Crystal form of lamotrigine hydrate, preparation method thereof and composition containing same

A technology of lamotrigine and hydrate, applied in the field of crystal form, its preparation method and composition comprising the same, can solve the problems of poor solubility, low drug loading in solution dosage form, unable to meet clinical needs and the like

Active Publication Date: 2021-08-06
SHANGHAI AUCTA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no oral liquid formulation of lamotrigine on the market, therefore, it is often necessary to crush the lamotrigine tablet to prepare a liquid formulation for the convenience of pediatric patients and patients with swallowing difficulties
However, this temporarily prepared preparation can easily lead to inaccurate dosage and drug contamination
[0005] Lamotrigine is a class II drug molecule in the Biopharmaceutical Classification System (BCS) and has poor solubility in aqueous media. Lowering the pH can increase partial solubility, but the effect is limited
Chinese patent applications CN201510288845.X and CN201510350210.8 disclose the prescription and preparation method of lamotrigine oral solution. The drug concentration of this preparation is less than 2mg / ml, which cannot meet the clinical needs
If a high-concentration prescription is required, organic solvents need to be added, which is not conducive to children's consumption
[0006] Development of suspensions with lamotrigine anhydrate is also not ideal
The applicant found through experiments that when the lamotrigine suspension was prepared by the common method, no blocky crystals were observed when it was just prepared, but after being placed at room temperature for 3 days, a large number of blocky crystals appeared, and as time went on , the crystals have a tendency to become larger, which can lead to inaccurate medication for patients
Chinese patent application CN201611175342.2A discloses a method for inhibiting hydrates, but the inhibition can only last for 24 hours, which brings inconvenience to patients for long-term medication
[0009] The current lamotrigine preparations have problems such as inaccurate dosage, low drug loading in solution dosage forms, and poor physical stability of suspensions.

Method used

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  • Crystal form of lamotrigine hydrate, preparation method thereof and composition containing same
  • Crystal form of lamotrigine hydrate, preparation method thereof and composition containing same
  • Crystal form of lamotrigine hydrate, preparation method thereof and composition containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1 - Preparation of a Suspension Containing Lamotrigine Hydrate Form A Using Lamotrigine Particles of Different Particle Sizes

[0158] The particle size (D90) of 10 parts by weight is respectively the lamotrigine particle (purchased from Indian Arabindu Pharmaceutical Co., Ltd.) of 8 μm, 12 μm and 60 μm, and the xanthan gum of 3 parts by weight (purchased from U.S. Co., Ltd.), added to 1000 parts by weight of purified water to disperse evenly, and placed at 4°C for 24 hours to prepare a suspension. The obtained suspension was placed at normal temperature for 1 month, and the suspension and the crystal form in the suspension were checked at different time points, and the results are shown in Table 1:

[0159] Unless otherwise specified, the XRPD results in the examples were all measured by a German Bruker D8 advance X-ray diffractometer, and the microscope results were all measured by a Nanjing Nanpai CM2000S microscope.

[0160] Table 1

[0161]

[0162]

...

Embodiment 2

[0164] Example 2 - Preparation of Suspensions Containing Lamotrigine Hydrate Form A Using Different Thickeners

[0165] 10 parts by weight of lamotrigine particles with a particle size (D90) of 8 μm, and 3 parts by weight of thickeners (xanthan gum, povidone, colloidal microcrystalline cellulose and sodium alginate) (where xanthan Glue was purchased from CP Kelco in the United States, povidone was purchased from BASF in Germany, colloidal microcrystalline cellulose was purchased from FMC in the United States, and sodium alginate was purchased from Qingdao Mingyue Seaweed Group) and added to 1000 parts by weight of purified water to disperse evenly , placed at 4°C for 24 hours to prepare a suspension. The obtained suspension was placed at normal temperature for 1 month, and the suspension and the crystal form in the suspension were checked at different time points, and the results are shown in Table 2:

[0166] Table 2

[0167]

[0168]

[0169] As shown in Table 2, usi...

Embodiment 3

[0170] Example 3 - Preparation of Suspensions Containing Lamotrigine Hydrate Form A Using Different Amounts of Thickening Agents

[0171] The particle diameter (D90) of 10 parts by weight is the lamotrigine particle of 8 μ m, and the xanthan gum that is respectively 0 weight part, 1 weight part and 5 parts by weight, joins the purified water of 1000 parts by weight and disperses evenly, puts A suspension was prepared by standing at 4°C for 24 hours. The obtained suspension was placed at normal temperature for 1 month, and the suspension and the crystal form in the suspension were checked at different time points, and the results are shown in Table 3:

[0172] table 3

[0173]

[0174] As shown in Table 3, using 1 and 5 parts by weight of thickener, the crystalline form in the suspension was Lamotrigine Hydrate Form A. No thickener is used, and the crystal form in the suspension contains unknown crystals after standing at room temperature for one week, and the stability of...

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Abstract

The invention relates to a lamotrigine hydrate crystal form, a preparation method thereof and a composition containing the same, in particular to a lamotrigine hydrate form A, a preparation method thereof and a composition containing the lamotrigine hydrate form A.

Description

technical field [0001] The present invention relates to a crystal form of lamotrigine hydrate, a preparation method thereof and a composition containing it, in particular to a lamotrigine hydrate form A, a preparation method thereof and a lamotrigine hydrate form A containing combination. Background technique [0002] Epilepsy is one of the most common neurological disorders. Seizures can lead to a progressive decline in brain function, causing cognitive impairment and mental decline. Sudden epileptic seizures are likely to cause accidental injuries, and status epilepticus can be life-threatening, seriously affecting the quality of life of patients, and generally requires lifelong medication. [0003] Lamotrigine (Lamotrigine, trade name Lamictal) mainly plays an antiepileptic effect by blocking voltage-gated sodium channels, reducing sodium influx, and increasing neuron stability. Lamotrigine was launched in Europe and the United States in 1991 and 1994, respectively. A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D253/075A61K31/53A61K31/55A61K31/7048A61K31/165A61K45/06A61K9/10A61K47/26A61K47/36A61K47/38A61P25/08A61P25/16A61P25/24A61P25/28
CPCA61K31/53A61K9/10A61K47/36A61K47/38A61K47/26A61P25/08A61P25/16A61P25/24A61P25/28A61K47/32A61K47/02A61K47/12A61K47/14C07D253/075A61K9/08C07B63/04C07B2200/13
Inventor 李守峰王勇
Owner SHANGHAI AUCTA PHARMA CO LTD
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