A magnesium hydroxide-based hydrogel formulation for the treatment of dermatitis and psoriasis and preparation thereof

Abstract

The application discloses a magnesium hydrogen-based hydrogel preparation for treating dermatitis and psoriasis and a preparation method of the magnesium hydrogen-based hydrogel preparation. The preparation takes a hydrogel as a carrier and loads magnesium hydride particles. The magnesium hydride particles loaded in the hydrogel preparation serve as a hydrogen gas donor. Compared with existing medical hydrogen supply modes, the magnesium hydride particles can realize local enrichment of hydrogen gas and have long-acting and slow-releasing performances. In addition, the magnesium hydride particles have excellent biological safety, are suitable for external treatment for treating dermatitis and psoriasis, can effectively regulate keratinocyte proliferation and sugar metabolism, significantly improve skin lesions and local inflammation, and can avoid side effects such as stimulation and erythema and drug resistance problems caused by common clinical medication.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials, specifically relating to a magnesium-hydrogen-based hydrogel formulation and its preparation for the treatment of dermatitis and psoriasis. Background Technology

[0002] In recent years, hydrogen has been reported to selectively neutralize strong free radicals, alleviate oxidative stress, and regulate apoptosis, gradually demonstrating its therapeutic effects on various inflammatory and immune-related diseases in clinical practice. The mechanism of hydrogen's action has become a research hotspot in various fields. The dermatology team at Huashan Hospital has also demonstrated through clinical controlled studies that hydrogen water bath therapy can improve psoriasis lesions. However, current clinical studies mainly use high-pressure hydrogen, hydrogen-rich water, and injection of saturated hydrogen saline, which involves large quantities and low efficiency. Patent CN109589332A discloses the use of hydrogen in the preparation of agents for the prevention and treatment of vitiligo, requiring a hydrogen concentration of 75% and pretreatment for at least 4 hours to achieve an antioxidant effect. Because hydrogen can explode at concentrations exceeding 4% in air, its clinical application is limited. Furthermore, under normal conditions, the solubility of hydrogen in water is only 1.83%, lower than the 3.1% of oxygen. This poor drug-likeness due to the inherent physicochemical properties of hydrogen greatly limits its clinical application. Magnesium hydride, as a solid magnesium-based hydrogen storage material, reacts with water to produce hydrogen in large quantities and with high efficiency. It is non-toxic and harmless, and has stable physicochemical properties at room temperature.

[0003] Psoriasis is a common, chronic, relapsing, immune-mediated inflammatory disease of the skin and joints, characterized by chronic, symmetrical erythematous scaling, papules, and plaques, which has a significant negative impact on patients' physical and mental health and social relationships. Currently, the global incidence of psoriasis in adults is approximately 0.51%-11.43%, and in children, it is 0%-1.37%. Psoriasis is an autoimmune disease that cannot be cured and requires lifelong medication. In the early stages of psoriasis treatment, biologics and topical medications should be used to rapidly improve the condition. However, existing first-line topical medications, such as corticosteroids and calcipotriol, have many adverse reactions, commonly including skin irritation, erythema, itching, pigmentation, and contact dermatitis. Therefore, it is essential to develop drugs based on new mechanisms and targets to achieve safe, effective, and less side-effect-prone treatments.

[0004] Although micro / nano magnesium hydride particles possess the aforementioned superior physicochemical properties compared to conventional hydrogen delivery methods such as high-pressure hydrogen and water electrolysis, their solid particle form cannot be directly used in topical medications for psoriasis. Therefore, this technical solution proposes utilizing the superior properties of magnesium hydride as a solid hydrogen storage material and employing a biocompatible, thermosensitive hydrogel as a formulation carrier to develop a novel method for developing a candidate topical hydrogen therapy drug. This method exhibits excellent biocompatibility and, for the first time, demonstrates a significant improvement in psoriasis-induced skin lesions, reduces local inflammation, and alters tissue energy metabolism levels, while avoiding the aforementioned drawbacks, side effects, and drug resistance issues of current clinical medications. Currently, there are no publicly reported studies on the use of hydrogen-delivered drug formulations in the treatment of psoriasis and other inflammatory skin diseases, nor on their beneficial effects. Patent CN114380292 discloses a method for preparing magnesium silicide two-dimensional nanosheets and their application in hydrogel wound dressings. Although the hydrogel can be used for the repair and regeneration of large-area burn wounds, its hydrogen production and long-term hydrogen release performance are insufficient, and it contains silicate byproducts that can promote hardening of tissues. Therefore, it cannot be used for the treatment of psoriasis. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of clinical drug use and the problem of insufficient hydrogen concentration at the disease target site in existing traditional hydrogen therapy by providing a magnesium-hydrogen-based hydrogel formulation and its preparation for the treatment of dermatitis and psoriasis.

[0006] This invention is the first to select thermosensitive hydrogels, including poloxamer 407, to load magnesium hydride, constructing a magnesium hydride hydrogel formulation. The selected thermosensitive hydrogels form gels through physical cross-linking, a simple process that facilitates large-scale production. Loading magnesium hydride particles with these hydrogels helps the constructed hydrogen sustained-release system to be more quickly translated into clinical applications. The gel maintains good fluidity and low viscosity for extended periods at low temperatures, making it easy to store; it also rapidly gels at room temperature or body temperature, suitable for applications in different temperature environments. The unique advantages of the poloxamer 407-loaded magnesium hydride hydrogel formulation are: ① The three-dimensional network structure of the hydrogel provides strong loading capacity and reduces the self-degradation and diffusion of magnesium hydride, facilitating the slow, controlled release of high-concentration hydrogen locally; ② Its unique thermosensitive properties make the formulation suitable for different temperature environments, allowing for immediate preparation and use, and its in-situ gelation at body temperature makes it applicable to local wounds of different shapes and depths.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides a magnesium hydride-loaded hydrogel formulation, wherein the magnesium hydride-loaded hydrogel formulation uses a thermosensitive hydrogel as a carrier to load magnesium hydride particles; the hydrogel and the particle surface interact through hydrogen bonds (OH) and ionic bonds (Mg-O) to form a composite hydrogel system that is stable at body temperature.

[0009] As one embodiment of the present invention, the thermosensitive hydrogel includes one or more hydrogel combinations selected from poloxamer 407, poloxamer 188, PNIPAM (poly-N-isopropylacrylamide), chitosan and its derivatives.

[0010] In one embodiment of the present invention, the magnesium hydride particles have a particle size of 0.1-100 μm. Due to safety limitations in the magnesium hydride manufacturing process, the minimum particle size of magnesium hydride particles is 100 nm. Furthermore, in the gel system of the present invention, the higher the particle size of the magnesium hydride particles, the slower the hydrogen release rate, which affects the local enrichment of hydrogen and fails to achieve an effective therapeutic concentration.

[0011] Secondly, the present invention provides a method for preparing the magnesium hydride-loaded hydrogel formulation, the method comprising the following steps: dissolving a gel matrix in physiological saline, allowing it to stand overnight at 0-8°C, adding magnesium hydride particles thereto, mixing evenly, allowing it to stand to form a gel, and obtaining the magnesium hydride-loaded hydrogel formulation.

[0012] In one embodiment of the present invention, the gel matrix is ​​poloxamer 407, and the concentration of the poloxamer 407 gel solution is 10-40 wt%. Since the present invention is a topical gel for skin use, too low a gel concentration will prevent gel formation at body temperature (37°C), while too high a gel concentration will result in high gel viscosity, preventing effective hydrogen release.

[0013] In one embodiment of the present invention, the gel matrix is ​​PNIPAM, and the concentration of the PNIPAM gel solution is 0.1-10%. Higher gel concentrations require higher concentrations of toxic crosslinking agents, which is detrimental to application.

[0014] In one embodiment of the present invention, the gel matrix is ​​a composite gel matrix of poloxamer 407 and poloxamer 188 with a mass concentration ratio of 30:(0-3). The present invention is a topical skin gel, and to prevent the inability to gel at body temperature (37°C) due to excessively high concentrations of poloxamer 188, a mass concentration ratio of 30:(0-3) is selected.

[0015] In one embodiment of the present invention, the gel matrix is ​​a composite gel matrix of PNIPAM and chitosan with a mass concentration ratio of 25:(1-10). This composite gel forms a double network structure. If the concentration ratio is too high, the mechanical properties of the gel are stronger, which is not conducive to application to wounds of different depths and shapes.

[0016] As one embodiment of the present invention, the temperature for settling and gelling is 20-37°C, and the settling and gelling time is 1-30 minutes.

[0017] Thirdly, the present invention provides the use of the aforementioned magnesium hydride hydrogel formulation in the preparation of dermatitis and psoriasis treatment agents.

[0018] In this invention, the magnesium hydride hydrogel formulation serves as a localized sustained-release and moisturizing agent for hydrogen, thereby achieving long-lasting localized controlled-release of hydrogen and improving pH fluctuations and excessive local magnesium ion levels in the microenvironment.

[0019] In this invention, the magnesium hydride-loaded hydrogel formulation contains magnesium hydride at a concentration of 0.5-10 mg / mL. Animal experiments have shown that excessively low magnesium hydride concentrations cannot achieve effective therapeutic results, while excessively high concentrations produce too much and too rapid gas, affecting the gel's network structure and hindering local hydrogen accumulation and sustained release. Therefore, the magnesium hydride concentration must be controlled within the range of 0.5-10 mg / mL. This magnesium hydride-loaded hydrogel formulation can be used externally to treat dermatitis and psoriasis, regulating tissue energy metabolism, modulating immunity, significantly improving skin lesions, and reducing local inflammation. Specifically, the sustained-release, locally high concentration of hydrogen can alleviate psoriatic lesions, reduce local inflammation, and regulate tissue energy metabolism, thereby achieving the therapeutic goal. The optimal therapeutic concentration is 5 mg / mL.

[0020] The magnesium hydride hydrogel formulation described in this invention can be administered via external application, providing theoretical support for its clinical translational application. Of course, when used as a therapeutic agent, it can also be used in combination with other drugs or sustained-release agents to enhance the therapeutic effect.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] (1) In order to solve the problems of easy diffusion, difficulty in enrichment and low local concentration of hydrogen gas in the current traditional treatment, the present invention discloses the preparation and application of a magnesium hydride-loaded hydrogel preparation, which has good local enrichment and sustained release performance of hydrogen gas, and provides a basis for the research of hydrogen-related drugs.

[0023] (2) The magnesium hydrogenated hydrogel formulation of this invention is based on a solid magnesium-based hydrogen storage material, combined with poloxamer 407 hydrogel. Utilizing the excellent water retention and tissue compatibility of the hydrogel, and assisting in the slow release of hydrogen, it has the potential to be prepared as a hydrogen-sustaining dressing. Its thermosensitive and in-situ gelling properties allow it to be applied to locally infected wounds of different shapes and depths. In its application to psoriasis, it has been found to alleviate skin lesions, reduce inflammation, and regulate metabolism, potentially becoming a strong alternative for the treatment of dermatitis and psoriasis.

[0024] (3) In the magnesium hydrogel formulation of the present invention, a stable composite hydrogel system at body temperature is formed through the interaction between the specific hydrogel and the particles, and the interaction between the specific hydrogel and the particle surface: hydrogen bond (O----H) and ionic bond (Mg-O); while achieving long-term local controlled release of hydrogen, it also improves the pH change and local magnesium ion excess in the microenvironment. Attached Figure Description

[0025] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0026] Figure 1 A schematic diagram of the magnesium hydride hydrogel formulation and a digital photograph of the back of a mouse after treatment;

[0027] Figure 2 Transmission electron microscopy image of magnesium hydride nanoparticles;

[0028] Figure 3 The gelation of magnesium hydride hydrogel formulation under different temperature conditions;

[0029] Figure 4 Digital photographs of the skin on the backs of mice in different experimental groups;

[0030] Figure 5 Pathological analysis of the back skin of mice in different experimental groups (HE staining). Detailed Implementation

[0031] The specific embodiments of the present invention will be described in detail below with reference to the examples. The following examples are implemented based on the technical solution of the present invention, providing detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following examples. Unless otherwise specified, all methods are conventional; the reagents and materials mentioned are commercially available unless otherwise specified.

[0032] It should be noted that in the following embodiments, magnesium hydride can be prepared with any particle size ranging from 0.1 to 100 μm to produce magnesium hydride-loaded hydrogel formulations with similar effects to those in the following embodiments.

[0033] Example 1: Preparation of magnesium hydride-loaded hydrogel formulation

[0034] Preparation of poloxamer 407 hydrogel loaded with nano-magnesium hydride: Depending on the application, a 25% poloxamer 407 saline solution was used. After complete dissolution at 4°C, the solution was placed in a refrigerator overnight to remove air bubbles. An appropriate amount of magnesium hydride was added at 4°C to prepare a hydrogel solution with a final magnesium hydride concentration of 5 mg / ml. The solution was then allowed to stand at room temperature to form a gel. Figure 1The hydrogel formulation was applied to psoriatic lesions, achieving optimal therapeutic effects. Compared with calcipotriol, a clinical treatment for psoriasis, it showed a certain advantage in improving erythema.

[0035] Example 2: Preparation of magnesium hydride-loaded hydrogel formulation

[0036] Preparation of PNIPAM hydrogel-supported magnesium hydride: Depending on the application, 0.5 g of N-isopropylacrylamide was dissolved in water, along with 0.12 mL of N,N'-methylenebisacrylamide (5% wt). The mixture was stirred until homogeneous, then a 1.5% potassium persulfate solution was added dropwise. After stirring for 30 min, the reaction was terminated by rapid cooling at 0-8°C. A suitable amount of magnesium hydride particles with a size of 100-500 nm was added at 4°C. Figure 2 Magnesium hydride was prepared into a hydrogel solution with a final concentration of 1 mg / ml and gelled in a 37°C water bath. The resulting microgel had weak mechanical strength and a viscous consistency, making it suitable for various wound shapes. Co-culturing with HaCaT cells revealed a decrease in the cells' DNA synthesis capacity and a reduction in the number of cells in a proliferative state. This evidence suggests that magnesium hydride-loaded hydrogels can reduce the viability and proliferation level of keratinocytes.

[0037] Example 3: Preparation of magnesium hydride-loaded composite hydrogel formulation

[0038] Preparation of magnesium hydride-loaded composite hydrogel: Depending on the application, a 23% poloxamer 407 saline solution was selected, and poloxamer 188 gelling agent powder with a final concentration of 1% was added. After complete dissolution at 4°C, the solution was placed in a refrigerator overnight to remove air bubbles. An appropriate amount of magnesium hydride particles with a size of 100-500 nm was added at 4°C to prepare a hydrogel solution with a final magnesium hydride concentration of 1 mg / ml. This hydrogel formulation exhibits thermosensitive gelation characteristics. Figure 3 Furthermore, the gelation temperature of the gel increases due to the addition of poloxamer 188.

[0039] Example 4: Preparation of magnesium hydride-loaded composite hydrogel formulation

[0040] Preparation of magnesium hydride-loaded composite hydrogel: 0.02 g chitosan and 0.5 g N-isopropylacrylamide were uniformly dissolved in water according to different applications. 0.12 mL of N,N'-methylenebisacrylamide solution (5 wt%) and 0.12 mL of potassium persulfate (1.5 wt%) were added separately, and the mixture was stirred until homogeneous. Then, an appropriate amount of magnesium hydride was added, and polymerization was initiated using TMEDA (N,N,N',N'-tetramethylethylenediamine) initiator to obtain magnesium hydride-loaded hydrogel. Co-incubation with HaCaT for 30 min significantly reduced the expression levels of LPS-stimulated inflammatory cytokines such as TNF-α, IL-1beta, and CCl20, which play a key role in the formation of psoriatic lesions. The results indicate that the magnesium hydride-loaded hydrogel exhibits anti-inflammatory properties in vitro.

[0041] Example 5: Determination of hydrogen release from magnesium hydride-loaded hydrogel formulation

[0042] 1 mg of magnesium hydride was uniformly distributed in 1 mL of poloxamer 407 gel solution (25%). After standing to form a gel, 15 mL of physiological saline was added to the top layer of the gel. The hydrogen release behavior of the hydrogel formulation in the liquid environment was observed using a hydrogen electrode. The results showed that the hydrogel substrate did not affect the hydrogen release behavior of the magnesium hydride particles. Compared with the efficient release of hydrogen for only 5-6 hours when the same amount of magnesium hydride was directly added to physiological aqueous solution, this hydrogel formulation achieved a long-lasting high concentration of hydrogen release, maintaining efficient sustained-release hydrogen behavior for at least 24 hours. In vitro experimental results showed that the generated hydrogen successfully inhibited the proliferation of keratinocytes and reduced the expression of intracellular inflammation-related factors, thus improving the therapeutic effect on dermatitis.

[0043] Example 6: Evaluation of the effect of magnesium hydride hydrogel formulation on alleviating psoriatic skin lesions

[0044] A mouse model of psoriasis was established using IMQ induction to evaluate the repair ability of a magnesium hydride hydrogel formulation on psoriasis-induced skin lesions. Different experimental groups were established: a positive control group (untreated group), a calcipotriol (first-line topical medication for psoriasis) treatment group, a magnesium ion gel treatment group, and a magnesium hydride hydrogel treatment group. Mice were scored using a psoriasis severity index. Results are as follows: Figure 4 As shown, the magnesium hydride gel group significantly improved erythema and scaling in psoriatic mice after treatment, and the infiltration (thickness) of the lesions was also greatly reduced. Compared with the calcipotriol treatment group, it showed comparable improvement in scaling, but had a certain advantage in improving erythema. The magnesium ion gel group alone had no significant effect on improving psoriatic lesions. In the HE staining results ( Figure 5 Compared with the control group, the magnesium-hydrogen gel treatment significantly reduced epidermal hyperplasia and improved the epidermal structure to near the normal mouse skin morphology, alleviating the degree of acanthosis and inflammatory infiltration.

[0045] In summary, this invention loads magnesium hydride particles into a hydrogel formulation as a hydrogen donor, achieving localized hydrogen enrichment and providing long-lasting sustained-release performance compared to existing medical hydrogen delivery methods. Furthermore, this invention exhibits excellent biocompatibility, making it suitable for topical treatment of dermatitis and psoriasis. It effectively regulates keratinocyte proliferation and glucose metabolism, significantly improving skin lesions and local inflammation, while avoiding the irritation, erythema, and drug resistance issues common in clinical medications.

[0046] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A magnesium hydride-loaded hydrogel formulation, characterized in that, The magnesium hydride-loaded hydrogel formulation uses a thermosensitive hydrogel as a carrier to load magnesium hydride particles; the hydrogel and the particle surface interact through hydrogen bonds and ionic bonds to form a composite hydrogel system that is stable at body temperature. The preparation method of the magnesium hydride-loaded hydrogel formulation includes the following steps: dissolving the gel matrix in physiological saline, letting it stand overnight at 0-8℃, adding magnesium hydride particles, and mixing evenly; letting it stand at 20-37℃ to form a gel, thereby obtaining the magnesium hydride-loaded hydrogel formulation. The gel matrix is ​​poloxamer 407, or the gel matrix is ​​PNIPAM, or a composite gel matrix of poloxamer 407 and poloxamer 188 with a mass concentration ratio of 30:(0-3), or a composite gel matrix of PNIPAM and chitosan with a mass concentration ratio of 25:(1-10); and the concentration of the poloxamer 407 gel solution is 10-40 wt%; the concentration of the PNIPAM gel solution is 0.1-10%.

2. The magnesium hydride-loaded hydrogel formulation according to claim 1, characterized in that, The magnesium hydride particles have a particle size of 0.1-100 μm.

3. The magnesium hydride-loaded hydrogel formulation according to claim 1, characterized in that, The settling time for gelation is 1-30 minutes.

4. Use of a magnesium hydride hydrogel formulation according to any one of claims 1 to 3 in the preparation of a dermatitis and psoriasis treatment agent.

5. The use according to claim 4, characterized in that, The magnesium hydride hydrogel formulation serves as a localized sustained-release and moisturizing agent for hydrogen, enabling long-term localized controlled-release of hydrogen and mitigating pH fluctuations and excessive local magnesium ion levels in the microenvironment.

6. The use according to claim 4 or 5, characterized in that, The magnesium hydride-loaded hydrogel formulation contains magnesium hydride at a concentration of 0.5-10 mg / mL.

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