A traditional Chinese medicine compound penetration-promoting external use gel for treating psoriasis and a preparation method thereof

Abstract

The present application relates to a kind of traditional Chinese medicine compound penetration-promoting external gel for treating psoriasis and its preparation method, the gel component includes hydrogel matrix, Huanglian extract, Huangbai extract, penetration-promoting agent;The penetration-promoting agent is exogenous nitric oxide donor.The obtained external gel has efficient penetration-promoting effect for alkaloids, Huanglian and Huangbai two medicinal materials synergistic effect, can reduce the expression of inflammatory factors, eliminate skin-related symptoms, for the treatment of psoriasis.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a traditional Chinese medicine compound external gel containing an exogenous nitric oxide (NO) donor, a preparation method thereof, and its application in the treatment of psoriasis. Background Art

[0002] Psoriasis (commonly known as psoriasis) is a common and easily relapsing chronic inflammatory skin disease, characterized by the appearance of red papules or plaques on the skin, covered with multiple layers of silver-white scales. Traditional drug treatment methods include chemical drug treatment, traditional Chinese medicine treatment, and biological agent treatment; conventional administration methods include topical administration and systemic administration.

[0003] The advantages of traditional Chinese medicine in treating psoriasis are as follows: 1. Traditional Chinese medicine syndrome differentiation treatment mainly regulates the patient's constitution, and the effect is ideal; 2. The toxic and side effects are relatively small; 3. It can reduce the probability of psoriasis attack, extend the onset time window, and reduce the recurrence rate.

[0004] The advantages of topical treatment of psoriasis are direct action on the skin lesions, rapid onset, convenient use, few systemic adverse reactions, and reduced adverse reactions. Conventional topical preparations include: creams, solutions, and gels. Among them, gels have the advantages of easy spreading, good comfort, no greasy feeling, easy to wash out, and no interference with the normal physiological functions of the skin. Modern traditional Chinese medicine gels have been increasingly applied to the topical treatment of skin diseases.

[0005] Thermosensitive hydrogel is a temperature-responsive reversible hydrogel that is liquid at low temperature and coagulates into a semi-solid state at high temperature. During the treatment of skin diseases, the liquid gel can become solid on the skin, separating the skin from the external environment and playing a temporary protective role. Thermosensitive gels can better control the morphology after gel administration, are easy to operate, non-toxic, have good biocompatibility, high transparency, are conducive to observing skin changes, and also have certain permeability enhancement, making them suitable as the main matrix of modern traditional Chinese medicine gels.

[0006] In order to enhance the permeability enhancement effect of active ingredients, penetration enhancers such as borneol, propylene glycol, and azone are usually added to topical preparations. For chemical drugs, the best penetration enhancer can be obtained through screening. However, traditional Chinese medicine has complex components, and usually multiple active ingredients work synergistically. Relying solely on one penetration enhancer may result in only some active ingredients being able to penetrate into the skin. Therefore, the selection of penetration enhancers for traditional Chinese medicine topical preparations is a technical problem. Summary of the Invention

[0007] The purpose of the present invention is to provide an external hydrogel mainly composed of extracts of two traditional Chinese medicines, Coptis chinensis and Phellodendron amurense, and using an exogenous nitric oxide donor compound as a penetration enhancer for topical treatment of psoriasis.

[0008] The solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0009] A traditional Chinese medicine compound external gel for promoting penetration, wherein the gel components include a hydrogel matrix, Coptis chinensis extract, Phellodendron chinense extract, and a penetration enhancer; wherein the penetration enhancer is an exogenous nitric oxide donor.

[0010] Further, the gel component comprises, by weight:

[0011] 22-36 parts of hydrogel matrix

[0012] 1-3 parts of Coptis chinensis extract

[0013] 1-3 parts of Phellodendron bark extract

[0014] 0.5-1 part of penetration enhancer.

[0015] Furthermore, the hydrogel matrix is ​​thermosensitive.

[0016] Furthermore, the hydrogel matrix components include poloxamer 407, poloxamer 188, and polyethylene glycol.

[0017] Furthermore, the polyethylene glycol is preferably polyethylene glycol 6000.

[0018] Furthermore, the mass ratio of poloxamer 407, poloxamer 188, and polyethylene glycol is (20~30):(1~3):(1~3), more preferably (22-22.5):(2-2.5):(1-1.5).

[0019] Furthermore, the exogenous nitric oxide donor is an S-nitrosothiol compound, including S-nitrosoglutathione, S-nitrosoacetylpenicillamine, and S-nitrosoacetylcysteine. The penetration enhancer can promote greater penetration of the relevant alkaloid components in the decoction of Coptis chinensis and Phellodendron amurense through the skin.

[0020] Furthermore, the relative density of the Coptis chinensis extract and the Phellodendron chinense extract is 1.01-1.02 g / ml.

[0021] This invention also provides a method for preparing a traditional Chinese medicine compound external gel for promoting penetration, comprising the following steps:

[0022] (1) Coptis chinensis extract and Phellodendron chinense extract were obtained by decoction and concentration.

[0023] (2) Obtain the hydrogel matrix solution;

[0024] (3) Add Coptis chinensis extract, Phellodendron chinense extract and penetration enhancer to the hydrogel matrix solution, stir to dissolve, and allow the gel to fully swell to obtain the Chinese herbal compound penetration enhancer external gel.

[0025] Furthermore, the method for decocting the Coptis chinensis extract and Phellodendron amurense extract is as follows: soak Coptis chinensis slices or Phellodendron amurense slices in 6-10 times the amount of water for 30-50 minutes, heat to boiling, decoct for 1-3 hours, filter, add water to the herbs and decoct several times, combine the decoctions, filter and concentrate until the relative density of the Coptis chinensis extract and Phellodendron amurense extract is 1.01-1.02 g / ml, which is the final product.

[0026] Further, the hydrogel matrix solution is prepared by: adding poloxamer 407, poloxamer 188, and polyethylene glycol to water at 0-4℃ and stirring to dissolve them, then carrying out a cross-linking reaction to obtain the hydrogel matrix solution. Further, the stirring speed is 3000-6000 r / min; the reaction time is 0.5-2 h.

[0027] Furthermore, the penetration enhancer is added to the hydrogel matrix under light-protected conditions.

[0028] This invention also provides the application of the above-mentioned traditional Chinese medicine compound penetration-enhancing external gel in the preparation of a medicament for treating psoriasis. The medicament for treating psoriasis can be applied by smearing, spraying, or pouring onto the affected skin.

[0029] This invention utilizes an exogenous nitric oxide donor compound as a penetration enhancer, combined with extracts of Coptis chinensis and Phellodendron chinense to prepare a traditional Chinese medicine compound topical gel for treating psoriasis. Experiments have demonstrated that the exogenous nitric oxide donor effectively promotes the penetration of berberine, phellodendronine, and gentianine in the extracts of Coptis chinensis and Phellodendron chinense, achieving a multi-component synergistic reduction of inflammatory factor expression, eliminating skin-related symptoms, and demonstrating significant advantages and efficacy in treating psoriasis. Furthermore, this invention uses a thermosensitive hydrogel as a matrix, exhibiting properties such as rapid phase transition and high viscosity. Attached Figure Description

[0030] Figure 1 The rheological scan and rheological property diagrams are shown for the temperature-sensitive changes of the drug-loaded gel obtained in Example 2.

[0031] Figure 2 The effects of different penetration enhancers on the penetration of Rhodamine B are shown in the figures: Blank represents the drug-loaded gel without penetration enhancer obtained in Example 1, CPG-A represents the hydrogel containing azone as a penetration enhancer obtained in Comparative Example 4, and CPG-S represents the hydrogel containing exogenous NO donor S-nitrosoacetylpenicillamine as a penetration enhancer obtained in Example 2.

[0032] Figure 3The effects of different penetration enhancers on the penetration of different alkaloid components in the decoction of traditional Chinese medicine were investigated. Among them, berberine (A, D), berberine (B, E), and phellodendron chinense (C, F) were included. GSNO represents S-nitrosoglutathione, Azone represents azone, Borneol represents borneol, SNAP represents S-nitrosoacetylpenicillamine, Blank represents drug-loaded gel without penetration enhancer, Prog represents propylene glycol, NOAC represents S-nitrosoacetylcysteine, and SNP represents sodium nitroprusside.

[0033] Figure 4 The figures illustrate the effects of Example 2, Comparative Example 4, and commercially available tacrolimus ointment (MFC) in treating imiquimod (IMQ)-induced psoriasis in mice. The subfigures represent the following: liver body index (A), spleen body index (B), interleukin IL-17A (C), leukocyte IL-23 (D), PASI skin redness score (E), and PASI area score (F) in mice.

[0034] Figure 5 The images show a comparison of the skin of the thermosensitive hydrogel obtained in Example 2 and Comparative Example 4 of this invention and the commercially available tacrolimus ointment (MFC) after treatment of an imiquimod-induced mouse psoriasis model.

[0035] Figure 6 This is a comparison of skin HE-stained sections after treatment of an imiquimod-induced mouse psoriasis model with the thermosensitive hydrogel obtained in Example 2 and Comparative Example 4 of the present invention and the commercially available tacrolimus ointment (MFC).

[0036] Figure 7 High-performance liquid chromatography (HPLC) chromatograms showing the effects of different permeation enhancers on the permeation-enhancing effects of berberine and coptisine in the decoction of traditional Chinese medicine.

[0037] Figure 8 High-performance liquid chromatography (HPLC) chromatograms showing the effects of different permeation enhancers on the permeation-enhancing effects of berberine in decoctions of traditional Chinese medicine. Detailed Implementation

[0038] To better understand the present invention, the following embodiments are further illustrations of the present invention, but the content of the present invention is not limited to the following embodiments.

[0039] Example 1

[0040] Take 30g of Coptis chinensis slices, add 300g of water, soak for 40 minutes, heat to boiling, decoct for 60 minutes, filter, add 300g of water again and decoct, decoct a total of 3 times, combine the 3 decoctions, filter and concentrate to a relative density of 1.01-1.02g / ml (25℃) to obtain Coptis chinensis decoction; take 30g of Phellodendron amurense slices, add 240g of water, soak for 40 minutes, heat to boiling, decoct for 40 minutes, decoct twice, combine the 2 decoctions, filter and concentrate to a relative density of 1.01-1.02g / ml (25℃) to obtain Phellodendron amurense decoction.

[0041] 5.625 g of poloxamer 407 was dissolved in 25 ml of deionized water at 0–4 °C. The solution was magnetically stirred at 3000 r / min until homogeneous, yielding a poloxamer 407 solution. 0.508 g of poloxamer 188 and 0.295 g of polyethylene glycol 6000 were then slowly added sequentially to the poloxamer 407 solution. The solution was magnetically stirred at 6000 r / min at 0–4 °C until homogeneous, yielding a blank gel solution.

[0042] At a temperature of 0-4℃ and a stirring speed of 6000 r / min, 1 ml of concentrated extracts of Coptis chinensis and Phellodendron chinense with a relative density of 1.01-1.02 g / ml were added to the blank gel solution above and stirred evenly to obtain a drug-loaded gel solution.

[0043] Example 2

[0044] Acetylpenicillamine was dissolved in methanol at a mass-to-volume ratio of 0.026. Concentrated hydrochloric acid was added at a mass-to-volume ratio of 0.3, using acetylpenicillamine as a control. A 0.094 g / ml aqueous solution of sodium nitrite at 0-5 °C was slowly added to the reaction solution. The reaction was carried out at 0-5 °C for 20 min, during which the solution changed from colorless to reddish-green and a solid was formed. The system was filtered under reduced pressure, the filter cake was washed with ice water, and dried at room temperature to obtain S-nitrosoacetylpenicillamine.

[0045] Under light-protected conditions, 1 g of the synthesized S-nitrosoacetylpenicillamine was added to 25 ml of blank drug-loaded gel solution prepared by the method described in Example 1. The mixture was stirred evenly at 6000 r / min at a temperature of 0-4°C, transferred to a glass container, and refrigerated at 2-6°C for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with S-nitrosoacetylpenicillamine as a permeation enhancer.

[0046] Example 3

[0047] Glutathione was dissolved in methanol at a mass-to-volume ratio of 0.026. Concentrated hydrochloric acid was added at a mass-to-volume ratio of 0.3, using glutathione as a control. A 0.094 g / ml aqueous solution of sodium nitrite at 0-5 °C was slowly added to the reaction solution. The reaction was carried out at 0-5 °C for 20 min, resulting in the formation of a solid. The system was filtered under reduced pressure, the filter cake was washed with ice water, and dried at room temperature to obtain S-nitrosoglutathione.

[0048] Under light-protected conditions, 1g of the synthesized S-nitrosoglutathione was added to 25ml of blank drug-loaded gel solution prepared by the method described in Example 1. The mixture was stirred evenly at 6000r / min at a temperature of 0-4℃, transferred to a glass container, and refrigerated at 2-6℃ for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with S-nitrosoglutathione as a penetration enhancer.

[0049] Example 4

[0050] Acetylcysteine ​​was dissolved in methanol at a mass-to-volume ratio of 0.026. Concentrated hydrochloric acid was added at a mass-to-volume ratio of 0.3, with glutathione as a control. A 0.094 g / ml aqueous solution of sodium nitrite at 0-5 °C was slowly added to the reaction solution. The reaction was carried out at 0-5 °C for 20 min, resulting in the formation of a solid. The system was filtered under reduced pressure, the filter cake was washed with ice water, and dried at room temperature to obtain S-nitrosoacetylcysteine.

[0051] Take 1g of S-nitrosoacetylcysteine ​​and add it to 25ml of blank drug-loaded gel solution prepared by the method described in Example 1. Stir evenly at 6000r / min at a temperature of 0-4℃, transfer to a glass container, and refrigerate at 2-6℃ for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with S-nitrosoacetylcysteine ​​as a penetration enhancer.

[0052] Comparative Example 1

[0053] Take 1g of propylene glycol and add it to 25ml of blank drug-loaded gel solution prepared by the method described in Example 1. Stir evenly at 6000r / min at a temperature of 0-4℃, transfer to a glass container, and refrigerate at 2-6℃ for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with propylene glycol as a penetration enhancer.

[0054] Comparative Example 2

[0055] Take 1g of borneol and add it to 25ml of blank drug-loaded gel solution prepared by the method described in Example 1. Stir evenly at 6000r / min at a temperature of 0-4℃, transfer to a glass container, and refrigerate at 2-6℃ for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with borneol as a penetration enhancer.

[0056] Comparative Example 3

[0057] Under light-protected conditions, 1g of sodium nitroprusside was added to 25ml of blank drug-loaded gel solution prepared by the method described in Example 1. The solution was stirred evenly at 6000r / min at a temperature of 0-4℃, transferred to a glass container, and refrigerated at 2-6℃ for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with sodium nitroprusside as a penetration enhancer.

[0058] Comparative Example 4

[0059] Take 1g of azone and add it to 25ml of blank drug-loaded gel solution prepared by the method described in Example 1. Stir evenly at 6000r / min at a temperature of 0-4℃, transfer to a glass container, and refrigerate at 2-6℃ for 24 hours to fully swell, thus obtaining a thermosensitive hydrogel with azone as a penetration enhancer.

[0060] Gel mechanical property analysis

[0061] a) The samples were tested using parallel P35 Ti L stainless steel plates (35 mm in diameter) with a 1 mm gap. The storage modulus (G′) and loss modulus (G″) were measured, and all tests were conducted at (35.0±0.5)℃. The linear viscoelastic range of the samples was determined by amplitude scanning (strain 0.01%~100%, frequency 10 rad / s) and frequency scanning (strain 0.1%, frequency scanning range 0.1~100Hz).

[0062] b) Then perform a temperature scan from 0 to 60°C.

[0063] The results are as follows Figure 1 As shown, both results indicate that the designed gel completed the transformation from liquid to semi-solid phase at (35.0±0.5)℃, which meets the design requirements. After contact with the skin, it can quickly complete the phase transformation and adhere to the skin.

[0064] In vivo osmosis enhancement analysis

[0065] The concentrated extracts of Coptis chinensis and Phellodendron chinense in Example 1 (blank group), Example 2, and Comparative Example 4 were replaced with Rhodamine B solution for transdermal drug delivery to mice. Skin samples were then collected from euthanized mice and examined under a cryo-section fluorescence microscope. The test results are as follows: Figure 2 As shown, the hydrogel using exogenous nitric oxide donor S-nitrosoacetylpenicillamine as a permeation enhancer exhibits superior performance in promoting the permeation of Rhodamine B through the skin compared to the blank group, positive solution group, and gel group using azone as a permeation enhancer, indicating that the former has a better permeation enhancement effect.

[0066] Selective osmosis enhancement analysis

[0067] To investigate whether different penetration enhancers have selective penetration-enhancing effects on different alkaloid components, gels containing different penetration enhancers from Example 1 (blank group), Examples 2-4, and Comparative Examples 1-4 were subjected to in vitro transdermal experiments. The content of alkaloids (berberine, berberine, and phellodendron chinense) in the receiving solutions was detected by HPLC. The results are as follows: Figure 3 , 7 As shown in Figure 8, the exogenous NO donor S-nitrosoacetylpenicillamine has a significant permeation-enhancing effect on all three alkaloids. Commercially available traditional permeation enhancers (azone) have a strong permeation-enhancing effect on berberine and berberine, but a poor permeation-enhancing effect on berberine, which may be an important factor affecting the final treatment effect on psoriasis in mice.

[0068] Treatment efficacy analysis

[0069] The positive control group was treated with commercially available tacrolimus cream (MFC), while the experimental groups were treated with hydrogels containing the exogenous NO donor S-nitrosoacetylpenicillamine as a penetration enhancer (CPG-S) and hydrogels containing azone as a penetration enhancer (CPG-A). These treatments were administered to mice with imiquimod (IMQ)-induced psoriasis. After seven days of treatment, the results were as follows: Figure 4 As shown. Tacrolimus cream (MFC) and the hydrogel of the present invention (CPG-S) can significantly reduce the liver body index (A) and spleen body index (B) in psoriatic mice; at the same time, they can reduce the levels of interleukins IL-17A (C) and IL-23 (D) in mouse serum; and can alleviate redness and swelling of psoriatic skin and reduce the area of ​​scales.

[0070] Final experimental results

[0071] Mouse experimental results as follows Figure 5 and Figure 6 As shown, the pure IMQ group had redder skin, a tile-like structure, and a deeper stratum corneum, while MFC had some effect in reducing redness and swelling, but its effect in removing scabs was not obvious; (CPG-A) had poor scab-removing effect and some redness and swelling. However, after treatment with the hydrogel (CPG-S) of this invention, the skin eventually approached that of the normal group, demonstrating the effects of reducing redness and swelling, removing scabs, and eliminating psoriasis symptoms. Experimental results show that CPG-S, which can simultaneously promote the penetration of three alkaloids through the skin, has a superior therapeutic effect on psoriasis compared to CPG-A, which can only promote the penetration of two alkaloids (berberine and phellodendronine). This indicates that the simultaneous action of the three alkaloids can improve the therapeutic effect of psoriasis. Figure 5 , 6 As shown.

[0072] The above description is merely a preferred embodiment of the present invention, and should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine compound external gel for promoting penetration, characterized in that, The components of the gel, by weight, include: 22-36 parts hydrogel matrix, 1-3 parts Coptis chinensis extract, 1-3 parts Phellodendron chinense extract, and 0.5-1 parts penetration enhancer; The penetration enhancer is an exogenous nitric oxide donor, S-nitrosoacetylpenicillamine; The hydrogel matrix comprises poloxamer 407, poloxamer 188, and polyethylene glycol.

2. The traditional Chinese medicine compound external gel for promoting penetration according to claim 1, characterized in that, The hydrogel matrix is ​​thermosensitive.

3. The traditional Chinese medicine compound external gel for promoting penetration according to claim 1, characterized in that, The mass ratio of poloxamer 407, poloxamer 188, and polyethylene glycol in the hydrogel matrix is ​​(20~30):(1~3):(1~3).

4. The traditional Chinese medicine compound external gel for promoting penetration according to claim 1, characterized in that, The relative densities of the Coptis chinensis extract and Phellodendron chinense extract at 25°C are 1.01-1.

02.

5. A method for preparing a traditional Chinese medicine compound external gel with enhanced penetration, characterized in that, Includes the following steps: (1) Coptis chinensis extract and Phellodendron chinense extract were obtained by decoction and concentration. (2) Under the conditions of 0~4℃, poloxamer 407, poloxamer 188 and polyethylene glycol were added to water and stirred to dissolve, so as to obtain a thermosensitive hydrogel matrix solution. (3) Add Coptis chinensis extract, Phellodendron chinense extract, and the penetration enhancer S-nitrosoacetylpenicillamine to the thermosensitive hydrogel matrix solution, stir to dissolve, and allow the gel to fully swell to obtain the traditional Chinese medicine compound penetration-enhancing external gel; the component amounts of the traditional Chinese medicine compound penetration-enhancing external gel are as follows (by weight): The mixture contains 22-36 parts hydrogel matrix, 1-3 parts Coptis chinensis extract, 1-3 parts Phellodendron amurense extract, and 0.5-1 parts penetration enhancer.

6. The application of the traditional Chinese medicine compound permeation-enhancing external gel according to any one of claims 1 to 4 or the traditional Chinese medicine compound permeation-enhancing external gel obtained by the preparation method according to claim 5, characterized in that, Used to prepare drugs for treating psoriasis.

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