US-20260124211-A1 - COMPOSITION CONTAINING LAMOTRIGINE, AND PREPARATION METHOD AND USE THEREOF

Abstract

The present disclosure provides a dry pharmaceutical composition, including a therapeutically effective amount of one or more lamotrigine hydrate crystals and one or more pharmaceutically acceptable excipients. The excipients include a thickener. The dry pharmaceutical composition is preferably a dry suspending agent. The dry pharmaceutical composition can be formulated into a suspension available for administration, which is stable for use for at least 1-3 months. The present disclosure further discloses methods for preparing the dry pharmaceutical composition and the dry suspending agent and use of the dry pharmaceutical composition and the dry suspending agent in the treatment of a neurological disease.

Inventors

• Xun Zheng
• Shaoqiong Lyu
• Boli Li
• Duoshuang Chen

Assignees

• SHANGHAI AUCTA PHARMACEUTICALS CO., LTD.

Dates

Publication Date

20260507

Application Date

20251231

Priority Date

20210416

Claims (20)

1. 1 . A method of preparing a powder for reconstitution into a suspension, comprising: (a) providing particles comprising lamotrigine hydrate optionally admixed with a first set of excipients; (b) processing the particles so that their D90 is less than 500 μm; and (c) mixing the processed particles with a second set of excipients comprising at least a thickener to obtain the powder as a uniform mixture.
2. 2 . The method of claim 1 , the lamotrigine hydrate of the particles of step (a) is admixed with the first set of excipients comprising one or more excipients selected from the group consisting of a filler, a sweetener, a pH modifier, a preservative, a glidant, an anti-forming agent, a flavoring agent, and a surfactant.
3. 3 . The method of claim 1 , wherein the particles of step (a) consists essentially of the lamotrigine hydrate.
4. 4 . The method of claim 1 , wherein the second set of excipients further comprises one or more excipients selected from the group consisting of a sweetener, a pH modifier, a preservative, a glidant, an anti-forming agent, a flavoring agent.
5. 5 . The method of claim 1 , wherein the weight ratio of the lamotrigine to the pH modifier is from about 10:0.1 to about 10:8.
6. 6 . The method of claim 1 , the weight ratio of the lamotrigine to the thickener is from about 10:1 to about 10:7.
7. 7 . The method of claim 1 , wherein the thickener is selected from the group consisting of xanthan gum, guar gum, locust bean gum carrageenan, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, starch, pre-gelatinized starch, alginate, acrylic copolymer, and aluminum magnesium silicate.
8. 8 . The method of claim 1 , wherein the lamotrigine hydrate ranges from 1% to 80% in the uniform mixture.
9. 9 . The method of claim 1 , further comprising, prior to step (a), adding anhydrous lamotrigine to water to obtain the lamotrigine hydrate in a suspension.
10. 10 . The method of claim 9 , further comprising isolating the lamotrigine hydrate from the suspension and removing excess water from the lamotrigine hydrate to form the particles.
11. 11 . The method of claim 9 , further comprising mixing the suspension with the first set of excipients to obtain wet granules comprising the lamotrigine hydrate, and removing excess water from the granules to form the particles.
12. 12 . The method of claim 1 , wherein the uniform mixture further comprises a pH modifier. which provides a pH ranging from about 3.0 to about 8.0.
13. 13 . The method of claim 1 , wherein the powder, after being prepared into the suspension, provides regenerated particles of lamotrigine hydrate, wherein the regenerated particles maintain a D90 of less than 500 μm for a period of at least 3 months in the suspension.
14. 14 . The method of claim 1 , further comprising filtering the uniform mixture with a mesh having a size less than 1000 μm.
15. 15 . The method of claim 1 , the particles of step (a) are essentially free from any thickener.
16. 16 . A powder for suspension prepared according to the method of claim 1 .
17. 17 . A powder for suspension comprising a therapeutically effective amount of lamotrigine hydrate having D90 of less than 200 μm, a thickener, a sweetener, a pH modifier, a preservative, a glidant, an anti-forming agent, a flavoring agent.
18. 18 . The powder of claim 17 , wherein thickener is selected from the group consisting of xanthan gum, povidone, sodium carboxymethylcellulose, sodium alginate, magnesium aluminum silicate, carbomer.
19. 19 . A method of treating a neurological disorder in a subject, comprising administer a suspension prepared from the powder of claim 17 to the subject in need thereof.
20. 20 . The method of claim 19 , wherein the neurological disorder is selected from one or more of Alzheimer's disease, depression, multiple sclerosis, Parkinson's disease, and epilepsy.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. Continuation-in-Part application Ser. No. 18/638,097, filed Apr. 17, 2024, which is a Continuation-in-Part of U.S. application Ser. No., filed, which is a U.S. national entry of International Application No. PCT/CN2022/087326, filed Apr. 18, 2022, which is a Continuation of U.S. application Ser. No. 17/366,295, filed on Jul. 2, 2021, now U.S. Pat. No. 11,447,456, which also claims priority to Chinese Application No. 202110412683.1, filed on Apr. 16, 2021, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION The present disclosure relates to the field of pharmaceutical preparations, and in particular to a dry composition and dry suspending agent containing lamotrigine, a preparation method thereof, and use in the treatment of diseases. BACKGROUND Epilepsy is one of the most common of the neurological diseases. Epileptic seizures may lead to a progressive decline in brain function, causing cognitive impairment and mental decline. Sudden epileptic seizures easily cause accidental injuries, and status epilepticus can be life-threatening, seriously affecting the patients' quality of life and usually requiring patients to be on medication for life. Lamotrigine (trade name Lamictal) exerts its antiepileptic effects primarily by blocking voltage-gated sodium channels, reducing sodium inward flow and increasing neuronal stability. Lamotrigine was marketed in Europe in 1991 and in the United States in 1994. Currently, lamotrigine is comparable to phenytoin and carbamazepine as monotherapy or adjunctive therapy for many types of epilepsy, especially in infants, adolescents, and elderly patients. At present, there are four dosage forms of lamotrigine approved for marketing both at home and abroad, namely, plain tablets, chewable tablets, orally disintegrating tablets and extended-release tablets. There is no oral liquid preparation of lamotrigine in the market, so it is often necessary to mill lamotrigine tablets to prepare the liquid preparation before when use for pediatric patients and patients with dysphagia. However, such improvised preparations are prone to inaccurate dosage of administration and contamination of the drug. Lamotrigine is a Biopharmaceutics Classification System (BCS) Class II drug that is poorly soluble in aqueous media. Decreasing the pH can increase partial solubility, but with limited effect. Chinese patent application Nos. CN201510288845.X and CN201510350210.8 respectively disclose a prescription and a preparation method of a lamotrigine oral solution. The drug concentration of this preparation is less than 2 mg/mL, which cannot meet the needs of clinical medication. If a highly concentrated prescription is required, an organic solvent needs to be added, which is not conducive to children. Single-dose products developed with lamotrigine anhydrate also have a number of drawbacks that cannot be avoided. If the patient's weight is low, there will be a large amount of single-dose product left each time, which may waste the drug or make the patient take the single-dose product several times. Moreover, for a single-dose dry suspending agent, the patient needs to add water for reconstitution before each use, which causes some inconvenience to his life and poor patient compliance. In contrast, multi-dose products can significantly improve patient compliance; and there is basically no waste of drug, and the patients do not have to continue taking medication beyond the expiration date after opening for fear of wasting it. Moreover, a multi-dose dry suspending agent only needs to be reconstituted before the first dose, and then taken normally according to the pharmacist's suggestion in the subsequent medication process, which is more convenient and faster and can significantly improve the patient compliance. It is not ideal to develop multi-dose suspending agents with lamotrigine anhydrate. The inventors of the present disclosure found through experiments that, when a lamotrigine suspension was prepared by conventional methods, no lumpy crystals were observed at the time of preparation. But after it was placed at room temperature for 3 days, a large number of lumpy crystals appeared, and the crystals had a tendency to become bigger as time went on, which would lead to the patient not being able to accurately take the drug. Chinese patent application CN106491539B discloses a method for inhibiting hydrate, but the inhibition can only be maintained for 24 h, which causes inconvenience to patients for long-term medication. For an active pharmaceutical ingredient (API), its crystalline state can affect many of its properties such as melting point, solubility, stability and bioavailability. Eutectic or hydrate of a drug can utilize hydrogen bonds or other noncovalent bonds to effectively improve the crystalline properties and physical and chemical properties of the drug without dest