A pharmaceutical salt of lamotrigine and pharmaceutical composition, preparation method and application thereof

Abstract

The application discloses a pharmaceutical salt of lamotrigine, a pharmaceutical composition, a preparation method and application. Through a drug-drug combination strategy, lamotrigine and thioctic acid are combined in the form of a salt or a mixture. In the treatment of epilepsy, the lamotrigine fragment can inhibit abnormal discharge and excessive excitement of the brain, and the thioctic acid fragment can enhance the resistance of the brain to seizures, reduce the damage to the brain after seizures, and play a synergistic multi-pathway treatment effect to delay the development of the disease. Meanwhile, the formed salt has better physical and chemical stability, dissolution, pharmacokinetics and pharmacodynamics, and is more beneficial to the preparation of a medicine, and an effective epilepsy treatment drug is provided.

Description

Technical Field

[0001] This invention relates to a pharmaceutical salt of lamotrigine, a pharmaceutical composition thereof, a preparation method thereof, and an application thereof, and particularly to a pharmaceutical salt of lamotrigine with excellent pharmaceutical properties, a pharmaceutical composition thereof, a preparation method thereof, and an application thereof. Background Technology

[0002] Epilepsy is a complex chronic central nervous system disorder characterized by recurrent seizures caused by highly synchronized abnormal discharges of neurons in the brain. The pathophysiological mechanisms of epilepsy involve a complex network of dysregulation across multiple targets and pathways, including ion channel dysfunction (such as voltage-gated sodium and calcium channels), excitatory / inhibitory neurotransmitter imbalances (such as hyperglutamateremia and insufficient GABAergic inhibition), neuroinflammation, oxidative stress damage, and mitochondrial dysfunction. Although existing antiepileptic drugs (AEDs) provide effective treatment for many patients, only a portion of patients experience seizure control after initial monotherapy, while others do not respond to treatment. Monotherapy typically targets only one or two targets, while epilepsy, especially drug-resistant epilepsy, often involves a complex network of multiple pathogenic pathways. Intervention at a single target is insufficient to restore the balance of the entire network, leading to treatment failure. This complexity and heterogeneity of the pathological mechanism is the fundamental reason why single-target drugs struggle to achieve complete seizure control. In addition, monotherapy is often accompanied by insufficient efficacy, dose-dependent side effects (such as cognitive impairment, rash, hepatotoxicity, etc.), and drug resistance problems that may occur with long-term use.

[0003] Lamotrigine is a phenyltriazine antiepileptic drug. As a broad-spectrum antiepileptic, it can be used to treat partial seizures and generalized tonic-clonic seizures. Its main mechanism of action is through inhibiting voltage-dependent sodium ion channels, stabilizing neuronal cell membranes, and inhibiting the release of excitatory neurotransmitters such as glutamate. However, given the large amounts of reactive oxygen species (ROS), reactive nitrogen species (RNS), and inflammatory factors generated during seizures, lamotrigine has limited regulatory effects on oxidative stress and cannot completely counteract the accumulation of free radicals and inflammatory responses caused by seizures. Furthermore, epilepsy is closely related to mitochondrial dysfunction, the mechanisms of which may include respiratory chain abnormalities, mitochondrial dynamics defects, mitophagy, and oxidative stress. Faced with these complex pathological mechanisms, lamotrigine struggles to exert an effective intervention. Summary of the Invention

[0004] Purpose of the invention: The first purpose of the invention is to provide a pharmaceutical salt of lamotrigine that is beneficial for drug preparation; the second purpose is to provide a pharmaceutical composition with a pharmaceutical salt of lamotrigine or a pharmaceutical combination containing lamotrigine as the active ingredient; the third purpose is to provide a method for preparing a pharmaceutical salt of lamotrigine; and the fourth purpose is to provide a pharmaceutical application of a pharmaceutical salt of lamotrigine and a pharmaceutical composition thereof.

[0005] Technical solution: The pharmaceutical salt of lamotrigine described in this invention is formed by lamotrigine and racemic lipoic acid in a molar ratio of 1:1; the pharmaceutical salt has a monoclinic crystal system, space group P21, and cell parameters a=19.468(3) Å, b=10.0989(17) Å, c=10.6183(17) Å, α=90 °, β=97.809(5) °, γ=90 °.

[0006] Preferably, the medicinal salt, expressed as a diffraction angle of 2θ±0.2°, has characteristic diffraction peaks at 4.5°, 9.1°, 12.6°, 13.6°, 16.3°, 16.8°, 19.0°, 19.8°, 20.2°, 21.1°, 22.1°, 23.1°, and 25.3°.

[0007] Further preferably, the medicinal salt, expressed as a diffraction angle of 2θ±0.2°, has characteristic diffraction peaks at 4.5°, 9.1°, 12.1°, 12.6°, 13.6°, 15.9°, 16.3°, 16.8°, 17.4°, 18.0°, 19.0°, 19.8°, 20.2°, 21.1°, 22.1°, 23.1°, 25.3°, 26.6°, 26.9°, 27.7°, 28.1°, 31.0°, 31.3°, 33.0°, and 38.0°.

[0008] Preferably, the medicinal salt has a characteristic melting peak at 136.2 ℃ ± 1 ℃.

[0009] Preferably, the medicinal salt has a weight loss of less than 1.4% in the range of 50 ℃ to 200 ℃.

[0010] Another pharmaceutical salt of lamotrigine described in this invention is formed by lamotrigine and (R)-lipoic acid in a molar ratio of 1:1; the pharmaceutical salt has a monoclinic crystal system, space group P21, and cell parameters a=19.4087(8) Å, b=10.0282(4) Å, c=10.4929(4) Å, α=90 °, β=97.243(1) °, γ=90 °.

[0011] Preferably, the medicinal salt, expressed as a diffraction angle of 2θ±0.2°, has characteristic diffraction peaks at 4.5°, 9.1°, 9.7°, 11.3°, 12.1°, 12.4°, 13.8°, 14.1°, 16.3°, 16.8°, 17.4°, 19.7°, 22.1°, 22.8°, 23.2°, 23.5°, 25.2°, 26.3°, 26.7°, 27.7°, and 28.3°.

[0012] Further preferably, the medicinal salt, expressed as a diffraction angle of 2θ±0.2°, exhibits characteristic diffraction peaks at 4.5°, 9.1°, 9.7°, 11.3°, 12.1°, 12.4°, 13.8°, 14.1°, 16.3°, 16.6°, 16.8°, 17.4°, 17.9°, 18.9°, 19.7°, 20.1°, 20.2°, 21.0°, 22.1°, 22.8°, 23.2°, 23.5°, 25.2°, 26.3°, 26.7°, 27.7°, 28.3°, 28.8°, 29.3°, 29.6°, 31.1°, 31.4°, 32.5°, 37.3°, and 38.1°.

[0013] Preferably, the medicinal salt has a characteristic melting peak at 126.0 ℃ ± 1 ℃.

[0014] Preferably, the medicinal salt has a weight loss of less than 2.8% in the range of 50 ℃ to 200 ℃.

[0015] The pharmaceutical composition of the present invention uses a pharmaceutical salt of one of the two lamotrigines described in the present invention or a combination of pharmaceuticals selected from any of the following as its active ingredient:

[0016] Drug combination 1: A mixture of lamotrigine and racemic thioctic acid in a molar ratio of (0.25-2):1;

[0017] Drug combination 2: a mixture of lamotrigine and (R)-lipoic acid in a molar ratio of (0.25-2):1.

[0018] Lipoic acid is an organosulfur compound of B vitamins with powerful antioxidant capabilities. It scavenge free radicals directly (by scavenging free radicals) and indirectly (by initiating the transcription of antioxidant enzymes in the cell nucleus, regenerating endogenous antioxidants, and upregulating antioxidant enzymes), thus enhancing the overall antioxidant defense system. Epileptic seizures are often accompanied by increased concentrations of hydrogen peroxide and nitric oxide in the brain, and decreased activity of antioxidant enzymes, leading to a significant increase in oxygen free radicals. This causes oxidative damage to macromolecules such as lipids, proteins, and DNA, which in turn damages cell membranes and even other cellular structures, leading to apoptosis. Therefore, oxidative stress plays a crucial role in the pathogenesis of brain damage caused by epilepsy. Lipoic acid exerts its antioxidant effects through the nuclear factor (erythrocyte-derived 2)-associated factor 2 (Nrf2) pathway, playing an important role in the inhibition and relief of epileptic seizures and the protection of neurons after seizures. In addition to its antioxidant effects, lipoic acid also has a significant multi-pathway neuroprotective mechanism. It can improve mitochondrial function, inhibit apoptosis pathways (such as caspase-3 activation), and reduce the release of neuroinflammatory factors (interleukin-2, gamma interferon, and tumor necrosis factor-α), thereby increasing the survival rate of neurons in the brain after epileptic seizures.

[0019]

[0020] This invention is based on a drug-drug combination strategy, combining lamotrigine (a basic drug) with racemic lipoic acid or (R)-lipoic acid (an acidic drug) to form a salt, or physically mixing the basic and acidic drugs for the treatment of epilepsy. Lamotrigine inhibits abnormal brain discharges and excessive neural excitation, controlling seizures. Racemic lipoic acid or (R)-lipoic acid enhances the brain's resistance to seizures, reducing post-seizure brain damage. Through multi-target treatment, it enhances the therapeutic effect on epilepsy, delaying epilepsy-related neurodegenerative diseases and the progression of epilepsy. Furthermore, the basic and acidic drugs used in this invention can also be combined through co-amorphous, supramolecular complex, or deep eutectic processes. The salts constructed using the above drug-drug combination strategy not only possess excellent physical stability, chemical stability, and dissolution properties, but also exhibit excellent efficacy in a rat acute epilepsy model, potentially improving drug safety and patient compliance, and providing a novel and more comprehensive therapeutic approach for epilepsy treatment.

[0021] The basic and acidic drugs used in this invention can contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound can be labeled with radioactive isotopes, such as tritium ( 3 H), C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life. All isotope transformations described in this invention, regardless of radioactivity, are included within the scope of this invention.

[0022] The pharmaceutical composition of this invention further comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be an excipient widely used in the pharmaceutical manufacturing field. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient may be an inert filler, or may provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipient may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0023] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0024] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0025] Preferably, the pharmaceutical composition is a suspension with the following formulation, wherein the particle size of the suspension is less than 50 μm:

[0026]

[0027] The method for preparing the pharmaceutical salt of lamotrigine described in this invention is selected from any of the following methods:

[0028] Method 1: Dissolve lamotrigine and racemic lipoic acid or (R)-lipoic acid in a solvent at a predetermined molar ratio, remove the solvent, and the pharmaceutical salt is obtained.

[0029] Method 2: Lamotrigine and racemic lipoic acid or (R)-lipoic acid are mixed in a solvent at a predetermined molar ratio to form a suspension. The suspension is stirred until it becomes a paste, and the solvent is removed to obtain the pharmaceutical salt.

[0030] Preferably, in the above method, the solvent is selected from one or more of ethyl acetate, ethanol, dichloromethane, tetrahydrofuran, and acetone.

[0031] More preferably, the solvent is selected from ethyl acetate or a toluene-dichloromethane mixture with a volume ratio of 5:95 to 1:1.

[0032] Preferably, the mass-to-volume ratio of lamotrigine to solvent is 1 mg:(5-500) μL.

[0033] More preferably, the mass-to-volume ratio of lamotrigine to solvent is 1 mg:(30-400) μL.

[0034] Preferably, the molar ratio of the alkaline drug to the acidic drug is (0.25-2):1.

[0035] More preferably, the molar ratio of the alkaline drug to the acidic drug is 1:1.

[0036] More preferably, the alkaline drug and the acidic drug are mixed in a molar ratio of 1:1, and the pharmaceutical salt is prepared using ethyl acetate (lamotrigine to solvent mass-volume ratio of 1 mg:30 μL) or a toluene-dichloromethane mixed solvent with a volume ratio of 5:95 to 1:1 (lamotrigine to mixed solvent mass-volume ratio of 1 mg:400 μL).

[0037] In the drug combination of lamotrigine and racemic lipoic acid (drug combination one) or (R)-lipoic acid (drug combination two) described in this invention, the molar ratio of the basic drug to the acidic drug is (0.25-2):1, preferably 1:1.

[0038] The pharmaceutical salts of one of the two lamotrigines described in this invention or the pharmaceutical compositions described in this invention are used in the preparation of medicaments for the prevention and / or treatment of focal or generalized epilepsy.

[0039] Preferably, the drug is a drug for the prevention and / or treatment of temporal lobe epilepsy.

[0040] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0041] This invention employs a drug-drug combination strategy, combining lamotrigine with lipoic acid (racemic or R configuration) through salt formation or mixtures. In the treatment of epilepsy, the lamotrigine fragment inhibits abnormal brain discharges and excessive neural excitation, while the lipoic acid fragment enhances the brain's resistance to seizures, reduces post-seizure brain damage, and exerts a synergistic multi-pathway therapeutic effect, delaying disease progression. Simultaneously, the resulting pharmaceutical salt exhibits superior physicochemical stability, dissolution, pharmacokinetics, and pharmacodynamic properties, making it more suitable for drug development and providing an effective treatment for epilepsy. Attached Figure Description

[0042] Figure 1 The X-ray single-crystal diffraction structure of lamotrigine-racemic thiooctanoate is obtained at 298 K.

[0043] Figure 2 The X-ray single-crystal diffraction structure of lamotrigine-(R)-thiocate is obtained at 163 K.

[0044] Figure 3 PXRD pattern of lamotrigine-racemic thiooctanoate;

[0045] Figure 4 PXRD pattern of lamotrigine-(R)-thiocate;

[0046] Figure 5 The image shows the DSC spectrum of lamotrigine-racemic thiooctanoate (melting point 136.2 ℃).

[0047] Figure 6 DSC spectrum of lamotrigine-(R)-lipoic acid salt (melting point 126.0 ℃);

[0048] Figure 7 TGA spectrum of lamotrigine-racemic thiooctanoate;

[0049] Figure 8 TGA spectrum of lamotrigine-(R)-lipoic acid salt;

[0050] Figure 9The concentration of lamotrigine in lamotrigine-racemic lipoic acid salt is the dissolution of lamotrigine in a pH 1.2 buffer solution.

[0051] Figure 10 The leaching of racemic lipoic acid in lamotrigine-racemic lipoic acid salt in a pH 1.2 buffer solution (lipoic acid concentration).

[0052] Figure 11 To accelerate the generation of the moisture absorption weight gain percentage spectrum of the samples in the experiment;

[0053] Figure 12 PXRD patterns of lamotrigine-racemic thiooctanoate under accelerated conditions over 30 days;

[0054] Figure 13 PXRD patterns of racemic lipoic acid under accelerated conditions over 30 days;

[0055] Figure 14 PXRD patterns of lamotrigine under accelerated conditions over 30 days;

[0056] Figure 15 The graph shows the remaining percentage of lipoic acid in the sample under high temperature (60 °C) conditions.

[0057] Figure 16 The graph shows the remaining percentage of lamotrigine in the sample under high temperature (60 °C) conditions.

[0058] Figure 17 The blood concentration spectrum of lamotrigine in pharmacokinetic experiments;

[0059] Figure 18 The blood concentration spectrum of lipoic acid in pharmacokinetic experiments;

[0060] Figure 19 Seizure activity in a rat model of acute epilepsy induced by lithium spirocarpine.

[0061] Figure 20 A graph showing the latency period of epilepsy in pharmacodynamic experiments;

[0062] Figure 21 A spectrum of survival rates in pharmacodynamic experiments;

[0063] Figure 22 This is a trajectory diagram of open field experiments in pharmacodynamics.

[0064] Figure 23 This is a graph of the total motion distance in an open field experiment during pharmacodynamic testing.

[0065] Figure 24 This is a graph of the total settling time in an open-field experiment during pharmacodynamic testing.

[0066] Figure 25This is a map of the activity distance in the central region of an open field experiment in pharmacodynamics.

[0067] Figure 26 Image of Nissl staining in the CA3 region of the rat hippocampus during a pharmacodynamic experiment;

[0068] Figure 27 Image of Tunel staining in the CA3 region of the rat hippocampus during a pharmacodynamic experiment;

[0069] Figure 28 Statistics on the survival rate of nerve cells in the CA3 region of the rat hippocampus during pharmacodynamic experiments;

[0070] Figure 29 This is a statistical analysis of the fluorescence intensity of Tunel staining in the CA3 region of the rat hippocampus during pharmacodynamic experiments. Detailed Implementation

[0071] The technical solution of the present invention will be further described below with reference to the embodiments.

[0072] Example 1: Preparation of lamotrigine-racemic thiooctanoate

[0073] Approximately 50 mg of lamotrigine and 40.3 mg of racemic thioctic acid were weighed into a 2 mL EP tube, 1.5 mL of ethyl acetate was added, and the mixture was stirred at room temperature for one day. The solid was collected by filtration and dried under vacuum overnight. PXRD analysis confirmed that the solid was lamotrigine-racemic thioctic acid salt.

[0074] Example 2: Preparation of lamotrigine-racemic thiooctanoate

[0075] Approximately 25 mg of lamotrigine and 20.14 mg of racemic thioctic acid were weighed into a 20 mL glass beaker. 10 mL of a toluene:dichloromethane mixture (1:1, V:V) was added to completely dissolve the solid. The mixture was then allowed to evaporate to dryness at room temperature until a solid precipitated. PXRD analysis confirmed that the solid was lamotrigine-racemic thioctic acid salt.

[0076] Example 3: Preparation of lamotrigine-(R)-thiocate

[0077] Approximately 50 mg of lamotrigine and 40.3 mg of (R)-lipoic acid were weighed into a 2 mL EP tube. 1.5 mL of ethyl acetate was added, and the mixture was stirred at room temperature for one day. The solid was collected by filtration and dried under vacuum overnight. PXRD analysis confirmed that the solid was lamotrigine-(R)-lipoic acid salt.

[0078] Example 4: Preparation of lamotrigine-(R)-thiocate

[0079] Approximately 25 mg of lamotrigine and 20.14 mg of (R)-lipoic acid were weighed into a 20 mL glass beaker. 10 mL of a toluene:dichloromethane mixture (5:95, V:V) was added to completely dissolve the solid. The mixture was then allowed to evaporate to dryness at room temperature until a solid precipitated. PXRD analysis confirmed that the solid was lamotrigine-(R)-lipoic acid salt.

[0080] Example 5: Crystal Structure Characterization

[0081] 1. Single crystal structure analysis

[0082] Lamotrigine-racemic thioctic acid salt (structure see...) Figure 1 ) and lamotrigine-(R)-lipoic acid salt (structure see Figure 2 The structural unit of lamotrigine is composed of a lamotrigine cation and a thioctic acid anion bonded together by an ionic bond. Specifically, the carboxyl group of the thioctic acid molecule undergoes deprotonation, and the released hydrogen ion is transferred to the second nitrogen atom on the triazine ring of the lamotrigine molecule, forming a lamotrigine ammonium cation and a thioctic acid carboxylate anion.

[0083] Specifically, the crystallographic data for lamotrigine-racemic lipooctanoate are as follows:

[0084]

[0085] Specifically, the crystallographic data for lamotrigine-(R)-lipoic acid salt are as follows:

[0086]

[0087] 2. PXRD Analysis

[0088] The samples were characterized using a Rigaku SmartLab SE PXRD, with PXRD data acquired via a copper target. The scan range was 3–40° (2θ), the step size was 0.02°, the voltage was 40 kV, the current was 40 mA, and the scan rate was 10° (2θ) / min.

[0089] Table 1 Parameters measured by PXRD

[0090]

[0091] Testing has shown that the error range for the 2θ values ​​can be ±0.2. Those skilled in the art should understand that these diffraction peaks do not represent an exhaustive picture of the diffraction peaks exhibited by lamotrigine-racemic lipoic acid and lamotrigine-(R)-lipoic acid. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly with variations in the machine and sample preparation, as well as between batches, and the values ​​cited are not considered absolute values. It should also be understood that the absolute intensity of the peaks may also vary with orientation effects. Therefore, the intensities shown in this invention are exemplary and not intended for absolute comparison.

[0092] The PXRD pattern of lamotrigine-racemic thiooctanoate prepared according to the method described in Example 1 is as follows: Figure 3 As shown.

[0093] The PXRD pattern of lamotrigine-(R)-lipoic acid salt prepared according to the method described in Example 3 is as follows. Figure 4 As shown.

[0094] Depend on Figure 3 It is known that the PXRD spectrum of lamotrigine-racemic thiooctanoate provided by the present invention has derived peaks at 2θ = 4.5°, 9.1°, 12.1°, 12.6°, 13.6°, 15.9°, 16.3°, 16.8°, 17.4°, 18.0°, 19.0°, 19.8°, 20.2°, 21.1°, 22.1°, 23.1°, 25.3°, 26.6°, 26.9°, 27.7°, 28.1°, 31.0°, 31.3°, 33.0°, and 38.0°, and the error range of the above 2θ values ​​is ±0.2.

[0095] Depend on Figure 4 It can be seen that the PXRD pattern of lamotrigine-(R)-lipoic acid salt provided by this invention is at 2θ=4.5°, 9.1°, 9.7°, 11.3°, 12.1°, 12.4°, 13.8°, 14.1°, 16.3°, 16.6°, 16.8°, 17.4°, 17.9°, 18.9°, 19.7°, 20.1°, 20.2°. Derivative peaks are observed at 21.0°, 22.1°, 22.8°, 23.2°, 23.5°, 25.2°, 26.3°, 26.7°, 27.7°, 28.3°, 28.8°, 29.3°, 29.6°, 31.1°, 31.4°, 32.5°, 37.3°, and 38.1°. The error range for the above 2θ values ​​is ±0.2.

[0096] 3. DSC Analysis

[0097] The differential scanning calorimeter model is TA Q2000. The specific operation method is as follows: weigh 3-5 mg of sample into a sealed aluminum crucible, heat to 200 ℃ at a rate of 10 ℃ / min, use indium metal for calibration, protect with high-purity nitrogen gas (>99.99%) as an inert gas, nitrogen flow rate of 50 mL / min, and use TA Universal Analysis software.

[0098] Lamotrigine-racemic thiooctanoate was prepared according to the method in Example 1, and its DSC spectrum is shown below. Figure 5 As shown in the figure. The spectrum shows that the salt has a single melting point of 136.2 °C.

[0099] Lamotrigine-(R)-thioctic acid salt was prepared according to the method in Example 3, and its DSC spectrum is shown below. Figure 6 As shown in the figure. The spectrum shows that the salt has a single melting point of 126.0 °C.

[0100] 4. TGA Analysis

[0101] Thermogravimetric analysis was performed using a TA Q500 TGA. The test environment was protected by high-purity (99.99%) nitrogen gas at a flow rate of 40 mL / min, and the temperature was increased from room temperature to 300 °C at a heating rate of 20 °C / min.

[0102] Lamotrigine-racemic thiooctanoate was prepared according to the method in Example 1, and its TGA spectrum is shown below. Figure 7 As shown in the figure, the salt exhibits a weight loss of less than 1.4% in the 200 °C range.

[0103] Lamotrigine-(R)-thioctic acid salt was prepared according to the method in Example 3, and its TGA spectrum is shown below. Figure 8 As shown in the figure, the salt exhibits a weight loss of less than 2.8% in the 200 °C range.

[0104] Example 6: Preparation of Suspension

[0105] Weigh 72.23 mg of lamotrigine-racemic thioctic acid salt, pass it through a 200-mesh sieve three times, observe the particle morphology using an inverted microscope, control the particle size to be below 50 μm, disperse the solid in a polymer solution, and the solution formulation is shown in Table 2.

[0106] Weigh 40 mg of lamotrigine and 32.23 mg of racemic lipoic acid, pass them through a 200-mesh sieve three times, observe the particle morphology with an inverted microscope, control the particle size to be below 50 μm, disperse the solids in a polymer solution, and the solution formulation is shown in Table 2.

[0107] Weigh 40 mg of lamotrigine, pass it through a 200-mesh sieve three times, observe the particle morphology using an inverted microscope, control the particle size to be below 50 μm, disperse the solid in a polymer solution, and the solution formulation is shown in Table 2.

[0108] Weigh 32.23 mg of racemic lipoic acid, pass it through a 200-mesh sieve three times, observe the particle morphology using an inverted microscope, control the particle size to be below 50 μm, disperse the solid in a polymer solution, and the solution formulation is shown in Table 2.

[0109] Table 2 Formulation of Suspension Polymer Solution

[0110]

[0111] Example 7: Powder dissolution evaluation

[0112] Lamotrigine, racemic lipoic acid, lamotrigine-racemic lipoic acid salt prepared according to the method of Example 1, and lamotrigine-(R)-lipoic acid salt prepared according to the method of Example 3 were each passed through a 200-mesh sieve three times to control particle size uniformity. A buffer solution with pH 1.2 was obtained by adding 34.2 mmol / L NaCl and 7 mL / L HCl to water and then adjusting the pH to 1.2. Four 30 mL aliquots of pH 1.2 buffer solution were taken, and respectively, 300 mg lamotrigine, 543 mg lamotrigine-racemic lipoic acid, 543 mg lamotrigine-(R)-lipoic acid, 243 mg racemic lipoic acid, and 543 mg lamotrigine-racemic lipoic acid in a 1:1 molar ratio were added. The aliquots were placed in a shaker at 37 ℃ and 100 rpm. At predetermined time intervals of 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h, 1 mL aliquots were taken, filtered through a 0.22 μm filter, diluted 100-fold, and the concentration was determined by HPLC. The experiment was repeated three times. Relevant results are shown below. Figures 9-10 .

[0113] Experimental conditions for high performance liquid chromatography:

[0114] Instrument: Shimadzu LC-20AT high performance liquid chromatograph;

[0115] Chromatography UV detector model: Shimadzu SPD-20A;

[0116] Chromatography quaternary pump model: Shimadzu LC-20AT;

[0117] Column: Agilent Puresuit XRs 5 C18 (250 × 4.6 mm);

[0118] Mobile phase: Phase A: methanol, Phase B: 0.01 mol / L KH2PO4 (adjusted to pH 3.8 with 0.1% phosphoric acid), Phase A / Phase B = 65% / 35% (V / V);

[0119] Column temperature: 40 ℃;

[0120] Flow rate: 1 mL / min;

[0121] Injection volume: 10 μm;

[0122] Detection wavelength: 215 nm.

[0123] The results above show that, under pH 1.2 conditions, for lamotrigine, lamotrigine-racemic lipoic acid salt exhibited a more moderate release within 0-15 min compared to the physical mixture of the two and lamotrigine alone, and maintained a higher drug concentration at subsequent time points up to 6 h. Lamotrigine-(R)-lipoic acid salt, compared to the physical mixture and lamotrigine alone, showed the highest drug concentration at all time points, demonstrating its rapid dissolution characteristic. Finally, the concentration of lamotrigine in each group was almost the same at 8 h.

[0124] For lipoic acid, lamotrigine-racemic lipoic acid salt and lamotrigine-(R)-lipoic acid salt maintained the highest drug concentrations within 6 hours, and the lipoic acid concentrations in each group were similar at 8 hours. Overall, there was no significant difference in the dissolution of lipoic acid between lamotrigine-racemic lipoic acid salt and lamotrigine-(R)-lipoic acid salt.

[0125] Considering that oral administration first comes into contact with the gastric acid environment, the dissolution results under pH 1.2 conditions are closer to the actual absorption behavior of the drug in the body. Therefore, the higher drug concentrations maintained by lamotrigine-racemic thioctic acid and lamotrigine-(R)-thioctic acid under pH 1.2 conditions are more beneficial for drug absorption.

[0126] Example 8: Stability Evaluation

[0127] 1. Physical stability evaluation

[0128] Accurately weigh 54 mg of lamotrigine-racemic lipoic acid, 54 mg of a 1:1 physical mixture of lamotrigine and racemic lipoic acid, 30 mg of lamotrigine active pharmaceutical ingredient, and 24 mg of lipoic acid active pharmaceutical ingredient, and spread them evenly at the bottom of a 20 mL vial. Sift the above powders through a 200-mesh sieve three times, controlling the particle size range to below 50 μm. Place the vial open in a desiccator at 40 ℃ and 75% RH ± 5% RH. Accurately weigh the sample after a period of time and calculate the moisture absorption percentage. The relevant experimental results are shown in [link to relevant experimental results]. Figure 11Next, samples were taken and PXRD spectra were measured. The results showed that lamotrigine-racemic lipoic acid, lamotrigine, and racemic lipoic acid did not undergo phase transformation within 30 days. The majority of the 1:1 physical mixture of lamotrigine and racemic lipoic acid was converted into lamotrigine-racemic lipoic acid. Relevant experimental spectra can be found in [reference needed]. Figures 12-14 In summary, under accelerated experimental conditions (40 °C, 75% RH ± 5% RH), lamotrigine-racemic lipoic acid showed minimal hygroscopic weight gain within 35 days, with no phase transition occurring. Both the physical mixture and lamotrigine alone exhibited significant hygroscopicity. In the physical mixture, both lamotrigine and racemic lipoic acid underwent a chemical transformation from their free forms to their salt forms. This transformation is related to the instability of the physical mixture, while the pre-formed salt showed better stability.

[0129] 2. Evaluation of chemical stability

[0130] 50 mg lamotrigine, 40 mg racemic lipoic acid, 90 mg of a physical mixture of the former two, and 90 mg lamotrigine-racemic lipoic acid were respectively spread evenly on the bottom of a sealed brown vial and exposed to a high temperature of 60 °C. Samples were taken at fixed time points, diluted with methanol, and dissolved by sonication. The percentage of remaining lipoic acid was determined by high performance liquid chromatography (HPLC) (experimental conditions were the same as in Example 7) (n=3). The results are shown in the figure. Figure 15 There was no significant difference in the percentage of residual lamotrigine content among the different groups, as shown in the results below. Figure 16 .Depend on Figures 15-16 It is known that lamotrigine-racemic thiooctanoate has better thermal stability, is easier to process and store drugs, and is more conducive to ensuring drug safety.

[0131] Example 9: Pharmacokinetic Evaluation

[0132] Male 7-week-old SD rats were used in the experiment. They were acclimatized for one week before the experiment, and a total of 32 rats were randomly divided into 4 groups of 8 rats each. Specifically, they were divided into lamotrigine monotherapy group, racemic thioctic acid monotherapy group, lamotrigine-racemic thioctic acid group, and physical mixture of lamotrigine and racemic thioctic acid group. All groups were administered the suspension formulation prepared by gavage using the excipient formulation described in Example 6, as follows: lamotrigine monotherapy group was given lamotrigine suspension (concentration 4 mg / mL) at a dose of 25 mg / kg; racemic thioctic acid monotherapy group was given racemic thioctic acid suspension (concentration 3.2 mg / mL) at a dose of 20.14 mg / kg; lamotrigine-racemic thioctic acid salt group was given a suspension of its salt (total concentration 7.2 mg / mL) at a dose of 45.14 mg / kg (equivalent to a lamotrigine dose of 25 mg / kg and a racemic thioctic acid dose of 20.14 mg / kg); physical mixture group was given a suspension of lamotrigine and racemic thioctic acid mixed in a 1:1 molar ratio (total concentration 7.2 mg / mL) at a dose of 45.14 mg / kg (component content was the same as the lamotrigine-racemic thioctic acid salt group).

[0133] Blood samples were collected from the orbital region of rats at predetermined time points of 15 min, 30 min, 45 min, 60 min, 2 h, 4 h, and 8 h after drug administration. The samples were centrifuged, frozen, and analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic results for each group are shown below. Figures 17-18 Tables 3-4.

[0134] Experimental conditions for liquid chromatography-mass spectrometry determination:

[0135] Instrument: Shimadzu LCMS-8045 230V CE;

[0136] Column: Waters Xterra RP18, 5 μm, 3.9 × 150 mm;

[0137] Mobile phase: Phase A: 0.1% acetic acid (adjusted to pH 4 with ammonia), Phase B: methanol, Phase A / Phase B = 55% / 45% (V / V);

[0138] Column temperature: 40 ℃;

[0139] Flow rate: 0.8 mL / min;

[0140] Detection was performed using an electrospray ionization (ESI) source with switching between positive and negative ions in multiple reaction monitoring (MRM) mode. Positive ion mode was used from 0-6 min, and negative ion mode from 6-13.5 min. The ion pairs used for quantitative analysis were m / z 256.1→211.1 (lamotrigine) and m / z 233.2→159.1 (lamotrigine internal standard, melatonin); m / z 205.1→171.1 (racemic lipoic acid) and m / z 229.1→185.2 (racemic lipoic acid internal standard, naproxen). Pharmacokinetic parameters were calculated using DAS 2.0 software.

[0141] Table 3. Pulsokine pharmacokinetic parameters of a single oral dose in rats based on lamotrigine concentration (n=8) (mean ± standard deviation)

[0142]

[0143] Table 4. Drug pharmacokinetic parameters of rats after a single oral administration based on lipoic acid concentration (n=8) (mean ± standard deviation)

[0144]

[0145] The results above show that, for lamotrigine, the plasma concentrations in the lamotrigine-racemic lipoic acid salt group were significantly higher than those in the physical mixture group and the lamotrigine monotherapy group at 45 min and 1 h post-administration. At subsequent time points of 4 h and 8 h, the plasma concentrations in the lamotrigine-racemic lipoic acid salt group were also significantly higher than the other two groups. In summary, in pharmacokinetic evaluation, the overall plasma concentrations in the lamotrigine-racemic lipoic acid salt group were higher than those in the physical mixture and monotherapy groups, demonstrating a significant advantage. Higher plasma exposure levels generally imply stronger and more precise therapeutic intensity. Combined with subsequent pharmacodynamic experiments in a rat epilepsy model, the salt group more effectively reduced the frequency and severity of seizures and prolonged the protective window, demonstrating that its pharmacokinetic advantages translated into clinical efficacy advantages. For patients, this means more effective disease control.

[0146] For lipoic acid, the time to peak plasma concentration (TTP) in the lamotrigine-racemic lipoic acid group was prolonged from 15 min in the monotherapy and physical mixture groups to 30 min, and the TTP concentration at 30 min was significantly higher than the other two groups. The unique pharmacokinetic characteristics of lamotrigine-racemic lipoic acid, particularly its prolonged TTP and increased plasma exposure at specific time points, will lead to certain pharmacodynamic differences. The prolonged TTP of lipoic acid means more gradual drug absorption, avoiding a "peak" in plasma concentration. For patients, this translates to increased compliance and reduced side effects.

[0147] In summary, lamotrigine-racemic lipoic acid salt exhibits superior blood drug exposure levels and more stable release kinetics compared to physical mixtures and monotherapy groups, laying a solid material foundation for improving actual clinical efficacy, tolerability, and patient compliance.

[0148] Example 10: Pharmacodynamic Evaluation

[0149] Male 7-week-old SD rats were used in the experiment. Thirty-six rats were acclimatized for one week before the experiment and randomly divided into 6 groups of 6 rats each: a control group, a model group, and drug treatment groups (including lamotrigine monotherapy, racemic thioctic acid monotherapy, lamotrigine-racemic thioctic acid salt, and a physical mixture of lamotrigine and racemic thioctic acid). The drug treatment groups were administered the drugs by gavage for three consecutive days before modeling, as follows: the lamotrigine monotherapy group received 25 mg / kg / day of lamotrigine by gavage; the lamotrigine-racemic thioctic acid salt group received 45.14 mg / kg / day of lamotrigine-racemic thioctic acid salt by gavage; the physical mixture group received a 1:1 molar ratio physical mixture of lamotrigine and racemic thioctic acid at 45.14 mg / kg / day by gavage; and the control and model groups received an equal volume of physiological saline. Each treatment group was administered a drug suspension via gavage, with excipient formulations as described in Example 6. During model establishment, the control group received an equal volume of physiological saline via intraperitoneal injection.

[0150] Lithium-pilocarpine was used to establish the epileptic seizure model. Rats in the modeling group and the drug treatment group received an intraperitoneal injection of lithium chloride at a dose of 127 mg / kg 18 hours before modeling. At the time of modeling, rats were first injected intraperitoneally with 1 mg / kg atropine sulfate, followed by an intraperitoneal injection of pilocarpine hydrochloride 30 mg / kg 30 minutes later. The control group received an equal volume of physiological saline intraperitoneally. After modeling, rats in each group were placed in transparent cages and their behavior was video-recorded for 2 hours. Behavioral data and the highest seizure severity at each time point were recorded. The Racine scale was used to quantify the severity of epileptic seizures. "0" represented normal rat behavior, "1" represented facial muscle twitching and chewing, "2" represented regular head nodding, "3" represented forelimb clonus, "4" represented the "kangaroo" posture, and "5" represented falls and severe clonic seizures with loss of posture. Results for each group are as follows: Figure 19 .

[0151] The latency period of epilepsy refers to the time from the injection of pilucapine into the rats until the first seizure with a Racine score of 3 or higher. Results for each group are as follows: Figure 20 As shown in the figure. The survival status of rats in each group was recorded three days after modeling. The results for each group are as follows. Figure 21 As shown. By Figures 19-21It was found that the drug-treated groups significantly controlled and reduced epileptic seizures compared to the model groups, prolonging the latency period of epilepsy and greatly improving the survival rate of rats. Among the drug-treated groups, the lamotrigine-racemic lipoic acid group showed the most significant effect, followed by the physical mixture group, with statistically significant differences.

[0152] One day after modeling, the rats were placed in an open field, and their activity trajectories were recorded over 10 minutes (the open field experimental device was manufactured by Beijing Zhongshidichuang Technology Development Co., Ltd., model number: ZS-KC). Anymaze software was used to analyze the rat activity trajectories. The results for each group of rats are shown below. Figure 22 As shown in the figure. The statistical results of the total distance traveled, the total time spent at rest, and the distance traveled in the central area of ​​the open field by rats in the open field experiment are as follows. Figures 23-25 As shown. By Figures 23-25 In the open field experiment, compared to the single-drug group, both the physical mixture group and lamotrigine-racemic lipoic acid showed greater movement distance, shorter resting time, and better central area exploration behavior. After epileptic seizures, the rats' behavior gradually returned to normal, and the anxiety associated with epilepsy was alleviated, indicating that the combination of the two drugs can further reduce behavioral abnormalities and restore normal brain function in rats.

[0153] Two days after modeling, rats were sacrificed and their brains were harvested and preserved in 4% paraformaldehyde solution. Hippocampal tissue was embedded in paraffin and sectioned. The sections were sequentially immersed in environmentally friendly dewaxing solution (Servicebio, G1128) for 40 min, anhydrous ethanol for 10 min, and 75% ethanol for 5 min, then rinsed with purified water. The sections were then fixed with tissue fixative (Servicebio, G1101) for 15 min, rinsed with purified water, and set aside for subsequent Nissl staining and fluorescent Tunel staining.

[0154] Nissl staining: The slides were immersed in the staining solution (Nissl staining kit (tar purple method) Servicebio) for 15 min, washed with water, rapidly dehydrated with anhydrous ethanol, then cleared in clean xylene for 5 min, mounted with neutral resin, examined under a microscope, and images of Nissl staining in the CA3 region of the hippocampus of rats in each group were collected. Figure 26 (See statistics on nerve cell survival rates) Figure 28 Nissl staining results showed severe neuronal loss in the model group, with loose cell arrangement, shrunken cell bodies in some neurons, nuclear condensation, and a reduction in Nissl bodies in the cytoplasm. The single-drug group showed slight improvement, but still exhibited a large number of shrunken cell bodies. The lamotrigine-racemic lipoic acid group and the physical mixture group recovered to near-normal levels.

[0155] Tunel staining: After slightly drying the slides, draw circles around the tissue with a histochemical pen (to prevent fluid from flowing away). Add proteinase K working solution (prepared as stock solution:PBS = 1:9) to the circle to cover the tissue and incubate at 37 °C for 20 min. Place the slides in PBS (pH 7.4) and wash three times on a destaining shaker, 5 min each time. After slightly drying the slides, add buffer to the circle to cover the tissue and incubate at room temperature for 10 min. Take an appropriate amount of TDT enzyme, dUTP, and buffer from the Tunel kit (Wuhan Saiwei Biotechnology Co., Ltd., G1504) and mix them in a 2:5:50 ratio. Add this mixture to the circle to cover the tissue. Place the slides flat in a humidified chamber and incubate at 37 °C for 1 h, adding a small amount of water to maintain humidity. Wash the slides three times with PBS (pH 7.4), 5 min each time. After removing PBS, DAPI staining solution (Wuhan Saiweier Biotechnology Co., Ltd., G1012) was added to the slide and incubated at room temperature in the dark for 10 min. The slide was then placed in PBS (pH 7.4) and washed three times on a decolorizing shaker for 5 min each time. The sections were slightly dried and mounted with anti-fluorescence quenching mounting medium. Finally, the sections were observed and images were acquired under a fluorescence microscope. In the images, the cell nuclei stained with DAPI appear blue under UV excitation (the kit used 488 fluorescein labeling), and positive apoptotic cells appear green. The results of TUNEL staining of the CA3 region of the rat hippocampus in each group are shown below. Figure 27 The statistical results of immunofluorescence intensity in each group are shown in the figure. Figure 29 Tunel staining revealed extensive green fluorescence in the model group neurons, indicating severe neuronal apoptosis. Lamotrigine monotherapy showed slightly weaker green fluorescence, while racemic lipoic acid monotherapy showed even less green fluorescence, demonstrating its strong neuroprotective effect, preventing neuronal apoptosis. In the physical mixture and salt groups, green fluorescence was almost invisible, reflecting the powerful protective effect of the two drugs on neurons after epileptic seizures.

[0156] Given that epileptic seizures are often accompanied by increased concentrations of hydrogen peroxide and nitric oxide in the brain, and decreased activity of antioxidant enzymes, leading to a significant increase in oxygen free radicals and causing oxidative damage to macromolecules such as lipids, proteins, and DNA, which in turn damages cell membranes and even other cellular structures, resulting in apoptosis, oxidative stress plays an important role in the pathogenesis of brain damage caused by epilepsy.

[0157] Because antiepileptic drugs can only suppress epileptic symptoms, such as abnormal discharges, but cannot prevent the development and progression of epilepsy or the deterioration of the brain's microenvironment, their efficacy in treating refractory epilepsy in clinical trials does not meet expectations. If left uncontrolled in the early stages, epilepsy continuously activates healthy glial cells, intensifying the vicious cycle of inflammation, oxidative stress, and glial proliferation, ultimately leading to refractory epilepsy and chronic neuronal damage. Therefore, other therapies are needed to complement antiepileptic drugs and reshape the brain's epileptic microenvironment to protect neurons.

[0158] This invention is based on a drug-drug combination strategy, employing lamotrigine and thioctic acid, which exhibit significantly superior antiepileptic and neuroprotective effects compared to monotherapy. Specifically, these effects include delaying seizures, increasing survival rates, alleviating seizure symptoms, reducing behavioral abnormalities, and restoring normal brain function. The combination is not a simple additive effect of the two components, but rather a synergistic effect. Furthermore, due to the alteration of the physicochemical properties, pharmacokinetics, and distribution properties of the two drugs by salt formation, the salt group demonstrates superior efficacy compared to the physical mixture.

[0159] In pharmacodynamic evaluation, for lamotrigine, administration using the salt designed in this invention significantly prolonged the latency period for epilepsy compared to the monotherapy control group (approximately 85 min for the salt form and approximately 50 min for the monotherapy group). Combined with pharmacokinetic evaluation results, at 45 min and 1 h post-administration, the plasma concentrations of lamotrigine in the salt form were significantly higher than those in the monotherapy control group. Therefore, the increased in vivo exposure level of this salt form is closely related to its more prolonged efficacy. For thioctic acid, the unique pharmacokinetic characteristics of this salt form, particularly its prolonged time to peak concentration and increased plasma exposure at specific time points, bring significant pharmacodynamic advantages. Based on the above pharmacokinetic data, the lamotrigine salt designed in this invention has the following positive implications for actual clinical use:

[0160] (1) Providing drug options with significantly enhanced efficacy: The excellent efficacy of the pharmaceutical salt designed in this invention in animal models directly indicates that it is expected to achieve a higher disease control rate in clinical applications. For epilepsy patients, this means a higher seizure-free probability, and its superior characteristics compared to standard monotherapy provide a new and effective solution for patients who do not respond well to existing treatments;

[0161] (2) Additional benefits beyond symptom control: The powerful antioxidant and neuroprotective properties of the lipoic acid component, through optimized synergy with lamotrigine, not only enhance the efficacy of anti-seizure symptom control but also have a beneficial effect on the underlying pathophysiological pathways of epilepsy (such as oxidative stress damage, mitochondrial dysfunction, and neuroinflammation). This will translate into improved long-term prognosis, such as reducing neuronal damage, slowing disease progression, and enhancing the brain's defense against seizures, achieving a leap from simply "controlling symptoms" to "preventing seizures."

[0162] (3) Achieving controllable “synergistic effect”: The formation of medicinal salt makes the two drugs appear as a single chemical entity with fixed composition and ratio and controllable quality, ensuring that each dose unit can provide the optimal basis for synergistic effect, greatly improving the predictability and reliability of the treatment effect.

[0163] (4) Improved drug tolerance and safety: Higher lamotrigine exposure efficiency means that a lower dose is required to achieve the same or better efficacy, thereby further reducing the risk of dose-dependent side effects (such as rash, drowsiness, etc.) and potentially improving the therapeutic index (efficacy / safety ratio).

[0164] (5) Simplified treatment regimen and improved compliance: This invention integrates two drugs with synergistic effects into a single unit, simplifying the dosing regimen. This not only makes it easier for patients to take the medication and reduces the chance of missed or incorrect doses, but more importantly, it ensures that the two active ingredients always enter the body in the optimal ratio simultaneously. This avoids problems such as inaccurate dosage and asynchronous medication times that may occur when patients use physical mixtures on their own, thereby ensuring the stable performance of the synergistic effect and ultimately improving long-term treatment compliance and efficacy.

[0165] In summary, this invention combines lamotrigine and thioctic acid via a salt-forming strategy to develop a novel lamotrigine-thioctic acid salt. Lamotrigine inhibits abnormal brain discharges and excessive neural excitation, while thioctic acid enhances the brain's resistance to epileptic seizures and reduces brain damage after a seizure. This strategy aims to simultaneously achieve synergistic effects in efficacy and improve pharmaceutical compatibility, resulting in a more effective, stable, and convenient novel antiepileptic drug.

Claims

1. A pharmaceutical salt of lamotrigine, characterized in that, It is formed by lamotrigine and racemic thioctic acid in a molar ratio of 1:1; the medicinal salt has a monoclinic crystal system, space group P21, and cell parameters a=19.468(3) Å, b=10.0989(17) Å, c=10.6183(17) Å, α=90 °, β=97.809(5) °, γ=90 °.

2. The pharmaceutical salt of lamotrigine according to claim 1, characterized in that, Expressed as a diffraction angle of 2θ±0.2°, the medicinal salt has characteristic diffraction peaks at 4.5°, 9.1°, 12.6°, 13.6°, 16.3°, 16.8°, 19.0°, 19.8°, 20.2°, 21.1°, 22.1°, 23.1°, and 25.3°.

3. The pharmaceutical salt of lamotrigine according to claim 1, characterized in that, The medicinal salt has a characteristic melting peak at 136.2℃±1℃.

4. A pharmaceutical salt of lamotrigine, characterized in that, It is formed by lamotrigine and (R)-lipoic acid in a molar ratio of 1:1; the medicinal salt has a monoclinic crystal system, space group P21, and cell parameters a=19.4087(8) Å, b=10.0282(4) Å, c=10.4929(4) Å, α=90 °, β=97.243(1) °, γ=90 °.

5. The pharmaceutical salt of lamotrigine according to claim 4, characterized in that, Expressed as a diffraction angle of 2θ±0.2°, the medicinal salt exhibits characteristic diffraction peaks at 4.5°, 9.1°, 9.7°, 11.3°, 12.1°, 12.4°, 13.8°, 14.1°, 16.3°, 16.8°, 17.4°, 19.7°, 22.1°, 22.8°, 23.2°, 23.5°, 25.2°, 26.3°, 26.7°, 27.7°, and 28.3°.

6. The pharmaceutical salt of lamotrigine according to claim 4, characterized in that, The medicinal salt has a characteristic melting peak at 126.0℃±1℃.

7. A pharmaceutical composition, characterized in that, It uses the pharmaceutical salt of lamotrigine as described in any one of claims 1-6 as its active ingredient.

8. A method for preparing a pharmaceutical salt of lamotrigine according to any one of claims 1-6, characterized in that, Choose from any of the following methods: Method 1: Dissolve lamotrigine and racemic lipoic acid or (R)-lipoic acid in a solvent at a molar ratio of (0.25-2):1, remove the solvent, and the pharmaceutical salt is obtained. Method 2: Lamotrigine and racemic lipoic acid or (R)-lipoic acid are mixed in a solvent at a molar ratio of (0.25-2):1 to form a suspension. The suspension is stirred until it becomes a paste, and the solvent is removed to obtain the pharmaceutical salt.

9. The use of a pharmaceutical salt of lamotrigine according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for the prevention and / or treatment of epilepsy.

10. The application according to claim 9, characterized in that, The medication described is for the prevention and / or treatment of focal or generalized epilepsy.

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