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CN-121717767-B - Pharmaceutical salt of lamotrigine, pharmaceutical composition, preparation method and application

CN121717767BCN 121717767 BCN121717767 BCN 121717767BCN-121717767-B

Abstract

The invention discloses a medicinal salt of lamotrigine, a medicinal composition, a preparation method and application thereof. According to the invention, by combining lamotrigine and lipoic acid in a salt formation or mixture mode through a medicine-medicine combination strategy, the lamotrigine fragment can inhibit abnormal discharge and nerve hyperexcitation in the brain in the treatment of epilepsy, the lipoic acid fragment can enhance the capacity of resisting epileptic seizures, reduce the damage to the brain after epileptic seizures, exert a synergistic multichannel treatment effect and delay the progression of the illness. Meanwhile, the formed salt also has better physicochemical stability, dissolution, pharmacokinetics and pharmacodynamics properties, is more beneficial to patent medicine as a whole, and provides an effective epileptic therapeutic drug.

Inventors

  • CAI TING
  • Guo Minshan
  • SUN MINGYANG
  • TIAN QIANQIAN
  • SU YUAN
  • BAI LANFANG

Assignees

  • 中国药科大学

Dates

Publication Date
20260508
Application Date
20260225

Claims (10)

  1. 1. A pharmaceutical salt of lamotrigine, which is characterized by comprising lamotrigine and racemic lipoic acid in a molar ratio of 1:1, wherein the pharmaceutical salt has a monoclinic system, P2 1 space group, unit cell parameters of a= 19.468 (3) a, b= 10.0989 (17) a, c= 10.6183 (17) a, a=90°, β= 97.809 (5) °, and γ=90°.
  2. 2. A pharmaceutically acceptable salt of lamotrigine according to claim 1, characterized in that said pharmaceutically acceptable 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 °,25.3 ° expressed in terms of diffraction angle 2Θ±0.2°.
  3. 3. A pharmaceutically acceptable salt of lamotrigine according to claim 1, wherein said pharmaceutically acceptable salt has a characteristic melting peak at 136.2 ± 1 ℃.
  4. 4. A pharmaceutical salt of lamotrigine, which is characterized by comprising lamotrigine and (R) -lipoic acid in a molar ratio of 1:1, wherein the pharmaceutical salt has a monoclinic system, P2 1 space group, unit cell parameters are a= 19.4087 (8) a, b= 10.0282 (4) a, c= 10.4929 (4) a, a=90°, β= 97.243 (1) °, and γ=90°.
  5. 5. The pharmaceutically acceptable salt of lamotrigine according to claim 4, characterized in that said pharmaceutically acceptable salt has a characteristic diffraction peak 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°,28.3°, expressed as diffraction angle 2Θ ± 0.2 °.
  6. 6. The pharmaceutically acceptable salt of lamotrigine of claim 4, wherein the pharmaceutically acceptable salt has a characteristic melting peak at 126.0 ± 1 ℃.
  7. 7. A pharmaceutical composition comprising as active ingredient a pharmaceutically acceptable salt of lamotrigine according to any one of claims 1 to 6.
  8. 8. A process for the preparation of a pharmaceutically acceptable salt of lamotrigine as claimed in any one of claims 1 to 6, selected from any one of the following processes: The first method comprises dissolving lamotrigine and racemic lipoic acid or (R) -lipoic acid in a molar ratio of (0.25-2) 1 in a solvent, and removing the solvent to obtain the medicinal salt; the second method comprises the steps of forming suspension of lamotrigine and racemic lipoic acid or (R) -lipoic acid in a solvent according to a molar ratio of (0.25-2): 1, stirring to pasty, and removing the solvent to obtain the medicinal salt.
  9. 9. Use of a pharmaceutically acceptable salt of lamotrigine as defined in any one of claims 1 to 6 or a pharmaceutical composition as defined in claim 7 for the preparation of a medicament for the prevention and/or treatment of epilepsy.
  10. 10. The use according to claim 9, wherein the medicament is a medicament for the prophylaxis and/or treatment of focal or generalized seizures.

Description

Pharmaceutical salt of lamotrigine, pharmaceutical composition, preparation method and application Technical Field The invention relates to a medicinal salt of lamotrigine, a medicinal composition, a preparation method and application thereof, in particular to a medicinal salt of lamotrigine with excellent patentability, a medicinal composition, a preparation method and application thereof. Background Epilepsy is a complex chronic central nervous system disorder characterized by recurrent seizures resulting from highly synchronized abnormal discharges of brain neurons. Pathophysiological mechanisms of epilepsy involve complex network disorders of multiple targets, pathways, including ion channel dysfunction (e.g., voltage-gated sodium channels, calcium channels), excitatory/inhibitory neurotransmitter imbalance (e.g., hyperalgesia, insufficient gamma-aminobutyric acid (GABA)) neuroinflammation, oxidative stress damage, and mitochondrial dysfunction, among others. Although the existing antiepileptic drugs (ANTIEPILEPTIC DRUGS, AEDs) provide effective treatment for many patients, only a fraction of patients have their seizures controlled after the first monotherapy, and still a fraction of patients have ineffective treatment. Of these, single drug therapies are usually directed to only one or two targets, whereas epilepsy, particularly drug-resistant epilepsy, is often followed by a complex network of multiple pathogenic pathways. Intervention at a single target is not sufficient to reform the balance of the overall network, resulting in treatment failure. The complexity and heterogeneity of this pathological mechanism is the root cause of the difficulty in achieving complete control of seizures with single-target drugs. In addition, single drug therapy is often accompanied by insufficient efficacy, dose-dependent side effects (e.g., cognitive impairment, rash, hepatotoxicity, etc.), and resistance problems that can occur with long-term administration. Lamotrigine (Lamotrigine) is a phenyl triazine anti-epileptic drug. As a broad spectrum antiepileptic, it can be used for treating epileptic partial seizure and general tonic clonic seizure. The main action mechanism is to stabilize the cell membrane of neurons and inhibit the release of excitatory neurotransmitters such as glutamic acid by inhibiting voltage-dependent sodium ion channels. Lamotrigine has limited regulation of oxidative stress in the face of the large amounts of Reactive Oxygen Species (ROS), reactive Nitrogen Species (RNS) and inflammatory factors that accompany seizures, and is unable to completely counteract free radical accumulation and inflammatory response caused by seizures. In addition, epilepsy is closely related to mitochondrial dysfunction, and its mechanisms may include abnormal respiratory chain, defects in mitochondrial dynamics, mitochondrial autophagy, and oxidative stress, and lamotrigine has difficulty in exerting effective intervention in the face of these complex pathological mechanisms. Disclosure of Invention The invention aims at providing a medicinal salt of lamotrigine which is beneficial to patent medicine, and the invention aims at providing a medicinal composition taking the medicinal salt of lamotrigine or a medicinal composition containing lamotrigine as an active ingredient, and the invention aims at providing a preparation method of the medicinal salt of lamotrigine, and the invention aims at providing a medicinal salt of lamotrigine and medicinal application of the medicinal composition. The pharmaceutical salt of lamotrigine is formed by lamotrigine and racemic lipoic acid in a molar ratio of 1:1, has a monoclinic system, is P2 1 space group, has unit cell parameters of a= 19.468 (3) A, b= 10.0989 (17) A, c= 10.6183 (17) A, alpha=90 degrees, beta= 97.809 (5) degrees and gamma=90 degrees. Preferably, the pharmaceutically acceptable 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 °,25.3 ° expressed in diffraction angle 2θ±0.2°. Further preferably, the pharmaceutically acceptable salt has a characteristic diffraction peak 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°,38.0°, expressed as diffraction angle 2θ±0.2°. Preferably, the pharmaceutically acceptable salt has a characteristic melting peak at 136.2 ± 1 ℃. Preferably, the pharmaceutically acceptable salt has a weight loss of less than 1.4% in the range of 50 ℃ to 200 ℃. The other medicinal salt of lamotrigine is formed by lamotrigine and (R) -lipoic acid in a molar ratio of 1:1, wherein the medicinal salt has a monoclinic system, P2 1 space group, unit cell parameters are a= 19.4087 (8) a, b= 10.0282 (4) a, c= 10.4929 (4) a, alpha=90 degrees, beta= 97.243 (1) degreesand gamma=90 degrees. Preferably, the pharmaceutically acceptable salt has a characteristic diffraction peak at 4.5°,9.1°,9