Application of XPO1 inhibitors in the preparation of drugs for the topical treatment of itching

Abstract

This invention relates to the field of biomedical technology, and more particularly to the application of XPO1 inhibitors in the preparation of drugs for the topical treatment of pruritus. Experimental studies have shown that XPO1 inhibitors have significant therapeutic effects on chronic and complex pruritus models, and may be applicable to pruritus caused by various etiologies, possessing broad-spectrum therapeutic potential. By administering the drug topically, it primarily acts on the local skin, greatly avoiding the serious systemic side effects (such as hematological toxicity and gastrointestinal reactions) associated with oral XPO1 inhibitors. Simultaneously, it also avoids the local side effects such as skin atrophy caused by long-term use of potent hormones. This invention provides a novel drug option for the treatment of intractable pruritus and related inflammatory skin diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the application of XPO1 inhibitors in the preparation of drugs for the topical treatment of itching. Background Technology

[0002] Itching is an unpleasant sensation that evokes the urge to scratch, and it is a core symptom of many skin diseases (such as atopic dermatitis, psoriasis, and contact dermatitis) and systemic diseases (such as chronic kidney disease and cholestasis). Persistent itching severely impacts patients' quality of life, leading to sleep disturbances, anxiety, and depression.

[0003] Currently, the main clinical methods for treating itching include: 1. Antihistamines: such as cetirizine and loratadine, are effective for urticaria caused by histamine release, but have limited efficacy for chronic pruritus mediated by nonhistaminergic pathways associated with most inflammatory skin diseases (such as atopic dermatitis).

[0004] 2. Topical corticosteroids: such as hydrocortisone and mometasone furoate, are standard treatments for many inflammatory skin diseases, with anti-inflammatory and antipruritic effects. However, long-term use may lead to local side effects such as skin atrophy, telangiectasia, pigmentation changes, and secondary infections, and they are not effective for itching caused by certain neurological or systemic etiologies.

[0005] 3. Topical calcineurin inhibitors: such as tacrolimus and pimecrolimus, can be used as an alternative to hormones, especially for sensitive areas such as the face and neck. However, there are concerns about initial burning sensation and increased risk of infection, and they are expensive. Long-term efficacy and safety data still need to be accumulated.

[0006] 4. Biologics: Monoclonal antibodies targeting specific inflammatory pathways (such as IL-4 / IL-13, IL-31, IL-17, etc.) (e.g., dupilumab, nemoglitumab, etc.) have shown significant efficacy in treating disease-related pruritus such as moderate to severe atopic dermatitis. However, these drugs require subcutaneous or intravenous injection, are extremely expensive, and carry the risk of adverse reactions such as conjunctivitis and oral herpes. Furthermore, their targets are relatively singular, and they may be ineffective for pruritus not mediated by Th2 pathways.

[0007] 5. Systemic drugs: such as immunosuppressants (cyclosporine) and opioid receptor modulators (naltrexone, butorphanol), are used for severe and refractory cases. However, these drugs can cause systemic adverse reactions such as liver and kidney toxicity, hypertension, and central nervous system side effects, which limits their long-term and widespread use.

[0008] The aforementioned effective drugs suffer from limitations in their therapeutic targets, exhibiting a single therapeutic target and poor efficacy against complex, non-histaminergic mediated chronic pruritus. They also have significant side effects, and existing effective drugs (such as potent hormones and systemic immunosuppressants) have poor long-term safety profiles. Therefore, there is an urgent need for a new drug that combines both safety and comprehensive efficacy.

[0009] XPO1 inhibitors (such as the approved oral drug Selinexor) have been approved by the US FDA for the treatment of certain relapsed or refractory hematologic malignancies, such as multiple myeloma and diffuse large B-cell lymphoma. Their antitumor mechanism of action is based on the inhibition of the nuclear export protein XPO1 (Exportin-1, also known as CRM1). Under physiological conditions, XPO1 is responsible for transporting various tumor suppressor proteins (such as p53, p21, and FOXO), growth regulatory proteins, and some mRNAs from the nucleus to the cytoplasm. In cancer cells, XPO1 is often overexpressed, leading to the excessive export and inactivation of these tumor suppressor proteins. XPO1 inhibitors, by covalently binding to the Cys528 site of XPO1, block its transport function, forcing the aforementioned tumor suppressor proteins to accumulate in the nucleus and reactivate, thereby selectively inducing apoptosis in cancer cells and simultaneously affecting the mRNA export of various oncogenic proteins, inhibiting tumor growth. However, current technologies are entirely focused on the systemic (oral) administration and antitumor applications of XPO1 inhibitors. Because its mechanism of action broadly affects nuclear-cytoplasmic transport, systemic administration is often accompanied by significant systemic side effects, including severe nausea, vomiting, anorexia, fatigue, thrombocytopenia, neutropenia, and hyponatremia. These side effects lead to poor patient tolerance, requiring dose adjustments and supportive care. Currently, there is no existing technology to demonstrate that XPO1 inhibitors can be used to treat non-cancerous diseases, particularly skin diseases or pruritus; nor has the application of XPO1 via local administration to avoid systemic toxicity and explore its role in novel pathophysiological processes been considered. Summary of the Invention

[0010] The purpose of this invention is to overcome the shortcomings of the existing technology and provide the application of XPO1 inhibitors in the preparation of drugs for the topical treatment of itching.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides the use of XPO1 inhibitors in the preparation of medicaments for the topical treatment of pruritus.

[0012] XPO1 inhibitors are compounds that specifically bind to and inhibit the function of the XPO1 protein, thereby blocking its mediated nucleocytoplasmic transport. Currently, XPO1 inhibitors are primarily used in systemic antitumor therapy, but they have serious side effects and limited application. This invention is the first to discover and demonstrate that XPO1 inhibitors, administered topically, can effectively treat itching caused by various factors, particularly chronic itching associated with skin inflammation.

[0013] This invention introduces the XPO1 target into the field of pruritus treatment for the first time, providing a completely new treatment option with a mechanism of action that is entirely different from traditional antihistamines and hormones, offering a new choice for patients who are insensitive to or intolerant of existing therapies.

[0014] This treatment plan has the following advantages: 1. High efficacy and broad spectrum: Preclinical trials have demonstrated that topical XPO1 inhibitors have significant efficacy in chronic and complicated pruritus models, and may be applicable to pruritus caused by a variety of etiologies, with broad-spectrum therapeutic potential.

[0015] 2. Topical administration with high safety: Administered topically, the drug primarily acts on the skin, greatly avoiding the severe systemic side effects (such as hematological toxicity and gastrointestinal reactions) associated with oral XPO1 inhibitors. It also avoids the local side effects such as skin atrophy caused by long-term use of potent hormones.

[0016] 3. “Repurposing existing drugs”, short development cycle, and low risk: The XPO1 inhibitor used is a known compound, and there is a large amount of data accumulated on its chemical properties, pharmacology and toxicology. Compared with developing a completely new chemical entity, the drug composition of this invention has a shorter development cycle, lower drug development risk, and can be transformed into clinical benefits more quickly.

[0017] Preferably, the itching includes itching associated with skin inflammation.

[0018] Preferably, the itching is chronic itching.

[0019] Preferably, the skin inflammation includes at least one of atopic dermatitis, psoriasis, contact dermatitis, seborrheic dermatitis, neurodermatitis, and eczema.

[0020] Preferably, the XPO1 inhibitor includes at least one of Selinexor, KPT-185, KPT-251, Eltanexor, Verdinexor, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

[0021] Preferably, the drug is a topical dosage form.

[0022] Topical formulations (such as creams and gels) offer a technical approach to achieve local drug delivery while minimizing systemic exposure.

[0023] Preferably, the topical dosage form includes cream, gel, liquid lotion, spray, or foam.

[0024] More preferably, the topical dosage form is a cream or gel, which is easy to apply, has good patient compliance, and facilitates drug retention at the lesion site.

[0025] In a second aspect, the present invention provides a pharmaceutical composition for treating topical pruritus, comprising an XPO1 inhibitor and a pharmaceutically acceptable carrier.

[0026] The pharmaceutical composition provided by this invention can effectively relieve itching symptoms, reduce skin inflammation, repair the skin barrier, and avoid serious systemic toxic side effects due to local administration.

[0027] Preferably, the XPO1 inhibitor includes at least one of Selinexor, KPT-185, KPT-251, Eltanexor, Verdinexor, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

[0028] Preferably, the amount of the XPO1 inhibitor added is 0.5% to 5% of the total weight of the pharmaceutical composition.

[0029] The experiments of this invention have shown that the above-mentioned dosage concentration range ensures good local tolerability while guaranteeing therapeutic efficacy.

[0030] Preferably, the drug is a topical dosage form.

[0031] Preferably, the carrier comprises at least one of a softener, emulsifier, thickener, penetration enhancer, preservative, stabilizer, pH adjuster, and solvent. The choice of carrier should ensure the stability of the active ingredient and the transdermal delivery efficiency.

[0032] Preferably, the solvent includes at least one of water, ethanol, and propylene glycol.

[0033] The beneficial effects of this invention are as follows: This invention opens up a revolutionary new application for XPO1 inhibitors. It repositions them from "systemic antitumor drugs" to "topical anti-inflammatory and antipruritic agents," providing a novel drug option for treating intractable pruritus and related inflammatory skin diseases. XPO1 inhibitors, by regulating nucleoplasmic transport, can stabilize the levels of multiple key anti-inflammatory proteins in the nucleus (such as p53 and IκBα) and limit the abnormal activation of pro-inflammatory transcription factors. This mechanism blocks the inflammatory cascade response from the upstream source of cellular metabolism and signal transduction, overcoming the limitations of existing drugs that target specific cytokines and exhibiting broader anti-inflammatory and antipruritic activity.

[0034] This invention provides a safer antipruritic solution. By preparing XPO1 inhibitors into topical formulations (such as creams or gels), the drug primarily acts on the skin lesions, greatly reducing or avoiding the severe gastrointestinal and hematologic toxicity associated with oral administration, while also avoiding the local side effects of long-term use of potent hormones. Attached Figure Description

[0035] Figure 1 Changes in itching after topical application of the XPO1 inhibitor Selinexor to a mouse model of chronic pruritus.

[0036] Figure 2 Changes in body weight in mice with a chronic pruritus model after topical application of the XPO1 inhibitor Selinexor.

[0037] Figure 3 The appearance of the skin after topical application of the XPO1 inhibitor Selinexor (3%) to a mouse model of chronic pruritus. Detailed Implementation

[0038] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0039] Unless otherwise specified, the experimental methods used in this invention are conventional methods, and the materials and reagents used are commercially available products that can be obtained through commercial channels.

[0040] Example 1: Therapeutic effect of topical application of XPO1 inhibitor on a mouse model of chronic pruritus 1. Laboratory Animals: Female C57BL / 6 mice, aged 8-10 weeks and weighing 20-25g, were selected. Mice were housed under standard conditions with free access to food and water. They were allowed at least 3 days to acclimatize to their environment before the experiment. The experimental protocol was approved by the relevant animal ethics committee.

[0041] 2. Animal Model Establishment: A mouse model of chronic pruritus due to xeroderma was induced by repeated treatment with acetone / ether / water (AEW). Three days before the experiment, a 2 cm × 2 cm area of ​​bare skin was shaved off the back of the mice using an electric shaver and depilatory cream. From day 1, twice daily (approximately 9 hours apart), a mixture of acetone and ether (1:1 volume ratio) was evenly applied to the shaved area with a cotton swab and left for 15 seconds. Immediately afterwards, another cotton swab soaked in distilled water was applied to the same area for 30 seconds. This procedure was repeated twice daily for 5 consecutive days to establish a stable model of chronic pruritus and skin barrier damage.

[0042] 3. Drug preparation: Test sample: Selinexor (purchased from Shanghai McLean Biochemical Technology Co., Ltd.) was selected as the representative drug for XPO1 inhibitor.

[0043] Stock solution: Selinexor powder was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution with a concentration of 100 mg / mL, and stored at -20℃. Dosage solution: Before each administration, the stock solution was diluted with an aqueous solution containing 2% (v / v) Tween 80 and 10% (v / v) PEG300, ensuring that the concentration of DMSO in the final dosage form did not exceed 5% (v / v) to minimize solvent irritation to the skin. Dosage solutions equivalent to 1%, 2%, and 3% Selinexor concentrations (w / w) were prepared (dosage volume was uniformly 20 μL). The vehicle control group used the same solvent system without Selinexor, i.e., an aqueous solution containing ≤5% DMSO, 2% Tween 80, and 10% PEG300.

[0044] 4. Grouping and drug administration: Mice with the model were randomly divided into four groups (n=4): a carrier control group, a Selinexor 1% group, a 2% group, and a 3% group. Starting from day 1 of modeling, drug intervention was administered daily after the first AEW treatment and complete drying (approximately 1 hour later). Before administration, mice were briefly anesthetized by inhalation with isoflurane to prevent licking. 20 μL of the appropriate concentration of drug solution or carrier was accurately pipetted and evenly applied to the treated skin area on the back of the mouse. Administration was once daily for 5 consecutive days.

[0045] 5. Observation and detection indicators: Pruritus behavior scoring: After each administration, mice were placed individually in opaque observation cages. After acclimatization for 30 minutes, scratching behavior was recorded using a high-definition camera over 60 minutes. A scratching round was defined as direct, continuous scratching of the treated area on the back with the hind paw (from raising the hind paw to lowering it or licking the paw). The total number of scratches by mice in each group during the observation period was statistically analyzed by observers unaware of the group assignments.

[0046] Weight measurement: To assess the systemic toxicity of the drug and the overall health of the animals, mice in each group were weighed daily at a fixed time (9:00-10:00 AM) using an electronic balance (accurate to 0.01 g). Before weighing, the mice's bladders were ensured to be empty (i.e., no deliberate fasting, but avoiding peak feeding times to reduce food weight interference), and data were recorded continuously until the end of the experiment. Weight data were expressed as a percentage change in relative body weight (i.e., daily body weight / initial body weight × 100%), and a weight change curve was plotted.

[0047] 6. Test Results Compared to the carrier control group, the various dose groups of topical Selinexor are expected to show improved effects: Itching behavior: In the Selinexor treatment groups, especially the 1%, 2%, and 3% groups, the number of scratches by mice during the 60-minute observation period was significantly lower than that in the vector control group. This indicates that the itching sensation has been effectively suppressed. Figure 1 ).

[0048] Safety observation: During the administration period, no significant signs of systemic toxicity (such as decreased activity or rapid weight loss) were observed in mice in any of the dosage groups. No additional irritation (such as ulceration or bleeding) was observed on the local skin after administration, indicating that the topical formulation at this concentration range was well tolerated. Figure 2 , Figure 3 ).

[0049] 7. Conclusion This invention demonstrates that the XPO1 inhibitor (Selinexor), formulated into a topical preparation, effectively alleviates AEW-induced chronic pruritus in mice at various dosages (particularly within the 1%-3% range). This provides solid preclinical experimental evidence for the novel use of XPO1 inhibitors in the topical treatment of pruritus.

[0050] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. Application of XPO1 inhibitors in the preparation of drugs for the topical treatment of pruritus.

2. The application as described in claim 1, characterized in that, The itching includes itching associated with skin inflammation.

3. The application as described in claim 2, characterized in that, The skin inflammation includes at least one of atopic dermatitis, psoriasis, contact dermatitis, seborrheic dermatitis, neurodermatitis, and eczema.

4. The application as described in claim 1, characterized in that, The XPO1 inhibitors include at least one of Selinexor, KPT-185, KPT-251, Eltanexor, Verdinexor, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

5. The application as described in claim 1, characterized in that, The drug is a topical dosage form.

6. The application as described in claim 5, characterized in that, The topical dosage forms include creams, gels, liquid lotions, sprays, or foams.

7. A pharmaceutical composition for treating topical pruritus, characterized in that, This includes XPO1 inhibitors and pharmaceutically acceptable carriers.

8. The pharmaceutical composition according to claim 7, characterized in that, The XPO1 inhibitors include at least one of Selinexor, KPT-185, KPT-251, Eltanexor, Verdinexor, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

9. The pharmaceutical composition according to claim 7, characterized in that, The amount of the XPO1 inhibitor added is 0.5% to 5% of the total weight of the pharmaceutical composition.

10. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition is a topical dosage form.

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