tattoo area of the experimental group (group 4) is reduced the most.

[0237] At the observation endpoint, part of the collected modeled and treated skin samples are paraffin-embedded and sectioned, and the sections are stained with HE. The HE-stained sections are shown in Figure 8. The skin of group 2 is severely damaged, the skin of group 3 is thickened, and the skin of group 4 is less affected. Part of the collected modeled and treated skin samples are homogenized, and then the expression levels of inflammatory cytokines TNF-α, IL-6, and MMP-9 are detected by ELISA. The detection results are shown in Figure 9. The results show that after two cycles of laser treatment, the skin damage in the laser irradiation treatment area of the experimental group 4 is better than that of the experimental groups 2 and 3, and the expression of inflammatory signals in the same area is less than that of the experimental groups 2 and 3.

[0238] Comparative Example 3

[0239] In the Bama pig model of benign pigmented lesions of subcutaneous tattoos in Example 8, a commercially available perfluorodecahydronaphthalene patch control group is added, and the visibility of Example 4 and the commercially available perfluorodecahydronaphthalene patch (product from Merz North America, Inc., product name PFD Patch) is investigated during the laser irradiation treatment of the skin. The evaluation method and results are shown in Example 9.

[0240] ​Example 9

[0241] In the Bama pig model of benign pigmented lesions of subcutaneous tattoos of Example 8, the visibility of the composite hydrogel and gel matrix prepared in Example 4, Comparative Example 1, and Comparative Example 3 was investigated when performing the skin operation of each laser irradiation treatment.

[0242] In the model of benign pigmented lesions of subcutaneous tattoos, the experimental operator was questioned when performing laser treatment each time, and the spot brightness, spot size, and ease of operation were evaluated on a scale of 0-5 from low to high. The scoring is shown in Table 3. By comparing each score and the total score, it was concluded that the composite hydrogel prepared in Example 4 had better visualization and was beneficial to the scattering of laser. At the same time, during treatment, the light intensity at half the distance between the treatment area and the laser treatment operator's eyes was detected using a luxmeter, and the results are shown in Table 3.

[0243] Table 3. Scoring of the visualization degree of the composite hydrogel and gel matrix in the model animal experiment

[0244] Conclusion: Comparative Example 3 had a lower score, mainly because the spot brightness was not enough, and the operator thought that the patch needed to be repeatedly removed and the skin surface needed to be wiped during use, which was cumbersome. Moreover, the reflected light intensity was very high, which posed a risk of blindness. Compared with Comparative Examples 1 and 3, Example 4 significantly reduced the reflected light intensity and avoided the risk of blindness. Compared with Comparative Example 1, Example 4 had a higher score, indicating that the presence of fluorocarbon material (perfluorocarbon or / and semi-fluorinated alkane) droplets enhanced the visualization effect during treatment.

[0245] Example 10

[0246] The stability of the different composite hydrogels prepared in the different examples described above was investigated.

[0247] The composite hydrogels and gel matrices prepared in Examples 1-6, Comparative Examples 1 and 2 were stored under the following conditions for a stability study of 6 months (accelerated) and 36 months (long-term). The results of the accelerated stability and long-term stability are shown in Tables 4 and 5, respectively.

[0248] Storage condition: stored in the dark and sealed.

[0249] Table 4. Results of the short-term stability investigation of the composite hydrogels and gel matrices prepared in the examples and comparative examples (accelerated, 40°C)

[0250] Table 5. Results of the long-term stability investigation of the composite hydrogels and gel matrices prepared in the examples and comparative examples (long-term, 25°C)

[0251] The photos of the samples of Example 2 (left) and Example 5 (right) at the end of the stability release in the long-term stability experiment are shown in Figure 10. As can be seen from Figure 10 and the evaluation in Table 4 and Table 5, the composite hydrogels prepared in Example 5 and Example 6 can be stably stored in the short term, but there is a problem of sedimentation and stratification in long-term storage.

[0252] The above is a schematic description of the present application and its embodiments, which is not restrictive, and the embodiments shown in the examples are only one of the embodiments of the present application, and the actual embodiments are not limited thereto. Therefore, if a person of ordinary skill in the art is inspired thereby, without departing from the spirit of the present application, similar embodiments and examples of the technical solutions are not creatively designed, which shall all belong to the protection scope of the present application.

Claims

1. A composite hydrogel, characterized in that, Include: Perfluorinated carbon and / or semifluorinated alkane comprising 1–60% by weight relative to the total weight of the composite hydrogel; and Gel matrix; The perfluorinated carbon and / or semifluorinated alkane are dispersed in the gel matrix in the form of droplets; In the droplets, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1 to 100 μm is not higher than 0.

1.

2. The composite hydrogel according to claim 1, characterized in that, The perfluorinated carbon is selected from one or more of perfluorotripropylamine, perfluorotributylamine, perfluorobromooctane, perfluoron-butyltetrahydrofuran, perfluorooctane, perfluoronaphthane, and perfluorophenanthrene; the hemifluorinated alkane has the molecular formula C2. a H 2a+1 -C b F 2b+1 , where a is selected from any integer value from 3 to 10, and b is selected from any integer value from 3 to 10; Preferably, the semifluorinated alkane is selected from C5H. 11 -C4F9,C6H 13 -C4F9,C6H 13 -C6F 13 C8H 17 -C6F 13 C9H 19 -C6F 13 C 10 H 21 -C6F 13 One or more of them.

3. A composite hydrogel, characterized in that, Include: The perfluorocarbon is perfluorooctane, comprising 1-60% by weight relative to the total weight of the composite hydrogel; and Gel matrix; The perfluorooctane is dispersed in the gel matrix in the form of droplets; In the droplets, the ratio of the number of droplet particles with a diameter greater than 100 μm to the number of droplet particles with a diameter of 1 to 100 μm is not higher than 0.

1.

4. The composite hydrogel according to any one of claims 1 to 3, characterized in that, The ratio of the number of droplets with a diameter greater than 100 μm to the number of droplets with a diameter of 1–100 μm is not higher than 0.

05.

5. The composite hydrogel according to any one of claims 1 to 4, characterized in that, The gel matrix contains a gel thickener, and the dynamic viscosity of the gel thickener at 25°C is not less than 20 Pa·s.

6. The composite hydrogel according to any one of claims 1 to 5, characterized in that, The gel matrix comprises a gel thickener, a pH adjuster, a humectant, an emulsifier, and water; Preferably, the gel thickener is selected from one or more of carbomer, hyaluronic acid, sodium hyaluronate, and sodium carboxymethyl cellulose; Preferably, the carbomer is selected from one or both of type B carbomer homopolymers and type C carbomer homopolymers; Preferably, the pH adjuster is selected from one or more of triethanolamine, sodium hydroxide, and potassium hydroxide; Preferably, the moisturizer is selected from one or more of glycerin, propylene glycol, and 1,2-pentanediol; Preferably, the emulsifier is selected from one or more of poloxamer, Tween, and phospholipids; Preferably, the gel matrix further comprises a bactericide and preservative; More preferably, the bactericidal preservative is selected from one or more of hydroxyphenyl ester, benzoate, sorbic acid or their salts.

7. The composite hydrogel according to any one of claims 1 to 6, characterized in that, The gel matrix comprises: The weight percentage of carbomer relative to the total weight of the composite hydrogel is 0.5% to 2.5%; The triethanolamine comprises 0.5% to 4% of the total weight of the composite hydrogel. The weight percentage of glycerol relative to the total weight of the composite hydrogel is 1-8%; An emulsifier comprising 1 to 6% by weight relative to the total weight of the composite hydrogel; A bactericide and preservative comprising 0 to 0.2% of the total weight of the composite hydrogel; and water.

8. A method for preparing the composite hydrogel according to any one of claims 1 to 7, characterized in that, Includes the following steps: a) Heating and stirring to swell the gel thickener; b) Add a pH adjuster to the mixture obtained in step a), and continue stirring and heating until a gel forms; c) Add a humectant, an emulsifier, and an optional bactericide and preservative to the mixture obtained in step b), while stirring and heating. d) Add perfluorinated carbon and / or semifluorinated alkane to the mixture obtained in step c), and keep stirring and heating to obtain a composite hydrogel.

9. The method for preparing the composite hydrogel according to claim 8, characterized in that, The stirring speed in steps a) to d) is 600 to 1500 rpm, preferably 800 to 1200 rpm; the heating temperature in steps a) to d) is 25 to 90°C, preferably 70 to 80°C.

10. The method for preparing the composite hydrogel according to claim 9, characterized in that, The stirring time in step a) is 30-60 min; the stirring time in step b) is 10-20 min; the stirring time in step c) is 10-20 min; and the stirring time in step d) is 20-720 min.

11. The use of the composite hydrogel according to any one of claims 1 to 7 in the removal of benign pigmentation.

12. The application according to claim 11, characterized in that, The benign pigmentation is selected from one or more of the following: nevus of Ota, seborrheic keratosis, melasma, café au lait, freckles, age spots, benign pigmentation, and tattoos.

13. The application according to claim 11, characterized in that, The composite hydrogel can be applied before, during, or after light irradiation of the skin by phototherapy devices.

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