Pharmaceutical composition for treating alveolar echinococcosis and application thereof

Abstract

The invention relates to the technical field of medicine preparation, in particular to a medicine composition for treating alveolar echinococcosis and application thereof, and the medicine composition comprises a therapeutically effective amount of MAPK blocker TRx0237 or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers or auxiliary materials. The medicine composition for treating the alveolar echinococcosis based on the MAPK blocker TRx0237, provided by the invention, has remarkable advantages in multiple aspects, realizes precise targeted treatment on the echinococcosis multilocularis by specifically inhibiting a key pathogenic mechanism, namely an MAPK signal channel, not only can directly inhibit the growth of parasites, but also can effectively inhibit the echinococcosis multilocularis, so that the effect of treating the echinococcosis multilocularis is achieved. Liver tissue damage can be relieved, and the immune microenvironment of the liver can be improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, in particular to a pharmaceutical composition for treating alveolar echinococcosis and application thereof. Background Art

[0002] Alveolar echinococcosis (AE) is a serious zoonotic parasitic disease caused by infection with Echinococcus multilocularis cysts. The disease primarily invades the liver, presenting as an infiltrative growth with clinical manifestations similar to those of a malignant tumor. If left untreated, it can lead to liver failure and even death. Currently, the first-line treatment for AE is albendazole, but its efficacy is limited, as it only inhibits parasite growth but cannot completely eliminate it. Patients require long-term medication and may develop drug resistance and hepatotoxicity. Therefore, the development of new, highly effective, and low-toxic anti-AE drugs is of great clinical significance.

[0003] Recent studies have revealed that the survival and proliferation of Echinococcus multilocularis are highly dependent on host cell signaling pathways, particularly the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway plays a key role in parasite growth and development, immune evasion, and host-parasite interactions. Inhibiting this pathway may offer a new strategy for treating AE. Existing technologies do not target key host signaling pathways that parasites rely on. Summary of the Invention

[0004] In response to the problems existing in the prior art, the present invention develops a new anti-AE drug based on MAPK pathway inhibition, especially using small molecule inhibitors such as TRx0237 to target host-parasite interactions, improve therapeutic effects and reduce side effects, and provide a new solution for the treatment of AE.

[0005] The present invention provides a pharmaceutical composition for treating alveolar echinococcosis, comprising a therapeutically effective amount of a MAPK blocker TRx0237 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0006] Furthermore, the dosage of the MAPK inhibitor TRx0237 is 0.1-100 mg / kg body weight / day.

[0007] Furthermore, the composition is administered orally.

[0008] Furthermore, the composition is in the form of tablets, capsules or oral liquids.

[0009] Furthermore, the composition is administered by injection.

[0010] Furthermore, the dosage form of the composition is injection or lyophilized powder injection.

[0011] Furthermore, the composition also contains at least one other anti-echinococcosis drug.

[0012] Furthermore, the other anti-echinococcosis drugs are selected from albendazole, mebendazole or praziquantel.

[0013] The present invention also discloses the use of the pharmaceutical composition in preparing a drug for treating alveolar echinococcosis and in preparing a drug for inhibiting Echinococcus multilocularis infection.

[0014] In summary, the present invention has the following beneficial effects: The pharmaceutical composition for treating alveolar echinococcosis, based on the MAPK blocker TRx0237, provided by the present invention, has significant advantages in many aspects. By specifically inhibiting the MAPK signaling pathway, a key pathogenic mechanism, it achieves precise targeted treatment of Echinococcus multilocularis. This not only directly inhibits parasite growth but also reduces liver tissue damage and improves the liver's immune microenvironment. Compared with traditional anti-echinococcosis drugs, this composition has outstanding advantages such as a novel mechanism of action, significant therapeutic effects, and low toxicity and side effects, effectively overcoming the drug resistance problem of existing drugs. The composition has a variety of dosage forms and can be used as a single drug or in combination with traditional anti-echinococcosis drugs to produce a synergistic effect. It shows broad application prospects in the treatment and prevention of alveolar echinococcosis. DETAILED DESCRIPTION

[0015] In order to further illustrate the technical means and efficacy adopted by the present invention to achieve the predetermined purpose of the invention, a pharmaceutical composition for treating alveolar echinococcosis and a method for inhibiting the protoscolex or germinal layer cells of multilocular Echinococcus in vitro according to the present invention, its specific implementation method, characteristics and efficacy are described in detail as follows.

[0016] Recent studies have revealed that the survival and proliferation of Echinococcus multilocularis are highly dependent on host cell signaling pathways, particularly the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway plays a key role in parasite growth and development, immune evasion, and host-parasite interactions. Inhibiting this pathway may offer a new therapeutic strategy for AE. TRx0237 (LMTXmesylate), a small molecule MAPK inhibitor, has been used in neurodegenerative disease research, but its application in the treatment of parasitic infections, particularly AE, has not been reported.

[0017] Currently, the treatment of AE still faces the following challenges: limited efficacy of existing drugs: benzimidazoles such as albendazole can only inhibit parasite metabolism and cannot completely eliminate the infection; long-term medication side effects: long-term use may cause liver damage and bone marrow suppression; lack of targeted therapy: existing therapies do not intervene in the key host signaling pathways that parasites depend on.

[0018] In response to the above problems, this specific embodiment provides a pharmaceutical composition for treating alveolar echinococcosis, comprising a therapeutically effective amount of the MAPK blocker TRx0237 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0019] It is understood that the pharmaceutical composition provided in this specific embodiment contains the MAPK blocker TRx0237 (LMTXmesylate) or a pharmaceutically acceptable salt form thereof as the core therapeutic ingredient of the composition, with a content of 0.1%-99% of the total weight of the composition; wherein, in the carrier and excipient system, the diluent may be microcrystalline cellulose, lactose and / or pregelatinized starch, etc.; the binder may be hydroxypropyl methylcellulose and / or polyvinyl pyrrolidone, etc.; the disintegrant may be cross-linked sodium carboxymethyl cellulose and / or low-substituted hydroxypropyl cellulose, etc.; the lubricant may be magnesium stearate and / or talc, etc.; the solvent may be purified water and / or ethanol, etc.; the cosolvent may be polyethylene glycol and / or propylene glycol, etc.; the flavoring agent may be steviol glycoside and / or mint essence, etc.; the preservative may be sodium benzoate and / or parahydroxybenzoates, etc.; in the injectable excipient, the pH adjuster may be a hydrochloric acid / sodium hydroxide buffer system; the isotonicity adjuster may be sodium chloride and / or glucose, etc.; and the lyoprotectant (lyophilized preparation) may be mannitol, sucrose, etc.

[0020] In some preferred implementations, the MAPK blocker TRx0237 is administered at a dosage of 0.1-100 mg / kg body weight / day.

[0021] The MAPK blocker TRx0237 used in this specific embodiment is administered in a dosage range of 0.1-100 mg / kg body weight / day. Its therapeutic principle is that this dosage range can effectively inhibit the MAPK signaling pathway on which the growth of Echinococcus multilocularis depends, while avoiding significant toxicity to normal host cells. The low dose of 0.1 mg / kg shows an inhibitory effect, while the high dose of 100 mg / kg still maintains good safety. Within this range, it can be flexibly adjusted according to the degree of infection and the patient's condition. This dosage regimen ensures that the drug can fully block the key growth pathways of the parasite while minimizing potential side effects, achieving the optimal balance between efficacy and safety, and providing reliable medication guidance for clinical treatment.

[0022] In some preferred embodiments, the composition is administered orally.

[0023] In some preferred embodiments, the composition is in the form of a tablet, capsule or oral solution.

[0024] In some preferred embodiments, the composition is administered by injection.

[0025] In some preferred embodiments, the composition is in the form of an injection or a lyophilized powder injection.

[0026] In some preferred embodiments, the composition further comprises at least one other anti-echinococcosis drug.

[0027] In some preferred embodiments, the other anti-echinococcosis drugs are selected from albendazole, mebendazole or praziquantel.

[0028] In this specific embodiment, the pharmaceutical composition achieves a multi-target synergistic mechanism by combining TRx0237 with traditional anti-echinococcosis drugs (such as albendazole, mebendazole, or praziquantel). In this combination therapy strategy, TRx0237 specifically inhibits the MAPK signaling pathway to block parasite proliferation and survival, while traditional anti-echinococcosis drugs exert their insecticidal effects by interfering with parasite microtubule function or calcium ion metabolism. This combination therapy not only produces significant synergistic effects, improving the overall therapeutic efficacy of alveolar echinococcosis, but also reduces toxic side effects by lowering the dosage of each drug, while effectively delaying the development of parasite drug resistance.

[0029] The present invention will be further described below with reference to specific embodiments. Example 1

[0030] The pharmaceutical composition provided in this example includes: an active ingredient: TRx0237 mesylate (purity ≥99%), accounting for 25% of the total weight; excipient composition: microcrystalline cellulose (60%), hypromellose (5%), croscarmellose sodium (7%) and magnesium stearate (3%).

[0031] The preparation method of the pharmaceutical composition provided in this example is as follows: the components are passed through an 80-mesh sieve and then mixed evenly, and tablets are prepared by wet granulation and tableting to prepare tablets containing 50 mg of TRx0237 per tablet. Example 2

[0032] The pharmaceutical composition provided in this example includes: active ingredients: TRx0237 mesylate (purity ≥99.5%), accounting for 30% of the total weight and mebendazole (USP standard), accounting for 15% of the total weight; lyophilized powder injection excipients: mannitol (45%), sucrose (8%) and phosphate buffer (pH 7.4, 2%).

[0033] The preparation method of the pharmaceutical composition provided in this example is as follows: each component is dissolved in water for injection, sterilized through a 0.22 μm filter membrane, and then packaged and freeze-dried to obtain a lyophilized powder injection containing 100 mg of TRx0237 and 50 mg of mebendazole per bottle. Example 3

[0034] The pharmaceutical composition provided in this embodiment includes: active ingredients: TRx0237 base (micronized, D90≤10μm), content 20 mg / mL, albendazole (nanocrystalline suspension), content 10 mg / mL; suspension system: sorbitol (30%, w / v), xanthan gum (0.5%, w / v), microcrystalline cellulose (1.2%, w / v); other excipients: glycerol (5%, v / v), citric acid buffer system (pH 4.5), methyl parahydroxybenzoate (0.018%, w / v) and strawberry flavor (0.2%, v / v).

[0035] The preparation method of the pharmaceutical composition provided in this embodiment is: S1. Pretreatment: TRx0237 base was pulverized by air flow to a specified particle size, and albendazole nanocrystals were prepared by antisolvent precipitation method; S2. Preparation of dispersed phase: dissolve sorbitol in 60% of the prescribed volume of purified water, add xanthan gum and microcrystalline cellulose, and disperse under high shearing conditions; S3, drug addition: first add TRx0237 micropowder, homogenize (10000 rpm, 15 min), then add albendazole nanocrystal suspension; S4. Prepare the preparation: add glycerol and the remaining purified water, adjust the pH to 4.5±0.2 with citric acid / sodium citrate, and finally add preservatives and flavoring agents. Example 4

[0036] The pharmaceutical composition provided in this example comprises: active ingredient TRx0237 mesylate (pellet core, drug loading 35%), accounting for 40% of the total weight, mebendazole (solid dispersion, HPMC carrier), accounting for 20% of the total weight; sustained-release coating system: enteric layer: Eudragit® L100-55 (6%), sustained-release layer: ethyl cellulose (10%), capsule shell: Hydroxypropyl methylcellulose (HPMC) enteric-coated capsule (Size 1).

[0037] The preparation method of the pharmaceutical composition provided in this embodiment is: A1. Preparation of TRx0237 pellets Drug-loaded micropellets: Fluidized bed bottom spraying process, with microcrystalline cellulose (MCC) as the inert pellet core; drug layer: TRx0237 mesylate + HPMC (3:1); coating weight gain: 30%.

[0038] A2. Mebendazole solid dispersion Hot melt extrusion method: Mix mebendazole and HPMC (1:2), extrusion temperature: 120℃, and crush the extrudate through a 40-mesh sieve.

[0039] A3. Pellets coating Enteric layer (Eudragit® L100-55): coating weight gain 6%, ensuring dissolution at pH ≥ 5.5; sustained-release layer (ethyl cellulose): coating weight gain 10%, controlled sustained-release over 12 hours.

[0040] A4, capsule filling Mixing ratio: TRx0237 micropellets (60%); mebendazole solid dispersion granules (40%); Filling quantity: Each capsule contains TRx0237 100mg + mebendazole 50mg.

[0041] Comparative Example 1 The pharmaceutical composition provided in this example includes: active ingredient: TRx0237 mesylate (purity 99.5%), accounting for 30% of the total weight (single-ingredient preparation); lyophilized excipients: mannitol (60%), dextran (10%).

[0042] Preparation method: The active ingredient is dry-mixed with mannitol and then directly packaged and freeze-dried.

[0043] Comparative Example 2 The pharmaceutical composition provided in this example includes: albendazole (nanocrystalline suspension), content 30 mg / mL; suspension system: sorbitol (30%, w / v), xanthan gum (0.5%, w / v), microcrystalline cellulose (1.2%, w / v); other excipients: glycerol (5%, v / v), citric acid buffer system (pH 4.5), methyl paraben (0.018%, w / v) and strawberry flavor (0.2%, v / v).

[0044] The preparation method of the pharmaceutical composition provided in this embodiment is: S1, pretreatment: albendazole nanocrystals were prepared by antisolvent precipitation method; S2. Preparation of dispersed phase: dissolve sorbitol in 60% of the prescribed volume of purified water, add xanthan gum and microcrystalline cellulose, and disperse under high shearing conditions; S3, drug addition: albendazole nanocrystal suspension; S4. Prepare the preparation: add glycerol and the remaining purified water, adjust the pH to 4.5±0.2 with citric acid / sodium citrate, and finally add preservatives and flavoring agents.

[0045] Comparative Example 3 The pharmaceutical composition provided in this example includes: active ingredient: TRx0237 base (micronized, D90≤10μm), content 30mg / mL; suspension system: sorbitol (30%, w / v), xanthan gum (0.5%, w / v), microcrystalline cellulose (1.2%, w / v); other excipients: glycerol (5%, v / v), citric acid buffer system (pH4.5), methyl parahydroxybenzoate (0.018%, w / v) and strawberry flavor (0.2%, v / v).

[0046] The preparation method of the pharmaceutical composition provided in this embodiment is: S1. Pretreatment: TRx0237 base was pulverized by air flow to a specified particle size, and albendazole nanocrystals were prepared by antisolvent precipitation method; S2. Preparation of dispersed phase: dissolve sorbitol in 60% of the prescribed volume of purified water, add xanthan gum and microcrystalline cellulose, and disperse under high shearing conditions; S3, drug addition: first add TRx0237 micropowder and homogenize (10000 rpm, 15 min); S4. Prepare the preparation: add glycerol and the remaining purified water, adjust the pH to 4.5±0.2 with citric acid / sodium citrate, and finally add preservatives and flavoring agents.

[0047] Performance Testing 1. Pharmacokinetic testing in Beagle dogs Healthy Beagle dogs (n=6 / group, half male and half female, weighing 10-12 kg); Dosage regimen: single administration of Examples 1-4 and Comparative Examples 1-3 (dosage is converted according to the clinical equivalent dose), tablets: 50 mg TRx0237 / dog (Example 1), lyophilized powder injection: 100 mg TRx0237 / dog (Example 2), oral suspension: 2 mL / kg (containing TRx0237 40 mg / kg, albendazole 20 mg / kg, Example 3), sustained-release capsules: 100 mg TRx0237 + 50 mg mebendazole / dog (Example 4), Comparative Examples 1-3 are adjusted according to equivalent doses.

[0048] Sampling: Blood was collected from the forelimb vein (0, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours). Analysis: LC-MS / MS was used to detect the concentrations of TRx0237 and co-drugs in plasma.

[0049] Parameter calculation: C~max~, T~max~, AUC~0-t~, AUC~0-∞~, t~1 / 2~.

[0050] The test results are shown in the table below.

[0051]

[0052] 2. Liver Lesion Inhibition Rate Test (Rabbit Model) Test Method New Zealand rabbit liver fibrosis model (CCl4-induced, n=8 / group); Dosage regimen: daily administration × 28 days (the dose is converted to 1 / 5 of the human equivalent dose); control group: normal saline.

[0053] Evaluation indicators: Histopathology: HE / Masson staining, percentage of liver fibrosis area; serum biochemistry: ALT, AST, HA (hyaluronic acid); Inhibition rate calculation: (lesion area of ​​control group - lesion area of ​​treatment group) / area of ​​control group × 100%.

[0054] The test results are shown in the table below.

[0055]

[0056] The above results indicate that different dosage forms and combination strategies have significant effects on the pharmacokinetics and liver lesion inhibition effects of TRx0237.

[0057] Pharmacokinetic results showed that the lyophilized powder injection (Example 2) exhibited optimal bioavailability, with its C~max~ (8.15±0.72 μg / mL) and AUC~0-24h~ (45.2±3.8 μg·h / mL) significantly higher than those of the tablet (Example 1) and Comparative Example 1 (p<0.05), while the sustained-release capsule (Example 4) successfully prolonged drug release (T~max~ 6.5±1.2 h, t~1 / 2~12.4±1.5 h).

[0058] In terms of pharmacodynamics, the nanocrystalline suspension of TRx0237 combined with albendazole (Example 3) exhibited the strongest synergistic effect, with a liver fibrosis inhibition rate of 59.9% (p<0.01 vs single-ingredient preparations), and serum ALT (85±10 U / L) and hyaluronic acid (150±18 ng / mL) levels were significantly reduced, confirming the synergistic effect of the combination.

[0059] In contrast, the inhibition rate in Example 2, using albendazole alone, was only 21.2%, highlighting the core therapeutic value of TRx0237. Furthermore, despite improved pharmacokinetic parameters for the sustained-release formulation (Example 4), its efficacy (45.5% inhibition rate) was not statistically different from that of the immediate-release tablet (Example 1, 41.1%) (p>0.05), suggesting that sustained-release formulations are not necessarily superior to immediate-release formulations in the treatment of liver disease. In summary, dosage form optimization and combination therapy strategies can significantly enhance the clinical potential of TRx0237, with the lyophilized powder injection and nanocrystal compound formulations holding the greatest development potential.

[0060] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been presented as a preferred embodiment, it is not intended to limit the present invention. Any technician familiar with the present profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A pharmaceutical composition for treating alveolar echinococcosis, characterized in that: The invention comprises a therapeutically effective amount of MAPK blocker TRx0237 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition according to claim 1, characterized in that The dosage of the MAPK inhibitor TRx0237 is 0.1-100 mg / kg body weight / day.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The composition is administered by oral route.

4. The pharmaceutical composition according to claim 3, characterized in that The dosage form of the composition is tablet, capsule or oral solution.

5. The pharmaceutical composition according to claim 1 or 2, characterized in that The composition is administered by injection.

6. The pharmaceutical composition according to claim 5, characterized in that The dosage form of the composition is injection or lyophilized powder injection.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The composition further comprises at least one other anti-echinococcosis drug.

8. The pharmaceutical composition according to claim 7, characterized in that The other anti-echinococcosis drugs are selected from albendazole, mebendazole or praziquantel.

9. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a drug for treating alveolar echinococcosis.

10. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a drug for inhibiting Echinococcus multilocularis infection.

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