CN116942606A

CN116942606A - Preparation method of lamotrigine suspension and dry suspension

Info

Publication number: CN116942606A
Application number: CN202210406533.4A
Authority: CN
Inventors: 李守峰; 王勇; 李博莉
Original assignee: Shanghai Aokeda Pharmaceutical Technology Co ltd
Current assignee: Shanghai Aokeda Pharmaceutical Technology Co ltd
Priority date: 2022-04-18
Filing date: 2022-04-18
Publication date: 2023-10-27

Abstract

The present invention relates to a process for preparing lamotrigine suspensions and dry suspensions, in particular to a process for preparing suspensions comprising lamotrigine hydrate form a, and a process for preparing dry suspensions comprising lamotrigine.

Description

Preparation method of lamotrigine suspension and dry suspension

Technical Field

Background

Epilepsy is one of the most common of neurological disorders. Seizures can lead to progressive decline in brain function, leading to cognitive impairment and decline in intelligence. The sudden onset of epilepsy is easy to cause accidental injury, the status epilepticus can endanger life, seriously affect the life quality of patients, and generally needs to be taken for life.

Lamotrigine (trade name Lamotrigine) exerts an antiepileptic effect by blocking voltage-gated sodium channels, reducing sodium influx, and increasing neuronal stability. Lamotrigine was marketed in europe and the united states in 1991 and 1994, respectively. At present, lamotrigine is used as a single drug treatment or an adjuvant treatment for various types of epilepsy, and especially for infants, adolescents and elderly patients, the curative effect is equivalent to that of phenytoin and carbamazepine.

At present, 4 dosage forms of lamotrigine approved to be marketed at home and abroad are common tablets, chewable tablets, orally disintegrating tablets and sustained release tablets respectively. There is no lamotrigine oral liquid formulation on the market, so lamotrigine tablets are often crushed to prepare the liquid formulation for convenient administration by children patients and dysphagia patients. However, such a temporarily formulated preparation is prone to inaccurate dosing and contamination of the drug.

Lamotrigine is a Biopharmaceutical Classification System (BCS) class II drug molecule that has poor solubility in aqueous media and decreasing pH increases partial solubility but has limited efficacy. Chinese patent applications CN2015188845. X and CN201510350210.8 disclose prescriptions and preparation methods of lamotrigine oral solutions, the drug concentration of which is less than 2mg/ml, which cannot meet clinical demands. If a prescription with high concentration is needed, an organic solvent is needed to be added, which is not beneficial to children to take.

Development of suspensions with lamotrigine anhydrate is also undesirable. The applicant found through experiments that the common method for preparing lamotrigine suspension, no bulk crystals were observed at the time of preparation, but after 3 days of standing at normal temperature, a large number of bulk crystals appeared and the crystals tended to grow larger with time, which resulted in inaccurate administration by patients. Chinese patent application CN201611175342.2A discloses a method of inhibiting hydrates, but the inhibition can only be maintained for 24 hours, which brings inconvenience to patients for long-term administration.

For a pharmaceutically active ingredient, its crystalline state can affect its properties such as melting point, solubility, stability and bioavailability. The pharmaceutical co-crystal or hydrate can utilize the action of hydrogen bond or other non-covalent bonds, can effectively improve the crystallization performance and physicochemical properties of the drug while not damaging the active ingredients of the drug, and has become a hot field for the research and development of solid preparations of the drug.

To date, there have been reported a variety of co-crystals of lamotrigine. Lamotrigine salts have been reported: 1:1 lamotrigine-4-hydroxybenzoic acid, 1:1 lamotrigine-saccharin, 1:3 lamotrigine-acetic acid, 1:1 lamotrigine-propionic acid, 2:1 lamotrigine-adipic acid, 2:1 lamotrigine-malic acid, 1:1 lamotrigine-methylparaben, 1:1 lamotrigine-nicotine, 1:1:1 lamotrigine-nicotine monohydrate, 1:1 lamotrigine-acetamide. Lamotrigine solvates have been reported: 1:2 lamotrigine methanol solvate, 1:1:1 lamotrigine ethanol monohydrate. However, the above co-crystals have not been studied and developed further for liquid dosage forms, and the problem of administration precision of lamotrigine has not been solved.

The prior lamotrigine preparation has the problems of inaccurate dosage, low drug loading rate of solution dosage forms, poor physical stability of suspension and the like.

Disclosure of Invention

In one aspect, the invention provides lamotrigine hydrate form a having an XRPD pattern comprising characteristic peaks at diffraction angles (2θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peak at one or more of diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees.

In another aspect, the present invention provides a method of preparing a dry suspension of lamotrigine, wherein the method comprises the steps of: the lamotrigine particles, the thickener and the pH adjustor are mixed, and the particle size (D90) of the lamotrigine particles is 1-30 μm, and the amount of the pH adjustor is such that the pH of the suspension obtained after mixing with the aqueous phase is 4.6-6.9.

In yet another aspect, the present invention provides a method of preparing a suspension comprising lamotrigine hydrate form a, the method comprising the steps of:

(a-i) mixing lamotrigine particles, a thickener and a pH adjustor, adding to an aqueous phase, or

(a-ii) mixing lamotrigine particles and a thickener with an aqueous phase comprising a pH regulator,

(b) Uniformly dispersed, and standing at a low temperature to obtain said suspension comprising lamotrigine hydrate form a, wherein the lamotrigine particles have a particle size (D90) of about 1-30 μm, wherein the low temperature is below about 25 ℃, wherein the pH of the suspension is 4.6-6.9, or the amount of said pH modifier is such that the pH of the suspension is 4.6-6.9.

In a further aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of lamotrigine particles and one or more pharmaceutically acceptable excipients, wherein the lamotrigine particles have a particle size (D90) of 1-30 μm and the excipients comprise a thickener and a pH adjuster in an amount such that the pharmaceutical composition, after mixing with an aqueous phase, results in a suspension having a pH of 4.6-6.9.

In a further aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of lamotrigine particles and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition, upon reconstitution in an aqueous phase, forms a suspension comprising lamotrigine hydrate form a, the lamotrigine particles having a particle size (D90) such that the lamotrigine hydrate form a in the suspension has a particle size of 20-80 μm, 20-60 μm, 20-40 μm or 20-30 μm, and the excipients comprise a thickening agent and a pH adjuster in an amount such that the pharmaceutical composition, upon mixing with the aqueous phase, the pH of the resulting suspension is 4.6-6.9.

In yet another aspect, the present invention provides a suspension comprising lamotrigine hydrate form a, the suspension comprising lamotrigine hydrate form a, a thickener, and a pH adjuster, wherein the particle size of lamotrigine hydrate form a in the suspension is 20-80 μm, 20-60 μm, 20-40 μm, or 20-30 μm, and the pH adjuster provides the suspension with a pH of 4.6-6.9.

In a further aspect, the invention provides a lamotrigine hydrate form a of the invention, a dry suspension of lamotrigine prepared by the process of the invention, a suspension comprising lamotrigine hydrate form a, and the use of a lamotrigine pharmaceutical composition in the manufacture of a medicament or for the treatment of a neurological disorder.

In a further aspect, the invention provides a kit comprising lamotrigine hydrate form a of the invention, a dry suspension of lamotrigine prepared by the process of the invention, a suspension comprising lamotrigine hydrate form a, and a lamotrigine pharmaceutical composition; optionally further comprising instructions for use of the drug and/or a drug delivery device.

In yet another aspect, the invention provides a method of treating a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of lamotrigine hydrate form a of the invention, a dry suspension of lamotrigine prepared by the method of the invention, a suspension comprising lamotrigine hydrate form a, and a lamotrigine pharmaceutical composition.

The method for preparing the suspension is simple, and the prepared suspension has excellent uniformity and stability and can meet the requirement of accurate administration. And the lamotrigine hydrate form A in the suspension has high content, high purity and less impurities.

Drawings

Figure 1 XRPD pattern of lamotrigine hydrate form a.

Figure 2 is a photomicrograph of lamotrigine hydrate form a.

Figure 3 XRPD pattern of lamotrigine hydrate form a containing unknown crystals.

Fig. 4. A-photomicrographs of lamotrigine hydrate form a of group 2 in table 7;

b-photomicrographs of lamotrigine hydrate form A of group 7 in Table 7;

c-photomicrographs of lamotrigine hydrate form A of group 14 in Table 7.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict, the present disclosure provides definitions.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The word "about" as used herein means that within the acceptable standard error of the values, e.g., ±0.05, ±0.1, ±0.2, ±0.3, ±0.5, ±1, ±2 or±3, etc., e.g., ±1%, ±2%, ±5%, ±10%, etc., as recognized by one of ordinary skill in the art.

The term "amorphous" as used herein refers to any solid material that is unordered in three dimensions. In some cases, the amorphous solid may be characterized by known techniques including XRPD crystal diffraction analysis, solid state nuclear magnetic resonance (ssNMR) spectroscopy, differential Scanning Calorimetry (DSC), or some combination of these techniques. The XRPD pattern generated by the amorphous solid was free of distinct diffraction signature peaks.

The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, as opposed to an amorphous solid material, that produces a characteristic XRPD pattern with well-defined peaks.

The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to experimentally observed diffraction patterns or parameters, data or values derived therefrom. XRPD patterns are typically characterized by peak position (abscissa) and/or peak intensity (ordinate).

The term "2θ" as used herein refers to the peak position in degrees (°) based on the settings in the X-ray diffraction experiment, and is typically the unit of abscissa in the diffraction pattern. If the incident beam is diffracted by reflection when it makes an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle 2θ. It should be understood that reference herein to a particular 2θ value for a particular crystalline form is intended to refer to a 2θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, use is made of 1.540598 and->1.544426 As a radiation source).

As used herein, the term "substantially the same" means taking into account representative peak positions and/or intensity variations. For example, for an X-ray diffraction peak, one skilled in the art will appreciate that the peak position (2θ) will show some variation, typically up to 0.1-0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. In addition, those skilled in the art will appreciate that the relative peak intensities will vary due to differences between instruments and the degree of crystallinity, preferred orientation, surface of the prepared sample, and other factors known to those skilled in the art, and should be considered as merely qualitative measurements.

The term "low temperature" as used herein refers to below ambient temperature (about 25 ℃).

As used herein, the term "D90" means that the lamotrigine particles have a lamotrigine particle diameter less than 90% of the particle diameter.

As used herein, the term "lamotrigine hydrate form a" may also be referred to as "form a" or "form a". Lamotrigine hydrate form a is formed after lamotrigine particles are mixed with water.

As used herein, the term "microscopic particle size" refers to the "particle size of lamotrigine hydrate form a" which refers to the diameter of several lamotrigine hydrate forms a in a suspension as observed and measured by a microscope when lamotrigine particles are mixed with water to form a suspension.

The term "antimicrobial stability" as used herein means that a product has antimicrobial stability when the product meets the antimicrobial effect specified according to USP <51 >. According to the antimicrobial acceptance criteria of USP <51> (class 3 product), the suspensions of the present invention need to meet the following criteria:

-bacteria: at 14 days, the log reduction value of the bacterial count compared with the initial time point is not less than 1.0, and from 14 days to 28 days, the log value of the bacterial count is not increased; and is also provided with

Yeasts and molds: at 14 days and 28 days, there was no increase relative to the initial count.

For relevant test methods and requirements see Microbiological Tsts/<51>Antimicrobial ffctivnss tsting 53,Th Unitd Stats Pharmacopial Convntion,2022 (https:// online. Uspnf. Com/uspnf/document/1_guid-772FE 032-8921-4345-810E-945ef5bf1b15_3_en-US), the entire contents of which are incorporated herein by reference.

Crystalline forms

In one embodiment, the XRPD pattern of lamotrigine hydrate form a has no characteristic peak at a diffraction angle (2θ) of about 15.9±0.2 degrees. In one embodiment, the XRPD pattern of lamotrigine hydrate form a has no characteristic peak at a diffraction angle (2θ) of about 30.7±0.2 degrees. In one embodiment, the XRPD pattern of lamotrigine hydrate form a has no characteristic peaks at diffraction angles (2θ) of about 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees. In a preferred embodiment, the lamotrigine hydrate form a has an XRPD pattern without characteristic peaks at diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees.

In one embodiment, the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at substantially the same diffraction angles (2θ) as shown in fig. 1, or alternatively, has XRPD peak positions substantially the same as shown in fig. 1.

The purity of lamotrigine hydrate form a in the present application was determined by XRPD quantitative analysis. The basic principle of XRPD quantitative analysis is that the intensity of the diffraction lines for each phase of a substance increases with the relative amount of that phase in the mixture. A constant standard substance is added into a powder sample to be tested to prepare a composite sample. And measuring the content of the phase to be measured by measuring the ratio of the intensity of a certain diffraction line of the phase to be measured in the composite sample to the intensity of a certain diffraction line of the internal standard substance. Selection of Al ₂ O ₃ As a standard substance.

In one embodiment, lamotrigine hydrate form a has a purity of at least about 60%. In one embodiment, lamotrigine hydrate form a has a purity of at least about 70%. In one embodiment, lamotrigine hydrate form a has a purity of at least about 80%; preferably, lamotrigine hydrate form a has a purity of at least about 90%; more preferably, lamotrigine hydrate form a has a purity of at least about 95%; and most preferably lamotrigine hydrate form a is substantially pure. By "substantially pure" is meant that the form contains less than about 3% by weight of impurities, including other crystalline, solvated, or amorphous forms.

XRPD patterns of lamotrigine hydrate form a having a purity of at least about 95% are shown in figure 1. The XRPD patterns of lamotrigine hydrate form a having a purity of at least about 95% described above present a series of characteristic peaks at diffraction angles (2θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and none at diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees. The microscope appearance of lamotrigine hydrate form a having a purity of at least about 95% is short prismatic and is shown in fig. 2. Thermogravimetric analysis of lamotrigine hydrate form a having a purity of at least about 95% as described above shows a weight loss of about 6.6% at 190 ℃, which lamotrigine hydrate form a is a monohydrate.

Preparation method of dry suspension

In one aspect, the present invention provides a method of preparing a dry suspension of lamotrigine, wherein the method comprises the steps of: the lamotrigine particles, the thickener and the pH adjustor are mixed, and the particle size (D90) of the lamotrigine particles is 1-30 μm, and the amount of the pH adjustor is such that the pH of the suspension obtained after mixing with the aqueous phase is 4.6-6.9.

The lamotrigine dry suspension needs to be reconstituted in an aqueous phase before being applied to a subject, so the stability of lamotrigine particles in the reconstituted suspension, namely the crystal form stability and the particle size stability, is of great significance to the development of lamotrigine liquid dry suspension. The stability of the crystal form is that the crystal form is kept consistent in the aqueous phase within a certain time range. Different crystal forms have different dissolution rates and larger stability difference, and the introduction of other crystal forms is avoided, so that the stability of crystal properties can be ensured, and the safety and reliability of products are ensured. The particle size stability, i.e. the particle size of the crystals in the aqueous phase is kept within a certain range within a certain time range, and the excessive particle size can affect the uniform state of the drug, and finally the dosage of the drug is inaccurate.

When the lamotrigine particles are mixed with the water, the lamotrigine particles form different crystal forms including lamotrigine hydrate form a. The method for preparing the lamotrigine dry suspension has simple steps, the lamotrigine particles are easy to be transformed into the lamotrigine hydrate form A after being prepared into the suspension, the content of the lamotrigine hydrate form A in the suspension is high, and the suspension has high purity and less impurities.

Experiments have found that the pH of the system after reconstitution of the dry suspension in the aqueous phase and the starting particle size (D90) of the lamotrigine particles contained in the dry suspension have a significant impact on the stability and homogeneity of the suspension after reconstitution, compared to the particle size of lamotrigine hydrate form a formed in the suspension.

In one embodiment, more than 80%, 85%, 90% or 95% of the lamotrigine is present as lamotrigine hydrate form a when the dry suspension is mixed with water to form a suspension.

In one embodiment, the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peak at one or more of diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; alternatively, the XRPD pattern of lamotrigine hydrate form a has no characteristic peaks at diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees.

In one embodiment, the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2θ) substantially the same as shown in fig. 1.

In one embodiment, the XRPD peak locations of the XRPD pattern of lamotrigine hydrate form a are substantially the same as shown in figure 1. In one embodiment, the XRPD peak locations of the XRPD pattern of lamotrigine hydrate form a are the same as shown in figure 1.

In one embodiment, lamotrigine dry suspension is prepared using lamotrigine particles having a particle size (D90) selected from one or more of the following: about 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 2.8 μm 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.0 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 6.1 μm, 6.8 μm 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm, 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.0 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm, 13.0 μm, 13.1 μm, 13.2 μm, 13.3 μm, 13.4 μm, 13.5 μm, 13.6 μm, 13.7 μm, 13.8 μm, 13.9 μm, 14.0 μm, 14.1 μm, 14.2 μm, 14.3 μm, 14.4 μm, 14.5 μm, 14.6 μm, 14.7 μm, 14.8 μm, 14.9 μm, 15.0 μm, 15.1 μm, 15.2 μm, 15.3 μm, 15.4 μm, 15.5 μm, 15.6 μm, 15.7 μm, 15.8 μm, 15.9 μm, 16.0 μm, 16.1 μm, 16.2 μm, 16.3 μm, 16.4 μm, 16.5 μm, 16.6 μm, 16.7 μm, 16.8 μm, 16.9 μm, 17.0 μm, 15.6 μm, 15.7 μm, 15.8 μm, 16.4 μm, 16.5 μm, 16.6 μm, 16.7 μm 17.1 μm, 17.2 μm, 17.3 μm, 17.4 μm, 17.5 μm, 17.6 μm, 17.7 μm, 17.8 μm, 17.9 μm, 18.0 μm, 18.1 μm, 18.2 μm, 18.3 μm, 18.4 μm, 18.5 μm, 18.6 μm, 18.7 μm, 18.8 μm, 18.9 μm, 19.0 μm, 19.1 μm, 19.2 μm, 19.3 μm, 19.4 μm, 19.5 μm, 19.6 μm, 19.7 μm, 19.8 μm, 19.9 μm, 20.0 μm, 20.1 μm, 20.2 μm 20.3 μm, 20.4 μm, 20.5 μm, 20.6 μm, 20.7 μm, 20.8 μm, 20.9 μm, 21.0 μm, 21.1 μm, 21.2 μm, 21.3 μm, 21.4 μm, 21.5 μm, 21.6 μm, 21.7 μm, 21.8 μm, 21.9 μm, 22.0 μm, 22.1 μm, 22.2 μm, 22.3 μm, 22.4 μm, 22.5 μm, 22.6 μm, 22.7 μm, 22.8 μm, 22.9 μm, 23.0 μm, 23.1 μm, 23.2 μm, 23.3 μm, 23.4 μm 23.5 μm, 23.6 μm, 23.7 μm, 23.8 μm, 23.9 μm, 24.0 μm, 24.1 μm, 24.2 μm, 24.3 μm, 24.4 μm, 24.5 μm, 24.6 μm, 24.7 μm, 24.8 μm, 24.9 μm, 25.0 μm, 25.1 μm, 25.2 μm, 25.3 μm, 25.4 μm, 25.5 μm, 25.6 μm, 25.7 μm, 25.8 μm, 25.9 μm, 26.0 μm, 26.1 μm, 26.2 μm, 26.3 μm, 26.4 μm, 26.5 μm, 26.6 μm, 26.7 μm, 26.8 μm, 26.9 μm, 27.0 μm, 27.1 μm, 27.2 μm, 27.3 μm, 27.4 μm, 27.5 μm, 27.6 μm, 27.7 μm, 27.8 μm, 27.9 μm, 28.0 μm, 28.1 μm, 28.2 μm, 28.3 μm, 28.4 μm, 28.5 μm, 28.6 μm, 28.7 μm, 28.8 μm, 28.9 μm, 29.0 μm, 29.1 μm, 29.2 μm, 29.3 μm, 29.4 μm, 29.5 μm, 29.6 μm, 29.7 μm, 29.8 μm, 29.9 μm and 30.0 μm, and a particle size (D90) range consisting of any two of the foregoing particle sizes (D90).

In one embodiment, lamotrigine dry suspension is prepared using lamotrigine particles having a particle size (D90) selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 5.4 μm 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm, 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm and 13.0 μm, and a particle diameter (D90) range consisting of any two particle diameters (D90) described above.

In one embodiment, lamotrigine dry suspension is prepared using lamotrigine particles having a particle size (D90) selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (D90) consisting of any two of the foregoing particle sizes (D90). In one embodiment, lamotrigine particles having a particle size (D90) selected from one or more of the following are used to prepare a suspension comprising lamotrigine hydrate form a or lamotrigine hydrate form a: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a range of particle sizes (D90) consisting of any two of the foregoing particle sizes (D90).

In one embodiment, the amount of the pH adjuster is such that the dry suspension, after mixing with the aqueous phase, results in a suspension having a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the amount of the pH adjuster is such that the dry suspension, after mixing with the aqueous phase, results in a suspension having a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values. In one embodiment, the amount of the pH adjuster is such that the dry suspension, after mixing with the aqueous phase, results in a suspension having a pH selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, a dry suspension of lamotrigine is prepared using lamotrigine particles having a particle size (D90), and the amount of the pH adjuster is such that the dry suspension, after mixing with water, results in a suspension having a pH, wherein the particle size (D90) is selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size (D90) consisting of any two of the foregoing particles (D90) and one or more selected from the following pH ranges: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, a dry suspension of lamotrigine is prepared using lamotrigine particles having a particle size (D90), and the amount of the pH adjuster is such that the dry suspension, after mixing with water, results in a suspension having a pH, wherein the particle size (D90) is selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a particle size (D90) range consisting of any two particle sizes (D90) described above, and the pH is selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the pH adjuster is one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate. In one embodiment, the pH adjuster is one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, and citric acid. In one embodiment, the pH adjuster is one or more of sodium dihydrogen phosphate and citric acid in combination. In one embodiment, the pH adjuster is one or more of a combination of disodium hydrogen phosphate and citric acid. In one embodiment, the pH adjuster is one or more of sodium dihydrogen phosphate and disodium hydrogen phosphate in combination. In one embodiment, the pH adjuster is sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, or sodium citrate.

In one embodiment, the amount of the pH adjuster is selected from one or more of the following based on about 10 parts by weight of the lamotrigine particles: about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 6.8 parts by weight, 6.9 parts by weight, 7.0 parts by weight, 7.1 parts by weight, 7.2 parts by weight, 7.3 parts by weight, 7.4 parts by weight, 7.5 parts by weight, 7.6 parts by weight, 7.7.7 parts by weight, 8 parts by weight, 7.9 parts by weight and 8.0 parts by weight, and a range of amounts consisting of any two of the foregoing amounts.

In one embodiment, the amount of the pH adjuster is selected from one or more of the following based on about 10 parts by weight of the lamotrigine particles: about 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1.0 part by weight, 1.1 part by weight, 1.2 part by weight, 1.3 part by weight, 1.4 part by weight, 1.5 part by weight, 1.6 part by weight, 1.7 part by weight, 1.8 part by weight, 1.9 part by weight, 2.0 part by weight, 2.1 part by weight, 2.2 parts by weight, 2.3 parts by weight, 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 part by weight, 3.1 part by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.5 parts by weight, 4.7 parts by weight, 4.5 parts by weight, and any of the foregoing.

In one embodiment, the amount of the pH adjuster is selected from one or more of the following based on about 10 parts by weight of the lamotrigine particles: about 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 7.7.7 parts by weight, 7.7 parts by weight, 7.7.7 parts by weight, 7.0 parts by weight, 7.7 parts by weight, and the above-mentioned ranges.

In one embodiment, the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, and the sum of the amounts of disodium hydrogen phosphate and citric acid is selected from one or more of the following: about 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 6.8 parts by weight, 6.9 parts by weight, 7.0 parts by weight, 7.1 parts by weight, 7.2 parts by weight, 7.3 parts by weight, 7.4 parts by weight, 7.5 parts by weight, 7.6 parts by weight, 7.7.7 parts by weight, 7.7 parts by weight, 6 parts by weight, 7.1 parts by weight, 7.1.2 parts by weight, 7.9 parts by weight, and 8.9 parts by weight of triazine.

In one embodiment, the pH adjuster is citric acid and the amount of citric acid is selected from one or more of the following: about 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1.0 part by weight, 1.1 part by weight, 1.2 parts by weight, 1.3 parts by weight, 1.4 parts by weight, 1.5 parts by weight, 1.6 parts by weight, 1.7 parts by weight, 1.8 parts by weight, 1.9 parts by weight, 2.0 parts by weight, 2.1 parts by weight, 2.2 parts by weight, 2.3 parts by weight, 2.4 parts by weight and 2.5 parts by weight, and the range of amounts consisting of any two of the foregoing, based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, the pH adjuster is sodium dihydrogen phosphate and the amount of sodium dihydrogen phosphate is about 3 parts by weight based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, a dry suspension of lamotrigine is prepared using lamotrigine particles having a particle size (D90), and the amount of the pH adjuster is such that the dry suspension, after mixing with water, results in a suspension having a pH, wherein the particle size (D90) is selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (90D) consisting of any two of the foregoing particle sizes (90); and is also provided with

The pH is selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two pH values recited above; and is also provided with

The pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate and citric acid; and the amount of the pH adjuster is selected from one or more of the following: about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3 2.4 parts by weight, 2.5 parts by weight, 2.6 parts by weight, 2.7 parts by weight, 2.8 parts by weight, 2.9 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 6.8 parts by weight, 6.9 parts by weight, 7.0 parts by weight, 7.1 parts by weight, 7.2 parts by weight, 7.3 parts by weight, 7.4 parts by weight, 7.5 parts by weight, 7.6 parts by weight, 7.7.7 parts by weight, 8 parts by weight, 7.9 parts by weight and 8.0 parts by weight, and a range of amounts consisting of any two of the foregoing amounts.

In one embodiment, a dry suspension of lamotrigine is prepared using lamotrigine particles having a particle size (D90), and the amount of the pH adjuster is such that the dry suspension, after mixing with water, results in a suspension having a pH, wherein the particle size (D90) is selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a particle size (D90) range consisting of any two particle sizes (D90) described above, and the pH is selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values; and is also provided with

The pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate and citric acid; and the amount of the pH adjuster is selected from one or more of the following: about 3.0 parts by weight, 3.1 parts by weight, 3.2 parts by weight, 3.3 parts by weight, 3.4 parts by weight, 3.5 parts by weight, 3.6 parts by weight, 3.7 parts by weight, 3.8 parts by weight, 3.9 parts by weight, 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 7.7.7 parts by weight, 7.7 parts by weight, 7.7.7 parts by weight, 7.0 parts by weight, 7.7 parts by weight, and the above-mentioned ranges.

In one embodiment, the thickener is selected from the group consisting of hydrocolloids such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof. In one embodiment, the thickener is selected from xanthan gum, povidone, colloidal microcrystalline cellulose, sodium alginate and combinations thereof. In one embodiment, the thickener is xanthan gum.

In one embodiment, the thickener is about 1 to 7 parts by weight based on about 10 parts by weight of the lamotrigine particles, and in one embodiment about 1 to 5 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the thickener is about 1 to 7 parts by weight based on about 10 parts by weight of the lamotrigine particles, and in one embodiment about 1 to 5 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the xanthan gum is about 2, 3, 4, 5, 6, or 7 parts by weight based on about 10 parts by weight of lamotrigine particles.

In one embodiment, the weight ratio of lamotrigine particles to thickener is from about 1:1 to about 20:1, from about 1:1 to about 15:1, from about 1:1 to about 10:1, from about 2:1 to about 10:1, from about 5:1 to about 10:1, or from about 3:1 to about 10:1. In one embodiment, the weight ratio of lamotrigine particles to thickener is about 10:1, about 10:2, about 10:3, about 10:4, about 10:5, about 10:6, about 10:7, or about 10:8.

In one embodiment, the method of the present invention for preparing a dry suspension of lamotrigine further comprises mixing lamotrigine particles, a thickener, and a pH adjuster together with a filler.

In one embodiment, the filler is one or more of mannitol, microcrystalline cellulose, sucrose, lactose, or a combination thereof. In one embodiment, the filler is mannitol. In one embodiment, the filler is about 20 to 60 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the filler is about 20 parts by weight based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, the method of the present invention for preparing a dry suspension of lamotrigine further comprises mixing lamotrigine particles, a thickener, and a pH adjuster together with a sweetener.

In one embodiment, the sweetener is one or more of sucralose, aspartame, sodium saccharin, and combinations thereof. In one embodiment, the sweetener is sucralose. In one embodiment, the sweetener is about 1 to 3 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the sweetener is about 1 part by weight based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, the method of the present invention for preparing a dry suspension of lamotrigine further comprises mixing lamotrigine particles, a thickener, and a pH adjuster together with a preservative.

In one embodiment, the preservative is one or more combinations of sodium propyl paraben, sodium methyl paraben, sodium benzoate, potassium sorbate. In one embodiment, the preservative is a combination of sodium propyl paraben and sodium methyl paraben. In one embodiment, the preservative is one or a combination of sodium benzoate or potassium sorbate. In one embodiment, the preservative is about 1 to 3 parts by weight, 1 to 2.22 parts by weight, 1 to 2.2 parts by weight, 1 to 2 parts by weight, 1 to 1.65 parts by weight, 1.65 to 3 parts by weight, 1.65 to 2.22 parts by weight, 1.65 to 2.2 parts by weight, 1.65 to 2 parts by weight, 2 to 3 parts by weight, 2 to 2.22 parts by weight, 2 to 2.2 parts by weight, 2.2 to 3 parts by weight, 2 to 2.22 parts by weight, and 2.22 to 3 parts by weight, based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, the method of the present invention for preparing a dry suspension of lamotrigine further comprises mixing lamotrigine particles, a thickener, a pH adjuster together with the foregoing preservative, sweetener, and filler.

In one embodiment, when the dry suspension of the present invention is mixed with water, lamotrigine hydrate form a in the suspension has a particle size selected from one or more of the following ranges: about 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm. In one embodiment, when the dry suspension of the present invention is mixed with water, the resulting suspension, after 24 hours at 4 ℃, has lamotrigine hydrate form a having a particle size selected from one or more of the following ranges: about 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm.

In one embodiment, the method of preparing a dry suspension of lamotrigine of the present invention comprises using lamotrigine particles having a D90 of about 4.5 μm or 8 μm and mixing the lamotrigine particles, a thickener, a pH adjuster, and the foregoing preservative, sweetener, and filler together, wherein the thickener is xanthan gum, the xanthan gum being about 3 parts by weight based on about 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, the pH adjuster being about 4 parts by weight (optionally 1.5 parts by weight of disodium hydrogen phosphate, and 2.5 parts by weight of citric acid) based on about 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is about 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on about 10 parts by weight of the lamotrigine particles; the filler is mannitol, the filler being about 20 parts by weight based on about 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, the sweetener is about 1 part by weight based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, the present invention produces a dry suspension of lamotrigine that, after mixing with water, results in a suspension having a pH of 5.3. In one embodiment, the invention provides a dry suspension of lamotrigine, wherein the lamotrigine hydrate form a has a particle size of about 20-30 μm after mixing with the water and standing the resulting suspension at 4 ℃ for 24 hours. In one embodiment, the dry suspension of lamotrigine prepared in accordance with the present invention has a particle size of from about 20 to about 30 μm in lamotrigine hydrate form a after the resulting suspension is left at ambient temperature for 6 days after mixing with the aqueous phase.

Method for producing suspensions

In another aspect, the present invention provides a method of preparing a suspension comprising lamotrigine hydrate form a, the method comprising the steps of:

(b) Uniformly dispersed, and standing at a low temperature to obtain said suspension comprising lamotrigine hydrate form a, wherein the particle size (D90) of the lamotrigine particles is 1-30 μm, wherein the low temperature is below 25 ℃, wherein the pH of the suspension is 4.6-6.9, or the amount of the pH modifier is such that the pH of the suspension is 4.6-6.9.

In one embodiment, more than about 80%, 85%, 90% or 95% of the lamotrigine in the suspension is present as lamotrigine hydrate form a.

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 2.8 μm 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.0 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 6.1 μm, 6.8 μm 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm, 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.0 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm, 13.0 μm, 13.1 μm, 13.2 μm, 13.3 μm, 13.4 μm, 13.5 μm, 13.6 μm, 13.7 μm, 13.8 μm, 13.9 μm, 14.0 μm, 14.1 μm, 14.2 μm, 14.3 μm, 14.4 μm, 14.5 μm, 14.6 μm, 14.7 μm, 14.8 μm, 14.9 μm, 15.0 μm, 15.1 μm, 15.2 μm, 15.3 μm, 15.4 μm, 15.5 μm, 15.6 μm, 15.7 μm, 15.8 μm, 15.9 μm, 16.0 μm, 16.1 μm, 16.2 μm, 16.3 μm, 16.4 μm, 16.5 μm, 16.6 μm, 16.7 μm, 16.8 μm, 16.9 μm, 17.0 μm, 15.6 μm, 15.7 μm, 15.8 μm, 16.4 μm, 16.5 μm, 16.6 μm, 16.7 μm 17.1 μm, 17.2 μm, 17.3 μm, 17.4 μm, 17.5 μm, 17.6 μm, 17.7 μm, 17.8 μm, 17.9 μm, 18.0 μm, 18.1 μm, 18.2 μm, 18.3 μm, 18.4 μm, 18.5 μm, 18.6 μm, 18.7 μm, 18.8 μm, 18.9 μm, 19.0 μm, 19.1 μm, 19.2 μm, 19.3 μm, 19.4 μm, 19.5 μm, 19.6 μm, 19.7 μm, 19.8 μm, 19.9 μm, 20.0 μm, 20.1 μm, 20.2 μm 20.3 μm, 20.4 μm, 20.5 μm, 20.6 μm, 20.7 μm, 20.8 μm, 20.9 μm, 21.0 μm, 21.1 μm, 21.2 μm, 21.3 μm, 21.4 μm, 21.5 μm, 21.6 μm, 21.7 μm, 21.8 μm, 21.9 μm, 22.0 μm, 22.1 μm, 22.2 μm, 22.3 μm, 22.4 μm, 22.5 μm, 22.6 μm, 22.7 μm, 22.8 μm, 22.9 μm, 23.0 μm, 23.1 μm, 23.2 μm, 23.3 μm, 23.4 μm 23.5 μm, 23.6 μm, 23.7 μm, 23.8 μm, 23.9 μm, 24.0 μm, 24.1 μm, 24.2 μm, 24.3 μm, 24.4 μm, 24.5 μm, 24.6 μm, 24.7 μm, 24.8 μm, 24.9 μm, 25.0 μm, 25.1 μm, 25.2 μm, 25.3 μm, 25.4 μm, 25.5 μm, 25.6 μm, 25.7 μm, 25.8 μm, 25.9 μm, 26.0 μm, 26.1 μm, 26.2 μm, 26.3 μm, 26.4 μm, 26.5 μm, 26.6 μm, 26.7 μm, 26.8 μm, 26.9 μm, 27.0 μm, 27.1 μm, 27.2 μm, 27.3 μm, 27.4 μm, 27.5 μm, 27.6 μm, 27.7 μm, 27.8 μm, 27.9 μm, 28.0 μm, 28.1 μm, 28.2 μm, 28.3 μm, 28.4 μm, 28.5 μm, 28.6 μm, 28.7 μm, 28.8 μm, 28.9 μm, 29.0 μm, 29.1 μm, 29.2 μm, 29.3 μm, 29.4 μm, 29.5 μm, 29.6 μm, 29.7 μm, 29.8 μm, 29.9 μm and 30.0 μm, and a particle size (D90) range consisting of any two of the foregoing particle sizes (D90).

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 5.4 μm 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm, 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm and 13.0 μm, and a particle diameter (D90) range consisting of any two particle diameters (D90) described above.

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (D90) consisting of any two of the foregoing particle sizes (D90). In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a range of particle sizes (D90) consisting of any two of the foregoing particle sizes (D90).

In one embodiment, the amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values. In one embodiment, the amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (90D) consisting of any two of the foregoing particle sizes (90); and the amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a range of particle sizes (D90) consisting of any two of the foregoing particle sizes (D90); and the amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, and the sum of the amounts of disodium hydrogen phosphate and citric acid is selected from one or more of the following: about 4.0 parts by weight, 4.1 parts by weight, 4.2 parts by weight, 4.3 parts by weight, 4.4 parts by weight, 4.5 parts by weight, 4.6 parts by weight, 4.7 parts by weight, 4.8 parts by weight, 4.9 parts by weight, 5.0 parts by weight, 5.1 parts by weight, 5.2 parts by weight, 5.3 parts by weight, 5.4 parts by weight, 5.5 parts by weight, 5.6 parts by weight, 5.7 parts by weight, 5.8 parts by weight, 5.9 parts by weight, 6.0 parts by weight, 6.1 parts by weight, 6.2 parts by weight, 6.3 parts by weight, 6.4 parts by weight, 6.5 parts by weight, 6.6 parts by weight, 6.7 parts by weight, 6.8 parts by weight, 6.9 parts by weight, 7.0 parts by weight, 7.1 parts by weight, 7.2 parts by weight, 7.3 parts by weight, 7.4 parts by weight, 7.5 parts by weight, 7.6 parts by weight, 7.7.7 parts by weight, 7.7 parts by weight, 7.1 parts by weight, 7.8 parts by weight, 6.9 parts by weight and 8.10 parts by weight of triazine.

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (90D) consisting of any two of the foregoing particle sizes (90); and is also provided with

The amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two pH values recited above; and is also provided with

In one embodiment, the lamotrigine particles have a particle size (D90) selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a range of particle sizes (D90) consisting of any two of the foregoing particle sizes (D90); the amount of the pH adjuster is such that the suspension has a pH selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values; and is also provided with

In one embodiment, the thickener is about 1 to 7 parts by weight based on about 10 parts by weight of the lamotrigine particles, and in one embodiment about 1 to 5 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the xanthan gum is about 2, 3, 4, 5, 6, or 7 parts by weight based on about 10 parts by weight of lamotrigine particles.

In one embodiment, the process of the present invention for preparing a suspension comprising lamotrigine hydrate form a further comprises mixing lamotrigine particles, a thickener, and a pH adjuster with a filler, adding to an aqueous phase, or mixing lamotrigine particles and a thickener with an aqueous phase comprising a pH adjuster and a filler.

In one embodiment, the process of the present invention for preparing a suspension comprising lamotrigine hydrate form a further comprises mixing lamotrigine particles, a thickener, and a pH adjuster with a sweetener, adding to the aqueous phase, or mixing the lamotrigine particles and thickener with an aqueous phase comprising a pH adjuster and a sweetener.

In one embodiment, the process of the present invention for preparing a suspension comprising lamotrigine hydrate form a further comprises mixing lamotrigine particles, a thickener, and a pH adjuster with a preservative, adding to an aqueous phase, or mixing lamotrigine particles and a thickener with an aqueous phase comprising a pH adjuster and a preservative. In one embodiment, the preservative is one or more combinations of sodium propyl paraben, sodium methyl paraben, sodium benzoate, potassium sorbate. In one embodiment, the preservative is a combination of sodium propyl paraben and sodium methyl paraben. In one embodiment, the preservative is one or a combination of sodium benzoate or potassium sorbate. In one embodiment, the preservative is about 1 to 3 parts by weight, 1 to 2.22 parts by weight, 1 to 2.2 parts by weight, 1 to 2 parts by weight, 1 to 1.65 parts by weight, 1.65 to 3 parts by weight, 1.65 to 2.22 parts by weight, 1.65 to 2.2 parts by weight, 1.65 to 2 parts by weight, 2 to 3 parts by weight, 2 to 2.22 parts by weight, 2 to 2.2 parts by weight, 2.2 to 3 parts by weight, 2 to 2.22 parts by weight, and 2.22 to 3 parts by weight, based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, lamotrigine hydrate form a in the suspension has a particle size selected from one or more of the following ranges: about 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm. In one embodiment, lamotrigine hydrate form a has a particle size selected from one or more of the following ranges: about 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm.

In one embodiment, pharmaceutical grade purified water is used as the aqueous phase. In one embodiment, the aqueous phase is about 100 to 5000 parts by weight, 500 to 2000 parts by weight, 100 parts by weight, 200 parts by weight, 300 parts by weight, 500 parts by weight, 600 parts by weight, 800 parts by weight, 1000 parts by weight, 1500 parts by weight, 2000 parts by weight, 2500 parts by weight, 3000 parts by weight, 3500 parts by weight, 4000 parts by weight, or 5000 parts by weight, based on 10 parts by weight of lamotrigine particles.

In one embodiment, the uniform dispersion may be achieved by one or more of mechanical stirring, magnetic stirring, or manual shaking. By homogeneously dispersed is meant that a homogeneous system is formed.

In one embodiment, the time to achieve uniform dispersion is about 1-120 minutes, 3-15 minutes, 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 25 minutes, 60 minutes, 90 minutes, 100 minutes, or 120 minutes.

In one embodiment, to save preparation time, uniform dispersion is achieved without setting specific dispersion time.

In one embodiment, the low temperature is selected from no more than about-20 ℃, no more than about-10 ℃, no more than about-5 ℃, no more than about 0 ℃, no more than about 4 ℃, no more than about 10 ℃, no more than about 20 ℃, and no more than about 25 ℃. In one embodiment, wen Xuanzi is about-20 ℃ to about 25 ℃, about-20 ℃ to about 20 ℃, about-20 ℃ to about 0 ℃, about 0 ℃ to about 20 ℃, about 0 ℃ to about 4 ℃, and about 4 ℃ to about 20 ℃.

In one embodiment, the low temperature is below 25 ℃, below 20 ℃, 4 ℃, 0 ℃, 20 ℃, 15 ℃ or 20 ℃.

In one embodiment, the time of standing at low temperature is at least 30 minutes, at least 1 hour, at least 2 hours, at least 8 hours, or at least 24 hours.

In one embodiment, the dispersion may be uniform and then left at a low temperature after a period of time.

In one embodiment, the interval between uniform dispersion and placement at low temperature is at most 12 hours, at most 8 hours, at most 2 hours, at most 60 minutes, at most 30 minutes, at most 20 minutes, at most 10 minutes, at most 5 minutes, at most 1 minute, or 0 minutes.

In one embodiment, to save preparation time, no time interval is provided, and the subsequent steps are directly performed after the completion of the previous step.

In one embodiment, the process of the present invention for preparing a suspension comprising lamotrigine hydrate form a comprises using lamotrigine particles having D90 of 4.5 μm or 8 μm, mixing lamotrigine particles, a thickener, a pH adjuster, a filler, a preservative, and a sweetener, adding to an aqueous phase, or mixing lamotrigine particles and a thickener with an aqueous phase comprising a pH adjuster, a filler, a preservative, and a sweetener, wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

In one embodiment, the pH of the suspension comprising lamotrigine hydrate form a prepared according to the present invention is 5.3. In one embodiment, the suspension prepared according to the present invention comprising lamotrigine hydrate form a has a particle size of 20-30 μm after 24 hours at 4 ℃. In one embodiment, the suspension prepared according to the present invention comprising lamotrigine hydrate form a has a particle size of 20-30 μm after 6 days of standing at normal temperature.

The method for preparing the suspension is simple, and the prepared suspension has excellent uniformity and stability. And the lamotrigine hydrate form A in the suspension has high content, high purity and less impurities.

Pharmaceutical compositions and products

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of lamotrigine particles and one or more pharmaceutically acceptable excipients, wherein the lamotrigine particles have a particle size (D90) of about 1-30 μm and the excipients comprise a thickening agent and a pH adjuster in an amount such that the pharmaceutical composition, when mixed with an aqueous phase, results in a suspension having a pH of about 4.6-6.9.

In one embodiment, the pharmaceutical composition is a dry suspension or suspension.

In one embodiment, more than about 80%, 85%, 90% or 95% of the lamotrigine is present as lamotrigine hydrate form a when the pharmaceutical composition is mixed with water to form a suspension.

In one embodiment, the particle size (D90) is selected from one or more of the following: about 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 2.8 μm 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.0 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 6.1 μm, 6.8 μm 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm, 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.0 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm, 13.0 μm, 13.1 μm, 13.2 μm, 13.3 μm, 13.4 μm, 13.5 μm, 13.6 μm, 13.7 μm, 13.8 μm, 13.9 μm, 14.0 μm, 14.1 μm, 14.2 μm, 14.3 μm, 14.4 μm, 14.5 μm, 14.6 μm, 14.7 μm, 14.8 μm, 14.9 μm, 15.0 μm, 15.1 μm, 15.2 μm, 15.3 μm, 15.4 μm, 15.5 μm, 15.6 μm, 15.7 μm, 15.8 μm, 15.9 μm, 16.0 μm, 16.1 μm, 16.2 μm, 16.3 μm, 16.4 μm, 16.5 μm, 16.6 μm, 16.7 μm, 16.8 μm, 16.9 μm, 17.0 μm, 15.6 μm, 15.7 μm, 15.8 μm, 16.4 μm, 16.5 μm, 16.6 μm, 16.7 μm 17.1 μm, 17.2 μm, 17.3 μm, 17.4 μm, 17.5 μm, 17.6 μm, 17.7 μm, 17.8 μm, 17.9 μm, 18.0 μm, 18.1 μm, 18.2 μm, 18.3 μm, 18.4 μm, 18.5 μm, 18.6 μm, 18.7 μm, 18.8 μm, 18.9 μm, 19.0 μm, 19.1 μm, 19.2 μm, 19.3 μm, 19.4 μm, 19.5 μm, 19.6 μm, 19.7 μm, 19.8 μm, 19.9 μm, 20.0 μm, 20.1 μm, 20.2 μm 20.3 μm, 20.4 μm, 20.5 μm, 20.6 μm, 20.7 μm, 20.8 μm, 20.9 μm, 21.0 μm, 21.1 μm, 21.2 μm, 21.3 μm, 21.4 μm, 21.5 μm, 21.6 μm, 21.7 μm, 21.8 μm, 21.9 μm, 22.0 μm, 22.1 μm, 22.2 μm, 22.3 μm, 22.4 μm, 22.5 μm, 22.6 μm, 22.7 μm, 22.8 μm, 22.9 μm, 23.0 μm, 23.1 μm, 23.2 μm, 23.3 μm, 23.4 μm 23.5 μm, 23.6 μm, 23.7 μm, 23.8 μm, 23.9 μm, 24.0 μm, 24.1 μm, 24.2 μm, 24.3 μm, 24.4 μm, 24.5 μm, 24.6 μm, 24.7 μm, 24.8 μm, 24.9 μm, 25.0 μm, 25.1 μm, 25.2 μm, 25.3 μm, 25.4 μm, 25.5 μm, 25.6 μm, 25.7 μm, 25.8 μm, 25.9 μm, 26.0 μm, 26.1 μm, 26.2 μm, 26.3 μm, 26.4 μm, 26.5 μm, 26.6 μm, 26.7 μm, 26.8 μm, 26.9 μm, 27.0 μm, 27.1 μm, 27.2 μm, 27.3 μm, 27.4 μm, 27.5 μm, 27.6 μm, 27.7 μm, 27.8 μm, 27.9 μm, 28.0 μm, 28.1 μm, 28.2 μm, 28.3 μm, 28.4 μm, 28.5 μm, 28.6 μm, 28.7 μm, 28.8 μm, 28.9 μm, 29.0 μm, 29.1 μm, 29.2 μm, 29.3 μm, 29.4 μm, 29.5 μm, 29.6 μm, 29.7 μm, 29.8 μm, 29.9 μm and 30.0 μm, and a particle size (D90) range consisting of any two of the foregoing particle sizes (D90).

In one embodiment, the particle size (D90) is selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 5.4 μm 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, 8.0 μm, 8.1 μm, 8.2 μm, 8.3 μm, 8.4 μm, 8.5 μm, 8.6 μm, 8.7 μm, 8.8 μm 8.9 μm, 9.0 μm, 9.1 μm, 9.2 μm, 9.3 μm, 9.4 μm, 9.5 μm, 9.6 μm, 9.7 μm, 9.8 μm, 9.9 μm, 10.0 μm, 10.1 μm, 10.2 μm, 10.3 μm, 10.4 μm, 10.5 μm, 10.6 μm, 10.7 μm, 10.8 μm, 10.9 μm, 11.0 μm, 11.1 μm, 11.2 μm, 11.3 μm, 11.4 μm, 11.5 μm, 11.6 μm, 11.7 μm, 11.8 μm, 11.9 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm and 13.0 μm, and a particle diameter (D90) range consisting of any two particle diameters (D90) described above.

In one embodiment, the particle size (D90) is selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (D90) consisting of any two of the foregoing particle sizes (D90). In one embodiment, the particle size (D90) is selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a range of particle sizes (D90) consisting of any two of the foregoing particle sizes (D90).

In one embodiment, the amount of the pH adjuster is such that the resulting suspension, after mixing with the aqueous phase, has a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the amount of the pH adjuster is such that the resulting suspension, after mixing with the aqueous phase, has a pH selected from one or more of the following: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values. In one embodiment, the amount of the pH adjuster is such that the resulting suspension, after mixing with the aqueous phase, has a pH selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the particle size (D90) is selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size (D90) consisting of any two of the foregoing particles (D90) and one or more selected from the following pH ranges: about 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the particle size (D90) is selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a particle size (D90) range consisting of any two particle sizes (D90) described above, and the pH is selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values.

In one embodiment, the pH adjuster is citric acid and the amount of citric acid is selected from one or more of the following: about 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1.0 part by weight, 1.1 part by weight, 1.2 parts by weight, 1.3 parts by weight, 1.4 parts by weight, 1.5 parts by weight, 1.6 parts by weight, 1.7 parts by weight, 1.8 parts by weight, 1.9 parts by weight, 2.0 parts by weight, 2.1 parts by weight, 2.2 parts by weight, 2.3 parts by weight, 2.4 parts by weight and 2.5 parts by weight, and the range of amounts consisting of any two of the foregoing, based on 10 parts by weight of the lamotrigine particles.

In one embodiment, the particle size (D90) is selected from one or more of the following: about 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (90D) consisting of any two of the foregoing particle sizes (90); and is also provided with

In one embodiment, the particle size (D90) is selected from one or more of the following: about 12 μm, 12.1 μm, 12.2 μm, 12.3 μm, 12.4 μm, 12.5 μm, 12.6 μm, 12.7 μm, 12.8 μm, 12.9 μm and 13.0 μm, and a particle size (D90) range consisting of any two particle sizes (D90) described above, and the pH is selected from one or more of the following: about 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85, and 6.9, and a pH range consisting of any two of the foregoing pH values; and is also provided with

In some embodiments, the particle size (D90) is between about 6-14, 8-12, 8-10, 7-9, 8-9, 9-10, 10-11, 10-12, 11-12, or 11-13 μm. In some embodiments, the suitable pH adjuster(s) (type and/or content) is selected such that the suspension has a pH of: 4.0-7.0, 4.2-6.8, 4.4-6.8, 4.6-6.6, 4.6-6.4, 4.6-6.2, 4.6-6.0, 4.6-5.8, 4.6-5.6, 4.6-5.4, 4.8-5.2, 5.0-6.8, 5.2-6.8, 5.4-6.8, 5.6-6.8, 5.8-6.8, 6.0-6.6, 6.8-6.6,5.8-6.6, 5.8-6.4, or 6.0-6.4. In some embodiments, the particle size (D90) is in the range of 8-10, 7-9, 7-8, or 8-9 μm, with the appropriate pH adjuster (type and/or content) being selected such that the suspension has a pH:4.6-6.8, 4.8-6.2, 4.8-6.0, 4.8-5.8 or 4.6-5.6. In some embodiments, the particle size (D90) is between 10-12, 11-13, 11-12, or 12-13 μm, with the appropriate pH adjuster (type and/or content) being selected such that the suspension has a pH:5.6-6.8, 5.8-6.6, 6.0-6.8, or 6.0-6.6.

In some embodiments, the suitable lamotrigine particle size (D90) is selected to provide a lamotrigine hydrate form a having a range of particle size increases in suspension selected from the group consisting of: the particle size increases by less than 150%, less than 100%, less than 80%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

In some embodiments, the suitable pH adjusting agent(s) (type and/or content) is selected to provide such that lamotrigine hydrate form a has a range of particle size increases in suspension selected from the group consisting of: the particle size increases by less than 150%, less than 100%, less than 80%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

In one embodiment, the thickener is about 1 to 7 parts by weight based on 10 parts by weight of the lamotrigine particles, and in one embodiment about 1 to 5 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the thickener is about 1 to 7 parts by weight based on about 10 parts by weight of the lamotrigine particles, and in one embodiment about 1 to 5 parts by weight based on about 10 parts by weight of the lamotrigine particles. In one embodiment, the xanthan gum is about 2, 3, 4, 5, 6, or 7 parts by weight based on about 10 parts by weight of lamotrigine particles.

In one embodiment, the lamotrigine pharmaceutical composition of the invention further comprises a filler.

In one embodiment, the filler is one or more of mannitol, microcrystalline cellulose, sucrose, lactose, or a combination thereof. In one embodiment, the filler is mannitol. In one embodiment, the filler is 20 to 60 parts by weight based on 10 parts by weight of the lamotrigine particles. In one embodiment, the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles.

In one embodiment, the lamotrigine pharmaceutical composition of the invention further comprises a sweetener.

In one embodiment, the lamotrigine pharmaceutical composition of the invention further comprises a preservative.

In one embodiment, the lamotrigine pharmaceutical composition of the invention further comprises the foregoing preservatives, sweeteners, and fillers.

In one embodiment, when the lamotrigine pharmaceutical composition of the invention is mixed with water, the resulting suspension is left at 4 ℃ for 24 hours, the lamotrigine hydrate form a having a particle size selected from one or more of the following ranges: about 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm.

In one embodiment, the lamotrigine pharmaceutical composition of the invention comprises lamotrigine particles having a D90 of 4.5 μm or 8 μm, a thickener, a pH adjuster, a preservative, a sweetener, and a filler, wherein the thickener is xanthan gum, the xanthan gum being about 3 parts by weight based on about 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, the pH adjuster being about 4 parts by weight (optionally 1.5 parts by weight of disodium hydrogen phosphate, and 2.5 parts by weight of citric acid) based on about 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is about 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on about 10 parts by weight of the lamotrigine particles; the filler is mannitol, the filler being about 20 parts by weight based on about 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, the sweetener is about 1 part by weight based on about 10 parts by weight of the lamotrigine particles.

In one embodiment, the composition may further comprise at least one additional drug. In one embodiment, the composition further comprises one or more additional drugs selected from oxcarbazepine (oxcarbazpin), carbamazepine (carbamazpin), phenytoin (phnytoin), valproic acid (valproic acid), ethosuximide (thospormid), febrile urethane (flbamate), gabapentin (gabapntin), levetiracetam (lvtiractam), tiagabine (tiagabin), pregabalin (prgablin), phenobarbital (phnobarbal), zonisamide (zonisamid), clonazepam (clomazpam), phenytoin sodium (phnytoin), valproat, clobazam (clobazam), vigabatrin (topiramate), and lacamamide (lacamid).

In one embodiment, lamotrigine hydrate form a or a composition thereof may also be packaged with other drugs in a kit. Lamotrigine hydrate form a or a composition thereof may be administered to a patient simultaneously or sequentially with other drugs.

In one embodiment, the composition may be administered to a patient in any suitable dosage form as lamotrigine hydrate form a described herein. Dosage forms include, but are not limited to: (a) Administration by the oral route, including capsules, tablets, granules, sprays, syrups or other such forms of dosage forms; (b) Non-oral routes of administration, such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraaural administration, including aqueous suspensions, oily formulations and the like or drops, sprays, suppositories, ointments, salves and the like; (c) Administration by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal, intrasternal injection, etc.; (d) Topical administration, including inhalation solutions, nasal sprays, implants, and the like; and (e) other dosage forms deemed suitable by those skilled in the art for delivering the active ingredient to the target tissue.

In one embodiment, the composition is in a form selected from the group consisting of a tablet, a capsule, a powder and a suspension, and is preferably a suspension or a dry suspension. In some embodiments, the suspension containing lamotrigine hydrate form a may be precisely metered (e.g., by a dispenser) and then administered by the oral route.

The exact formulation, route of administration and dosage of the composition may be selected by the physician according to the patient's condition. In one embodiment, the dose of lamotrigine hydrate form a administered to a patient ranges from 0.1mg/kg to 1000mg/kg. The dosage may be administered in a single dosage unit or in multiple dosage units over a period of one or more days, depending on the patient's needs. Where a certain dosage has been used clinically, the lamotrigine hydrate form a composition may be used in that dosage, or in a range of about 0.1% to about 500%, more preferably in a range of about 25% to about 250% of that dosage.

Due to toxicity or organ dysfunction, the clinician will know how and when to terminate or adjust the dose. Conversely, if the clinical response is inadequate (eliminating the toxic response), the clinician will also know to adjust the therapeutic dose to a higher level. In the diseases treated, the size of the dose administered will vary with the severity of the disease being treated and the route of administration. The severity of the condition can be assessed, for example, by standard prognostic assessment methods. In addition, the dosage will also be adjusted according to the age, weight and individual differences of the patient.

Although the exact dosage varies from case to case, in most cases some generalization of the dosage can be made: the daily dosage regimen for an adult patient may be from about 0.1mg to about 2000mg, preferably from about 1mg to about 500mg, most preferably from about 5mg to about 200mg, for oral administration; intravenous, subcutaneous, or intramuscular injection is preferably from about 0.01mg to about 100mg, most preferably from about 0.1mg to about 60mg. In one embodiment, the composition is administered 1-4 times per day. For other cases lamotrigine hydrate form a may be used by continuous intravenous infusion, preferably up to about 1000mg per day. Those skilled in the art will appreciate that in some instances it may be necessary to use lamotrigine hydrate form a in amounts exceeding or well above the preferred dosage ranges described above in order to effectively and aggressively treat particularly critical conditions. In one embodiment, lamotrigine hydrate form a is used continuously for one week or several months or several years or longer.

In one embodiment, the time to release the lamotrigine hydrate form a-containing composition after administration is from about 1 hour to 12 hours, preferably from 3 hours to 12 hours, more preferably from 6 hours to 12 hours. In one embodiment, the orally administered lamotrigine hydrate form a composition may be administered in a single dose or multiple doses once to four times a day. Oral dosage forms may be conveniently administered in single doses and may be prepared by methods well known in the pharmaceutical arts.

If desired, the lamotrigine hydrate form a-containing composition may be stored in a packaging material or in a drug delivery device, which may contain one or more unit doses. The packaging material may be a metal or plastic film, a blister pack. The packaging or administration device may also be accompanied by instructions. Such instructions may be prescription drug labels approved by the drug administration or instructions for formulating a lamotrigine hydrate form a-containing composition in a compatible container.

Medicine box

The present invention provides a kit comprising at least one composition as described herein before, at least one method of preparation as described herein before to prepare a suspension, at least one suspension as described herein before, or at least one dry suspension as described herein before, wherein

Lamotrigine and other ingredients as previously described herein (e.g., one or more selected from pH adjusters, preservatives, thickeners, bulking agents, sweeteners, etc.) are contained in the same container;

or alternatively

Lamotrigine and other ingredients as previously described herein (e.g., one or more selected from pH adjusters, preservatives, thickeners, fillers, sweeteners, etc.) are contained in one or more separate containers.

In some embodiments, lamotrigine particles in the kit may be mixed with other ingredients (e.g., one or more selected from pH adjusters, preservatives, thickeners, fillers, sweeteners, etc.) and added to water to form a suspension

In some embodiments, lamotrigine particles in the kit can be mixed with an aqueous solution comprising other ingredients (e.g., one or more selected from pH adjusters, preservatives, thickeners, fillers, sweeteners, etc.) to formulate a suspension.

In some embodiments, the suspension, the dry suspension, the lamotrigine, and the type, content, D90 particle size, microscope particle size, antimicrobial stability, etc., of, for example, pH adjusters, preservatives, thickeners, fillers, sweeteners, etc., are as described in the previous section herein.

Therapeutic methods and uses

In another aspect, the invention provides a method of treating a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of lamotrigine hydrate form a of the invention or a composition of the invention.

In another aspect, the invention provides the use of lamotrigine hydrate form a of the invention or the composition of the invention in the manufacture of a medicament for the treatment of a neurological disorder.

In another aspect, the invention provides lamotrigine hydrate form a of the invention or the composition of the invention for use in the treatment of neurological disorders.

In one embodiment, lamotrigine hydrate form a may be used alone or in combination with other drugs to treat neurological disorders.

In one embodiment, lamotrigine hydrate form a has a purity of greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95%. In one embodiment, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90% or more than about 95% of the lamotrigine in the lamotrigine hydrate form a composition is present as lamotrigine hydrate form a, preferably more than about 90% of the lamotrigine is present as lamotrigine hydrate form a, more preferably more than about 95% of the lamotrigine is present as lamotrigine hydrate form a.

In one embodiment, the neurological disorder is selected from one or more of alzheimer's disease, depression, multiple sclerosis, parkinson's disease, and epilepsy.

In one embodiment, the medicament is for use in combination with other medicaments for the treatment of the neurological disease, preferably the other medicaments are selected from one or more of oxcarbazepine (oxcarbazpin), carbamazepine (carbazpin), phenytoin (phnytoin), valproic acid, ethosuximide (thospormid), felbamate (flbamat), gabapentin (gabapntin), levetiracetam (lvtiramm), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbal), zonisamide (zonisamid), clonazepam (clomazpam), phenytoin sodium (phnytoin), valproat sodium (clobazem), vigabatrin (topiramate) and kaamide (lac).

In one embodiment, the drug is in the form of a suspension.

In one embodiment, more than about 80% of the lamotrigine in the medicament is present in the form of lamotrigine hydrate form a, preferably more than about 90% of the lamotrigine is present in the form of lamotrigine hydrate form a, and more preferably more than about 95% of the lamotrigine is present in the form of lamotrigine hydrate form a.

The lamotrigine hydrate form A prepared by the invention has high purity, good solubility and high chemical stability, and the physical stability of the lamotrigine hydrate form A in an aqueous phase environment is obviously improved (the physical stability of the suspension prepared by the invention is good), so that the lamotrigine hydrate form A is suitable for controlling long-term epilepsy.

The following examples are only for further illustration of the invention and do not limit the scope of the invention to these examples. The raw materials and reagents used in the present invention may be commercially available.

EXAMPLE 1 preparation of a suspension containing lamotrigine hydrate form A Using lamotrigine particles of different particle sizes

10 parts by weight of lamotrigine particles (D90) having particle diameters of 8 μm, 12 μm and 60 μm, respectively (purchased from Alabine pharmaceutical Co., india), and 3 parts by weight of xanthan gum (purchased from Sbi Keke Co., USA) were added to 1000 parts by weight of purified water to be uniformly dispersed, and left at 4℃for 24 hours to prepare a suspension. The resulting suspension was allowed to stand at room temperature for 1 month, and the suspensions and crystal forms in the suspensions were examined at various time points, and the results are shown in table 1:

unless otherwise specified, XRPD results were determined by a Bruker D8 advance type X-ray diffractometer, germany, and microscopic results were determined by a Nanjing Nandina CM2000S type microscope.

TABLE 1

As shown in table 1, the crystalline form in suspension was lamotrigine hydrate form a using 8 μm and 12 μm lamotrigine particles. With 60 μm lamotrigine particles, the crystal form in suspension contains unknown crystals and stability of the crystal properties cannot be ensured. XRPD results for lamotrigine hydrate form a containing unknown crystals are shown in fig. 3.

The above results suggest that whether stable lamotrigine hydrate form a will form in suspension is not entirely limited by the size of the particle size of the final lamotrigine hydrate form a in solution, but will depend more on the starting particle size of lamotrigine hydrate form a. It is speculated that if the starting particle size of lamotrigine hydrate form a is too large, it is difficult to form a pure crystalline form from the beginning.

EXAMPLE 2 preparation of a suspension containing lamotrigine hydrate form A Using different thickeners

10 parts by weight of lamotrigine particles having a particle diameter (D90) of 8 μm and 3 parts by weight of a thickener (xanthan gum, povidone, colloidal microcrystalline cellulose and sodium alginate) (wherein xanthan gum is purchased from Sbikeke corporation, USA, povidone is purchased from Basoff corporation, germany, colloidal microcrystalline cellulose is purchased from FMC corporation, USA, and is purchased from the Qingdao, moon seaweed group) were added to 1000 parts by weight of purified water to be dispersed uniformly, and left at 4℃for 24 hours to prepare a suspension. The resulting suspension was allowed to stand at room temperature for 1 month, and the suspensions and crystal forms in the suspensions were examined at various time points, and the results are shown in table 2:

TABLE 2

As shown in table 2, xanthan gum, povidone, colloidal microcrystalline cellulose and sodium alginate were used as thickeners, the crystalline forms in suspension were all lamotrigine hydrate form a.

EXAMPLE 3 preparation of lamotrigine hydrate form A-containing suspensions Using varying amounts of thickening Agents

10 parts by weight of lamotrigine particles having a particle diameter (D90) of 8 μm and 0 part by weight, 1 part by weight and 5 parts by weight of xanthan gum, respectively, were added to 1000 parts by weight of purified water to be uniformly dispersed, and left at 4℃for 24 hours to prepare a suspension. The resulting suspension was allowed to stand at room temperature for 1 month, and the suspensions and crystal forms in the suspensions were examined at various time points, and the results are shown in table 3:

TABLE 3 Table 3

As shown in table 3, the crystalline form in suspension was lamotrigine hydrate form a using 1 part by weight and 5 parts by weight of thickener. Without using a thickener, the crystal form in the suspension after leaving for one week at normal temperature contains unknown crystals, and the stability of the crystal properties cannot be ensured.

EXAMPLE 4 preparation of lamotrigine hydrate form A-containing suspension Using different Low temperature Placement temperatures

10 parts by weight of lamotrigine particles having a particle diameter (D90) of 8 μm and 3 parts by weight of xanthan gum were added to 1000 parts by weight of purified water to be uniformly dispersed, and left at low temperature (-20 ℃, 4 ℃ and 20 ℃) for 24 hours to prepare a suspension. The resulting suspension was allowed to stand at room temperature for 1 month, and the suspensions and crystal forms in the suspensions were examined at various time points, and the results are shown in table 4:

TABLE 4 Table 4

As shown in table 4, the crystalline forms in suspension were lamotrigine hydrate form a using low temperature holding temperatures of-20 ℃, 4 ℃ and 20 ℃.

EXAMPLE 5 preparation of lamotrigine hydrate form A-containing suspension Using different times of standing at Low temperature

10 parts by weight of lamotrigine particles having a particle diameter (D90) of 8 μm and 3 parts by weight of xanthan gum were added to 1000 parts by weight of purified water to be uniformly dispersed, and left at 4℃for 0 hours, 2 hours, 8 hours and 24 hours, respectively, to prepare suspensions. The resulting suspension was allowed to stand at room temperature for 1 month, and the suspensions and crystal forms in the suspensions were examined at various time points, and the results are shown in table 5:

TABLE 5

As shown in table 5, the crystalline form in suspension was lamotrigine hydrate form a using periods of low temperature standing for 2 hours, 8 hours and 24 hours. The crystal form in the suspension after leaving at normal temperature for one week contains unknown crystals without leaving at low temperature (0 hours at 4 ℃), and the stability of the crystal properties cannot be ensured.

EXAMPLE 6 dissolution and stability

2.5ml of the suspension prepared in example 5 above was allowed to stand at 4℃for 24 hours, and the lamotrigine hydrate form A in the suspension was subjected to dissolution measurement by a paddle method at a rotation speed of 50rpm and a temperature of 37.+ -. 0.5℃with 900ml of 0.1N hydrochloric acid as a dissolution medium. The dissolution rate was more than 85% (w/w) at 15 min. The dissolution result is equal to that of the quick-release lamotrigine tablet on the market 25 mg) results are consistent, and the dissolution rate of lamotrigine hydrate form A can meet the clinical application.

The prepared suspension was left at room temperature for 1 month, and the suspensions and the crystal forms in the suspensions were examined at different time points as follows: appearance, microscopic particle size, XRPD crystalline form, dissolution, content and related substances, and the results are shown in table 6. The results at different time points meet the limit requirements, and the suspension has good stability and can meet the long-term medication requirements of patients.

Dissolution rate measurement: the dissolution was determined by a paddle method, rotation speed 50rpm, temperature 37.+ -. 0.5 ℃ and dissolution medium 900ml of 0.1N hydrochloric acid, sampling at 15min, UV absorbance.

Content and related substances determination: taking a certain amount of suspension, and measuring by a high performance liquid phase method after the mobile phase and the methanol are subjected to constant volume.

TABLE 6

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EXAMPLE 7 preparation of suspensions containing hydrate form A thereof at different pH Using lamotrigine having D90 starting particle size of 8 μm or less

Suspensions were prepared according to the components of each experimental group shown in table 7 below and their content (in parts by weight) to observe the appearance of suspensions prepared from lamotrigine particles of different D90 particle sizes at different pH values and the microscopic particle sizes of the particles in the suspensions.

All of the components of each group shown in Table 7 were placed in a suitably sized hopper, mixed at 20 rpm for 5 minutes, then passed through a 475 micron screen, and then placed in the hopper for further mixing for 10 minutes to give a dry suspension that could be further used. The dry suspension is compounded into a suspension before administration. The crystalline forms in suspension were examined at different time points as follows: appearance, microscopic particle size, XRPD crystalline form observation and determination.

TABLE 7

After the suspensions of groups 2 to 15 were left at 4℃for 24 hours in the pH range 4.6 to 6.85, the appearance of the suspension was milky white, and the lamotrigine hydrate form A was contained in the suspension, and the particle size was determined to be in the range 20 to 60 μm by microscopy (groups 2 to 6 and 9 to 10: 20 to 30 μm by microscopy, groups 7 to 8 and 11 to 12: about 30 μm by microscopy, and groups 13 to 15: 50 to 60 μm by microscopy). In this pH range, the overall trend is that the microscopic particle size of lamotrigine hydrate form a increases with increasing pH.

After continuing to stand for 1 day at normal temperature, the suspension of groups 2 to 15 still exhibited a milky suspension in appearance, and the particle size of the crystals of each group remained substantially unchanged relative to the particle size after standing at 4 ℃ for 24 hours. After 6 days of standing at normal temperature, the microscope particle size of group 13-15 increased slightly to 70-80 μm, but the appearance of the suspension still appeared as a milky suspension; the results of the observations and measurements of groups 2-12 were substantially the same as those after 1 day of standing at ambient temperature, and the particle size of the crystals in the suspension remained substantially unchanged over this longer period of time. Again, group 2-group 15 were microscopically observed and still form a lamotrigine hydrate was found in suspension. All suspensions of groups 2 to 15 showed excellent uniformity and stability after 6 days of standing at normal temperature. More than 95% of the lamotrigine in the suspension is present in the form of lamotrigine hydrate form a. Finally, groups 2-15 also met the antimicrobial effect according to USP <51 >.

At pH 4.5, the suspensions of group 1 had begun to appear non-uniform after 24 hours at 4 ℃ and had significant massive crystallization observed with the naked eye, severely affecting the uniformity of the suspension. After 6 days of standing at normal temperature, the large blocks are more crystallized. Excessive crystallization can affect the uniformity of the drug upon administration, ultimately leading to inaccurate dosing.

Fig. 4 shows photomicrographs of lamotrigine hydrate form a of several representative groups in table 7. Fig. 4 a illustrates a photomicrograph of lamotrigine hydrate form a of group 2 of table 7 showing that lamotrigine hydrate form a exhibits melon seed shape under a microscope at pH 4.6. Fig. 4B shows a photomicrograph of lamotrigine hydrate form a of group 7 of table 7, showing that as pH increases to 5.3, lamotrigine hydrate form a starts to take on a short prism-like and melon seed-like mixed shape under the microscope. Fig. 4C shows a photomicrograph of lamotrigine hydrate form a of group 14 in table 7 showing that lamotrigine hydrate form a exhibits short prisms under the microscope as the pH continues to increase to 6.8. The particle states under the two microscopes, namely the short prism shape and the melon seed shape, have no influence on the crystal form, are both the A crystal form, and can keep a stable form for a certain time.

The above results suggest that the pH has an effect on the stability of the suspension of the solution. At a pH below 4.6, the starting particle size of the lamotrigine particle size D90 of 8 μm does not form a uniform, stable suspension. In the pH range of 4.6-6.85, when the lamotrigine particle diameter D90 is less than 8 μm, the suspension can be kept uniform and stable for at least one week at normal temperature.

Notably, a pH in the range of 4.6-5.6 is particularly advantageous for the particle size of lamotrigine hydrate form a. Within this pH range, lamotrigine hydrate form A not only initially exhibits a microscopic particle size of 20-30 μm, but also remains unchanged after standing at room temperature over a period of time. When the pH is greater than 5.6, for example at a pH of 5.9-6.9, a small increase in the microscopic particle size of lamotrigine hydrate form a occurs over time. This suggests that the pH range of 4.6-5.6 is particularly advantageous for particle size stability as well as crystal form stability, which is important for the suspension to remain homogeneous and stable over a longer period of time.

EXAMPLE 8 preparation of lamotrigine hydrate form A-containing suspension Using different pH and D90 starting particle size of greater than 8 μm

Suspensions were prepared according to the components of each experimental group shown in table 8 below and their content (in parts by weight) to observe the appearance of suspensions prepared from lamotrigine particles of different D90 particle sizes at different pH values and the microscopic particle sizes of the particles in the suspensions.

All of the components of each group shown in Table 8 were placed in a suitably sized hopper, mixed at 20 rpm for 5 minutes, then passed through a 475 micron screen, and then placed in the hopper for further mixing for 10 minutes to give a dry suspension that could be further used. The dry suspension is compounded into a suspension before administration. The crystalline forms in suspension were examined at different time points as follows: appearance, microscopic particle size, XRPD crystalline form observation and determination.

TABLE 8

Group of	1	2	3	4	5	6
							pH of the system	5.5	5.8	6.5	6.5	6.85	6.8
D90 particle diameter (μm)	12.42	12.15	12	12.42	12.42	35
							Lamotrigine particles	10	10	10	10	10	10
Mannitol (mannitol)	20	20	20	20	20	20
							Xanthan gum	3	3	3	3	3	3
Sucralose	1	1	1	1	1	1
							Citric acid	2.5	2.5	2.5	2.5	---	---
Disodium hydrogen phosphate	2.3	3	5.5	5.5	---	---
							Sodium dihydrogen phosphate	-	-	---	-	3	3
Sodium methylparaben	2	2	2	2	2	2
							Sodium propylparaben	0.2	0.2	0.2	0.2	0.22	0.2
Potassium sorbate			---			---
							Sodium benzoate	---	---	---	---	---	---

After the suspensions of groups 2 to 5 were left at 4℃for 24 hours in the pH range 5.8 to 6.85, the appearance was a milky suspension, and the lamotrigine hydrate form A was contained in the suspension as determined by microscopic determination, and the particle size was in the range 20 to 40. Mu.m (group 2: microscopic particle size 30 to 40. Mu.m, group 3: microscopic particle size 20 to 30. Mu.m, group 4: microscopic particle size 20 to 30. Mu.m, and group 5: microscopic particle size 20 to 30. Mu.m). After further standing at normal temperature for 1 day, the suspensions of groups 2 to 5 still show a milky suspension in appearance, and again, the lamotrigine hydrate form A in the suspension is found by observation with a microscope. When the suspension is left for 6 days at normal temperature, the appearance of the suspension is unchanged, and the particle size is basically the same as that of the suspension after being left for 1 day at normal temperature. More than 95% of the lamotrigine in the suspension is present in the form of lamotrigine hydrate form a. This suggests that the pH range of 5.8-6.85 is advantageous for particle size stability and crystal form stability. Furthermore, when the D90 particle size of lamotrigine particles is about 12 μm, the microscopic particle size of lamotrigine hydrate form a decreases with increasing pH in the overall trend in the range of ph=5.8-6.85. Finally, groups 2-5 also met the antimicrobial effect according to USP <51 >.

From the above results, it was also found that when the D90 starting particle diameter of more than 8 μm was used, the suspension of group 1 (pH of less than 5.8) was left at 4℃for 24 hours, and it was observed that large-sized crystal agglomerates had appeared, and the agglomerates could not be dispersed any more, seriously affecting the uniformity of the suspension. After 6 days of standing at normal temperature, the large blocks are more crystallized.

From the above results, it was also found that when an excessively large D90 starting particle diameter was used, for example, when a D90 starting particle diameter of 35 μm was used for group 6, at a pH range of 6.8, the suspension was visually observed to have exhibited an uneven appearance after 24 hours at 4 ℃.

The above results suggest that the pH has an effect on the stability of the suspension of the solution and that the range of pH values for which different D90 starting particle sizes are suitable is different. When the lamotrigine particle size D90 has an initial particle size of about 12 μm, the suspension is maintained at a uniform, stable pH above 5.8. The suspension is uniform and stable over at least one week at ambient temperature in the pH range of 5.8-6.85 when the lamotrigine particle size D90 has a starting particle size of about 12 μm.

It is expected that the pH of the suspension will also affect the uniformity and stability of the lamotrigine particle size D90 suspension starting at a particle size of 8 μm to 12. Mu.m.

Example 9

10 parts by weight of lamotrigine particles with the particle size (D90) of 12 mu m and 7 parts by weight of xanthan gum are added into 1000 parts by weight of purified water to be uniformly dispersed, and the mixture is placed at the temperature of 4 ℃ for 24 hours, so that a suspension containing lamotrigine hydrate form A is obtained. Filtering the suspension to obtain lamotrigine hydrate form A.

XRPD analysis was performed on lamotrigine hydrate form a obtained. The XRPD pattern of lamotrigine hydrate form a presents a series of characteristic peaks at diffraction angles (2θ) of 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees. There is no characteristic peak at the diffraction angle (2θ) of 15.9±0.2 degrees.

XRPD quantitative analysis was performed on lamotrigine hydrate form a obtained. Selection of Al ₂ O ₃ As a standard substance, the XRPD measurement equipment is Bruker D8 advance, voltage is 40kV, current is 40mA, step size: 0.02 degree, scan speed: the lamotrigine hydrate form a was found to have a purity of 87.2% (w/w) at 0.1 seconds/step.

Example 10

10 parts by weight of lamotrigine particles with the particle size (D90) of 8 mu m and 3 parts by weight of povidone are added into 1000 parts by weight of purified water to be uniformly dispersed, and the mixture is placed at 20 ℃ for 2 hours, so that a suspension containing lamotrigine hydrate form A is obtained. Filtering the suspension to obtain lamotrigine hydrate form A.

XRPD analysis was performed on lamotrigine hydrate form a obtained. The XRPD pattern of lamotrigine hydrate form a presents a series of characteristic peaks at diffraction angles (2θ) of 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees. There are no characteristic peaks at diffraction angles (2θ) of 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees.

The lamotrigine hydrate form a has a short prismatic appearance under the microscope.

For the lamotrigine obtainedThe hydrate form a was subjected to XRPD quantitative analysis. Selection of Al ₂ O ₃ As a standard substance, the XRPD measurement equipment is Bruker D8 advance, voltage is 40kV, current is 40mA, step size: 0.02 degree, scan speed: 0.1 seconds/step, the lamotrigine hydrate form A was measured to have a purity of 91.4% (w/w).

Example 11

10 parts by weight of lamotrigine particles with the particle size (D90) of 8 mu m and 3 parts by weight of xanthan gum are added into 1000 parts by weight of purified water to be uniformly dispersed, and the mixture is placed at the temperature of 4 ℃ for 24 hours, so that a suspension containing lamotrigine hydrate form A is obtained. Filtering the suspension to obtain lamotrigine hydrate form A.

XRPD analysis was performed on lamotrigine hydrate form a obtained. The XRPD pattern of lamotrigine hydrate form a presents a series of characteristic peaks at diffraction angles (2θ) of 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees. There are no characteristic peaks at diffraction angles (2θ) of 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees.

XRPD quantitative analysis was performed on lamotrigine hydrate form a obtained. Selection of Al ₂ O ₃ As a standard substance, the XRPD measurement equipment is Bruker D8 advance, voltage is 40kV, current is 40mV, step size: 0.02 degree, scan speed: 0.1 seconds/step, the lamotrigine hydrate form A was found to have a purity of 97.7% (w/w). The XRPD patterns are shown in FIG. 1. The microscope appearance is shown in FIG. 2.

EXAMPLE 12 suspension

10 parts by weight of lamotrigine particles having a particle diameter (D90) of 8 μm, 5 parts by weight of xanthan gum, 20 parts by weight of mannitol (purchased from Roget Corp., france), 1 part by weight of sucralose (purchased from Merck, germany), 2 parts by weight of sodium dihydrogen phosphate (purchased from St. Full Co., USA) and 1 part by weight of sodium oxybenzoate (purchased from St. Full Co., USA) were added to 5000 parts by weight of purified water to be dispersed uniformly, and left at 20℃for 30 minutes, to obtain a suspension containing lamotrigine hydrate form A. The suspension is a lamotrigine hydrate form a-containing suspension for use by a patient.

EXAMPLE 13 Dry suspension

10 parts by weight of lamotrigine particles having a particle size (D90) of 30 μm, 3 parts by weight of xanthan gum, 20 parts by weight of mannitol, 1 part by weight of sucralose, 2 parts by weight of sodium dihydrogen phosphate and 2 parts by weight of a combination of sodium methylparaben and sodium propylparaben, wherein the weight ratio of sodium methylparaben and sodium propylparaben is 9:1, were each passed through a 1016 μm sieve, and then all placed in a hopper of suitable size and mixed at a speed of 20 revolutions per minute for 10 minutes. And obtaining the dry suspension which can be further applied.

Before the patient uses the medicine, the dry suspension is added into purified water for compounding. Adding the dry suspension into purified water, shaking manually, dispersing uniformly, and standing at 4deg.C for 24 hr to obtain lamotrigine hydrate form A suspension for patients.

Example 14

The components of the recipe shown in Table 7 were each passed through a 1016 micron screen and then all placed in a suitably sized hopper and mixed at 20 revolutions per minute for 10 minutes. And obtaining the dry suspension which can be further applied. Before the patient uses the medicine, the dry suspension is added into purified water for compounding. Adding the dry suspension into purified water, shaking manually, dispersing uniformly, and standing at 4deg.C for 24 hr to obtain lamotrigine hydrate form A suspension for patients.

More than 95% of the lamotrigine in the suspension is present as lamotrigine hydrate form a.

TABLE 7

EXAMPLE 15 tablet

10 parts by weight of lamotrigine hydrate form A and 30 parts by weight of microcrystalline cellulose were each passed through a 1016 micron screen, and then all placed in a suitably sized hopper and mixed at 20 revolutions per minute for 10 minutes. The mixed material was placed in a tablet press to obtain lamotrigine hydrate form a-containing tablets for patient use at a tablet speed of 20rpm and a hardness of 80N. The tablet specification was 100mg. The tablet can be used for treating nervous system diseases.

EXAMPLE 16 Capsule

10 parts by weight of lamotrigine hydrate form A, 10 parts by weight of oxcarbazepine, 3 parts by weight of xanthan gum, 30 parts by weight of lactose, were each passed through a 1016 micron sieve, and then all placed in a suitably sized hopper and mixed at a speed of 20 revolutions per minute for 10 minutes. The mixed materials were placed in a wet granulator, and water was added at a shear rate of 200rpm and a stirring rate of 200rpm to prepare wet granules. The wet granules are granulated and dried at 40 ℃ by a fluidized bed to obtain dry granules, and then the dry granules are screened by a 1016 micron screen to obtain the preparation granules. After filling the granules into a 1# capsule with a capsule filling machine, a capsule containing lamotrigine hydrate form a for use by a patient is obtained. The capsule can be used for treating epilepsy.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention, it being understood that variations and modifications can be made by those skilled in the art without departing from the spirit of the invention, which is therefore intended to be covered by the appended claims.

Technical scheme set

Technical scheme group a:

1. a pharmaceutical composition comprising a therapeutically effective amount of lamotrigine particles and one or more pharmaceutically acceptable excipients, wherein the lamotrigine particles have a particle size (D90) of 1-30 μm and the excipients comprise a thickener and a pH adjuster in an amount such that the pH of the resulting suspension is 4.6-6.9 after mixing the pharmaceutical composition with an aqueous phase.

2. The pharmaceutical composition according to 1, wherein the pharmaceutical composition is a dry suspension.

3. The pharmaceutical composition according to claims 1-2, wherein the pH adjusting agent is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; and/or

Wherein the pH adjustor is about 0.5 to 8 parts by weight based on about 10 parts by weight of the lamotrigine particles.

4. The pharmaceutical composition of any one of claims 1-3, wherein more than about 80%, 85%, 90% or 95% of the lamotrigine is present as lamotrigine hydrate form a when the pharmaceutical composition is mixed with water to form a suspension; and/or

When the pharmaceutical composition is mixed with water to form a suspension, the lamotrigine hydrate form a in the suspension has a particle size of 20-80 μm.

5. The pharmaceutical composition of claim 4, wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; and/or the number of the groups of groups,

the XRPD pattern of lamotrigine hydrate form a has no characteristic peaks at diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; or alternatively

Wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2θ) substantially the same as shown in figure 1; or alternatively

Wherein the XRPD peak locations of the XRPD pattern of lamotrigine hydrate form a are substantially the same as shown in figure 1; or alternatively

Wherein the XRPD peak locations of the XRPD pattern of lamotrigine hydrate form a are the same as shown in figure 1.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the lamotrigine particles have a particle size (D90) of about 4.5-8 μm and the amount of the pH adjusting agent is such that the pH of the suspension is about 4.6-6.9; and/or about 0.5 to 5.1 parts by weight of the pH adjuster based on about 10 parts by weight of the lamotrigine particles; and/or the number of the groups of groups,

The pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid and sodium citrate.

7. The pharmaceutical composition according to any one of claims 1-5, wherein the lamotrigine particles have a particle size (D90) of about 12-13 μm and the amount of the pH adjusting agent is such that the pH of the suspension is about 5.8-6.9; and/or about 3-8 parts by weight of the pH adjuster based on about 10 parts by weight of the lamotrigine particles; and/or the number of the groups of groups,

8. The pharmaceutical composition according to any one of claims 1-7, wherein the thickener is selected from the group consisting of hydrocolloids, such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

optionally, the thickener is selected from xanthan gum, povidone, colloidal microcrystalline cellulose, sodium alginate, and combinations thereof;

Optionally, the thickener is xanthan gum; and/or

The thickener is present in an amount of about 1 to 7 parts by weight based on about 10 parts by weight of the lamotrigine particles.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition further comprises a preservative;

optionally, the preservative is one or a combination of more of sodium propyl hydroxybenzoate, sodium methylparaben, sodium benzoate and potassium sorbate;

optionally, wherein the preservative is about 1-3 parts by weight based on about 10 parts by weight of the lamotrigine particles.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition further comprises a filler;

optionally, wherein the filler is one or more of mannitol, microcrystalline cellulose, sucrose, lactose;

optionally, wherein the filler is about 20-60 parts by weight based on about 10 parts by weight of the lamotrigine particles.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the pharmaceutical composition further comprises a sweetener;

optionally, wherein the sweetener is one or more of sucralose, aspartame, sodium saccharin;

Optionally, wherein the sweetener is about 1-3 parts by weight based on about 10 parts by weight of the lamotrigine particles.

12. The pharmaceutical composition according to any one of claims 1-11, wherein the pharmaceutical composition further comprises a preservative, a sweetener, and a filler;

optionally, the preservative is one or a combination of more of sodium propyl hydroxybenzoate, sodium methylparaben, sodium benzoate and potassium sorbate; and/or wherein the preservative is about 1 to 3 parts by weight based on about 10 parts by weight of the lamotrigine particles;

optionally, wherein the filler is one or more of mannitol, microcrystalline cellulose, sucrose, lactose; and/or wherein the filler is about 20 to 60 parts by weight based on about 10 parts by weight of the lamotrigine particles;

optionally, wherein the sweetener is one or more of sucralose, aspartame, sodium saccharin; and/or wherein the sweetener is about 1 to 3 parts by weight based on about 10 parts by weight of the lamotrigine particles.

13. The pharmaceutical composition according to any one of claims 1-12, wherein the lamotrigine particles have a particle size (D90) of 4.5 μm or 8 μm, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

14. The pharmaceutical composition according to any one of claims 1-13, which may further comprise a medicament for other neurological diseases; optionally, the other drug is selected from one or more of oxcarbazepine (oxcarbazpin), carbamazepine (carbamazepin), phenytoin (phtin), valproic acid (valproic acid), ethosuximide (thospormid), febrile amine (flbamate), gabapentin (gabapntin), levetiracetam (lvtiractam), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbital), zonisamide (zonisamid), clonazepam (clonazepam), phenytoin sodium (phtomin), valproate (valproat), clobazam (clobazam), vigabatrin (topiramate) and lacamamide (lacamide).

15. The pharmaceutical composition according to any one of claims 1-13, the suitable lamotrigine particle size (D90) being selected to provide a lamotrigine hydrate form a having in suspension a range of particle size increases selected from the group consisting of: the particle size increases by less than 150%, less than 100%, less than 80%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

16. A suspension prepared from the pharmaceutical composition according to any one of claims 1-15, comprising mixing the pharmaceutical composition according to any one of claims 1-14 with an aqueous phase.

Technical scheme group B:

1. a pharmaceutical composition comprising a therapeutically effective amount of lamotrigine particles and one or more pharmaceutically acceptable carriers, wherein the size of the lamotrigine particles (D90) is selected such that the lamotrigine particles reconstitute in an aqueous phase to provide lamotrigine hydrate form a having a particle size in one or more ranges selected from the group consisting of: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm;

and wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.0±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees, or the XRPD pattern of lamotrigine hydrate form a has no characteristic peaks at diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; or alternatively

The XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2θ) substantially the same as shown in figure 1; or alternatively

The XRPD pattern of lamotrigine hydrate form a is substantially the same as shown in figure 1.

2. The pharmaceutical composition according to claim 1, wherein the lamotrigine particles have a particle size (D90) selected from one or more of the following: 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (90D) consisting of any two of the foregoing particle sizes (D90); for example 6-14 μm, 8-12 μm, 8-10 μm, 7-9 μm, 8-9 μm, 10-12 μm, 11-12 μm or 11-13 μm.

3. The pharmaceutical composition according to claim 1 or 2, further comprising a pH adjuster, wherein the suitable pH adjuster (type and/or content) is selected to control such that the suspension of lamotrigine particles after reconstitution in the aqueous phase has a pH selected from one or more of the following: 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85 and 6.9, and a pH range consisting of any two of the foregoing pH values, for example: 4.0-7.0, 4.2-6.8, 4.4-6.8, 4.6-6.6, 4.6-6.4, 4.6-6.2, 4.6-6.0, 4.6-5.8, 4.6-5.6, 4.6-5.4, 4.8-5.2, 5.0-6.8, 5.2-6.8, 5.4-6.8, 5.6-6.8, 5.8-6.8, 6.0-6.6, 6.8-6.6, 5.8-6.4, or 6.0-6.4;

Optionally, a suitable pH adjuster (type and/or content) is selected to control such that the lamotrigine particles are reconstituted in the aqueous phase to provide lamotrigine hydrate form a having a particle size in one or more ranges selected from the group consisting of: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm;

optionally, a suitable pH-adjusting agent (type and/or content) is selected to control such that the suspension of lamotrigine particles reconstituted in the aqueous phase has a stability as defined by a-4.

4. A pharmaceutical composition according to any one of claims 1-3, the appropriate pH modifier (type and/or content) being selected to provide that lamotrigine hydrate form a has a range of particle size increases selected from the group consisting of: the particle size increase is less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

5. The pharmaceutical composition according to any one of claims 1-4, the suitable lamotrigine particle size (D90) being selected to provide a lamotrigine hydrate form a having in suspension a range of particle size increases selected from the group consisting of: the particle size increases by less than 150%, less than 100%, less than 80%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

6. The method according to claims 1-5 further comprising a preservative, wherein the preservative provides antimicrobial stability for at least one week, at least two weeks, at least three weeks, at least one month, at least two months, or at least three months according to an acceptance criteria specified by USP <51 >; optionally, the acceptance criteria specified by USP <51> are:

Technical scheme group C:

1. a pharmaceutical composition comprising a therapeutically effective amount of lamotrigine particles and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition forms a suspension comprising lamotrigine hydrate form a after reconstitution in an aqueous phase, the particle size (D90) of the lamotrigine particles being such that the particle size of lamotrigine hydrate form a in the suspension is at least one selected from the group consisting of: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm, and

The auxiliary material comprises a thickening agent and a pH regulator, wherein the pH regulator is used for enabling the pH of the obtained suspension to be 4.6-6.9 after the pharmaceutical composition is mixed with water.

2. The pharmaceutical composition according to claim 1, wherein the pH adjuster is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; and/or

Wherein the pH regulator is 0.5 to 8 parts by weight based on 10 parts by weight of the lamotrigine particles.

3. The pharmaceutical composition of any one of claims 1-2, wherein more than 80%, 85%, 90% or 95% of the lamotrigine is present as lamotrigine hydrate form a when the pharmaceutical composition is mixed with water to form a suspension.

4. The pharmaceutical composition of any one of claims 1-3, wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; and/or the number of the groups of groups,

5. The pharmaceutical composition according to any one of claims 1-4, wherein the lamotrigine particles have a particle size (D90) such that the lamotrigine hydrate form a in the suspension has a particle size of 20-60 μm and the amount of the pH adjusting agent is such that the pH of the resulting suspension is 4.6-6.9 after mixing the pharmaceutical composition with an aqueous phase; optionally, the lamotrigine particles have a particle size (D90) of 4.5-8 μm.

6. The pharmaceutical composition according to claim 5, wherein the pH adjuster is 0.5 to 5.1 parts by weight based on 10 parts by weight of the lamotrigine particles; and/or the pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid and sodium citrate.

7. The pharmaceutical composition according to any one of claims 1-4, wherein the lamotrigine particles have a particle size (D90) such that the lamotrigine hydrate form a in the suspension has a particle size of 20-40 μm and the amount of the pH adjusting agent is such that the pH of the resulting suspension is 5.8-6.9 after mixing the pharmaceutical composition with an aqueous phase; optionally, the lamotrigine particles have a particle size (D90) of 12-13 μm.

8. The pharmaceutical composition according to claim 7, wherein the pH adjuster is 3-8 parts by weight based on 10 parts by weight of the lamotrigine particles; and/or the pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid and sodium citrate.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the lamotrigine hydrate form a has a particle size of the suspension after 24 hours at 4 ℃.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the thickener is selected from the group consisting of hydrocolloids, such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

optionally, the thickener is xanthan gum; and/or

The thickener is 1 to 7 parts by weight based on 10 parts by weight of the lamotrigine particles.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the pharmaceutical composition further comprises a preservative;

optionally, wherein the preservative is 1-3 parts by weight based on 10 parts by weight of the lamotrigine particles.

12. The pharmaceutical composition according to any one of claims 1-11, wherein the pharmaceutical composition further comprises a filler;

optionally, wherein the filler is 20-60 parts by weight based on 10 parts by weight of the lamotrigine particles.

13. The pharmaceutical composition according to any one of claims 1-12, wherein the pharmaceutical composition further comprises a sweetener;

optionally, wherein the sweetener is 1-3 parts by weight based on 10 parts by weight of the lamotrigine particles.

14. The pharmaceutical composition according to any one of claims 1-13, wherein the pharmaceutical composition further comprises a preservative, a sweetener, and a filler;

Optionally, the preservative is one or a combination of more of sodium propyl hydroxybenzoate, sodium methylparaben, sodium benzoate and potassium sorbate; and/or wherein the preservative is about 1 to 3 parts by weight based on 10 parts by weight of the lamotrigine particles;

optionally, wherein the filler is one or more of mannitol, microcrystalline cellulose, sucrose, lactose; and/or wherein the filler is about 20 to 60 parts by weight based on 10 parts by weight of the lamotrigine particles;

optionally, wherein the sweetener is one or more of sucralose, aspartame, sodium saccharin; and/or wherein the sweetener is about 1 to 3 parts by weight based on 10 parts by weight of the lamotrigine particles.

15. The pharmaceutical composition according to any one of claims 1-14, wherein the lamotrigine particles have a particle size (D90) of 4.5 μm or 8 μm and lamotrigine hydrate form a in the suspension has a particle size of 20-30 μm, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

16. The pharmaceutical composition according to any one of claims 1-15, which may further comprise a medicament for other neurological diseases; optionally, the other drug is selected from one or more of oxcarbazepine (oxcarbazpin), carbamazepine (carbamazepin), phenytoin (phtin), valproic acid (valproic acid), ethosuximide (thospormid), febrile amine (flbamate), gabapentin (gabapntin), levetiracetam (lvtiractam), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbital), zonisamide (zonisamid), clonazepam (clonazepam), phenytoin sodium (phtomin), valproate (valproat), clobazam (clobazam), vigabatrin (topiramate) and lacamamide (lacamide).

Technical scheme group D:

1. a suspension comprising lamotrigine hydrate form a, the suspension comprising lamotrigine hydrate form a, a thickener, and a pH adjuster, wherein the particle size of lamotrigine hydrate form a in the suspension is at least one selected from the group consisting of: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm, and the pH regulator provides the suspension with a pH of 4.6-6.9.

2. The suspension according to claim 1, wherein the pH adjuster is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; and/or

3. The suspension of any one of claims 1-2, wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; and/or the number of the groups of groups,

4. A suspension according to any one of claims 1-3, wherein the lamotrigine hydrate form a is formed from lamotrigine particles having a particle size (D90) of 4.5-8 μm and the amount of the pH adjusting agent is such that the pH of the suspension is 4.6-6.9; and/or the number of the groups of groups,

based on 10 parts by weight of the lamotrigine particles, 0.5-5.1 parts by weight of the pH regulator; and/or the number of the groups of groups,

5. A suspension according to any one of claims 1-3, wherein the lamotrigine hydrate form a is formed from lamotrigine particles having a particle size (D90) of 12-13 μm and the amount of the pH adjusting agent is such that the pH of the suspension is 5.8-6.9; and/or the number of the groups of groups,

3-8 parts by weight of the pH regulator based on 10 parts by weight of the lamotrigine particles; and/or the number of the groups of groups,

6. The suspension of any one of claims 1-5, wherein more than 80%, 85%, 90% or 95% of the lamotrigine in the suspension is present in the form of lamotrigine hydrate form a.

7. The suspension according to any one of claims 1-6, wherein the thickener is selected from the group consisting of hydrocolloids, such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

optionally, the thickener is xanthan gum; and/or

8. The suspension of any one of claims 1-7, further comprising a preservative;

9. The suspension of any one of claims 1-8, further comprising a filler;

10. The suspension of any one of claims 1-9, further comprising a sweetener;

11. The suspension of any one of claims 1-10, further comprising a preservative, sweetener, and filler;

12. The suspension according to any one of claims 1-11, wherein the suspension remains homogeneous, stable for at least 24 hours at low or room temperature.

13. The suspension according to any one of claims 1-12, wherein the lamotrigine particles have a particle size (D90) of 4.5 μιη or 8 μιη and lamotrigine hydrate form a in the suspension has a particle size of 20-30 μιη, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

14. The suspension according to any one of claims 1-13, wherein the suspension is applicable as a suspension.

15. Suspension according to any one of claims 1-14, the suitable pH modifier (type and/or content) being selected to provide a pH range such that lamotrigine hydrate form a has an increase in particle size selected from the group consisting of: the particle size increase is less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

16. The suspension of any one of claims 1-14, lamotrigine hydrate form a having a range of particle size increases in the suspension selected from the group consisting of: the particle size increases by less than 150%, less than 100%, less than 80%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

Technical scheme group E:

1. a suspension comprising

(a) Lamotrigine hydrate form a having a particle size in one or more ranges selected from the group consisting of: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm;

(b) A pH adjuster, wherein the pH adjuster causes the suspension to have a pH selected from one or more of: 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85 and 6.9, and a pH range consisting of any two of the foregoing pH values.

2 the suspension according to claim 1, wherein the particle size (D90) is in the range of 8-10, 7-9, 7-8 or 8-9 μm, while the suitable pH modifier (type and/or content) is selected such that the suspension has a pH:4.6-6.8, 4.8-6.2, 4.8-6.0, 4.8-5.8 or 4.6-5.6.

3 the suspension according to claim 1, wherein the particle size (D90) is between 10-12, 11-13, 11-12 or 12-13 μm, while the suitable pH modifier (type and/or content) is selected such that the suspension has a pH:5.6-6.8, 5.8-6.6, 6.0-6.8 or 6.0-6.6.

4. The suspension of any one of claims 1-3, wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; and/or the number of the groups of groups,

5. The suspension according to any one of claims 1-4, wherein the lamotrigine particles have a particle size (D90) of 4.5-8 μm and the amount of the pH modifier is such that the dry suspension, after mixing with the aqueous phase, results in a suspension having a pH of 4.6-6.9; and/or the number of the groups of groups,

6. The suspension according to any one of claims 1-4, wherein the lamotrigine particles have a particle size (D90) of 12-13 μm and the amount of the pH modifier is such that the dry suspension, after mixing with an aqueous phase, results in a suspension having a pH of 5.8-6.9; and/or the number of the groups of groups,

7. The suspension according to any one of claims 1-6, wherein the suspension further comprises a thickener selected from the group consisting of hydrocolloids, such as xanthan gum, guar gum, locust bean gum, and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

optionally, the thickener is xanthan gum; and/or

8. The suspension of any one of claims 1-7, wherein the suspension further comprises a combination of lamotrigine particles, a thickener, a pH adjustor, and a preservative;

9. The suspension of any one of claims 1-8, wherein the suspension further comprises a combination of lamotrigine particles, a thickener, a pH adjustor, and a filler;

10. The suspension of any one of claims 1-9, wherein the suspension further comprises a combination of lamotrigine particles, a thickener, a pH adjustor, and a sweetener;

11. The suspension of any one of claims 1-10, wherein the suspension further comprises a combination of lamotrigine particles, a thickener, a pH adjustor, a preservative, a sweetener, and a filler;

12. The suspension according to any one of claims 1-11, wherein the lamotrigine particles have a particle size (D90) of 4.5 μιη or 8 μιη, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

Technical scheme group F:

1. a method of preparing a dry suspension of lamotrigine, wherein the method comprises the steps of: mixing lamotrigine particles having a particle diameter (D90) of 1-30 μm, a thickener, and a pH adjuster

The amount of the pH regulator is such that the pH of the suspension obtained after mixing the dry suspension with the water phase is 4.6-6.9.

2. The method according to claim 1, wherein the pH adjuster is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; and/or

3. The method of any one of claims 1-2, wherein more than 80%, 85%, 90% or 95% of the lamotrigine is present as lamotrigine hydrate form a when the dry suspension is mixed with water to form a suspension; and/or

When the dry suspension is mixed with water to form a suspension, the lamotrigine hydrate form A in the suspension has a particle size of 20-80 μm.

4. The method of claim 3, wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; and/or the number of the groups of groups,

5. The process according to any one of claims 1 to 4, wherein the lamotrigine particles have a particle size (D90) of 4.5 to 8 μm and the amount of the pH adjuster is such that the dry suspension, after mixing with the aqueous phase, results in a suspension having a pH of 4.6 to 6.9; and/or the number of the groups of groups,

6. The process according to any one of claims 1 to 4, wherein the lamotrigine particles have a particle size (D90) of 12 to 13 μm and the amount of the pH adjuster is such that the dry suspension, after mixing with the aqueous phase, results in a suspension having a pH of 5.8 to 6.9; and/or the number of the groups of groups,

7. The method according to any one of claims 1-6, wherein the thickener is selected from the group consisting of hydrocolloids, such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

optionally, the thickener is xanthan gum; and/or

8. The method of any one of claims 1-7, further comprising mixing lamotrigine particles, a thickener, and a pH adjuster together with a preservative;

9. The method of any one of claims 1-8, further comprising mixing lamotrigine particles, a thickener, and a pH adjuster together with a filler;

10. The method of any one of claims 1-9, further comprising mixing the lamotrigine particles, the thickener, and the pH adjustor with a sweetener;

11. The method of any one of claims 1-10, further comprising mixing lamotrigine particles, a thickener, a pH adjuster, and a preservative, sweetener, and filler together;

12. The process of any one of claims 1-11, wherein the lamotrigine particles have a particle size (D90) of 4.5 μιη or 8 μιη, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

13. A dry suspension prepared according to the method of any one of claims 1-12.

Technical scheme group G:

1. a process for preparing a suspension comprising lamotrigine hydrate form a, the process comprising the steps of:

3. The method of any one of claims 1-2, wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2Θ) of about 11.5±0.2, 13.4±0.2, 15.3±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2Θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; and/or the number of the groups of groups,

4. A process according to any one of claims 1 to 3, wherein the lamotrigine particles have a particle size (D90) of 4.5 to 8 μm and the amount of the pH adjuster is such that the pH of the suspension is 4.6 to 6.9; and/or the number of the groups of groups,

5. A process according to any one of claims 1 to 3, wherein the lamotrigine particles have a particle size (D90) of 12 to 13 μm and the amount of the pH adjuster is such that the pH of the suspension is 5.8 to 6.9; and/or the number of the groups of groups,

6. The method of any one of claims 1-5, wherein more than 80%, 85%, 90% or 95% of the lamotrigine in the suspension is present as lamotrigine hydrate form a; and/or

The lamotrigine hydrate form a in the suspension has a particle size of 20-80 μm.

optionally, the thickener is xanthan gum; and/or

8. The method of any one of claims 1-7, further comprising mixing the lamotrigine particles, the thickener, and the pH adjustor with the preservative, adding to the aqueous phase, or mixing the lamotrigine particles and the thickener with the aqueous phase comprising the pH adjustor and the preservative;

9. The process of any one of claims 1-8, further comprising mixing the lamotrigine particles, the thickener, and the pH adjuster with the filler, adding to the aqueous phase, or mixing the lamotrigine particles and the thickener with the aqueous phase comprising the pH adjuster and the filler;

10. The method of any one of claims 1-9, further comprising mixing the lamotrigine particles, the thickener, and the pH adjuster together with a sweetener, adding to the aqueous phase, or mixing the lamotrigine particles and the thickener with an aqueous phase comprising the pH adjuster and the sweetener;

11. The method of any one of claims 1-10, further comprising mixing the lamotrigine particles, the thickener, the pH adjuster with the preservative, the sweetener, and the filler, adding to the aqueous phase, or mixing the lamotrigine particles and the thickener with the aqueous phase comprising the pH adjuster, the preservative, the sweetener, and the filler;

12. The method according to any one of claims 1-11, wherein the uniform dispersion is achieved by mechanical stirring, magnetic stirring and/or manual shaking for about 1-120 minutes.

13. The method of any one of claims 1-12, wherein the low temperature is less than about 25 ℃;

preferably, the time of the incubation at low temperature is at least about 30 minutes.

14. The method of any one of claims 1-13, wherein the interval between uniform dispersion and placement at low temperature is at most about 12 hours.

15. The process of any one of claims 1-14, wherein the lamotrigine particles have a particle size (D90) of 4.5 μιη or 8 μιη and lamotrigine hydrate form a in the suspension has a particle size of 20-30 μιη, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

16. A suspension prepared according to the method of any one of claims 1-15.

17. The method of any one of claims 1-16, wherein the suspension is applicable as a suspension.

18. The process of any one of claims 1-17, further comprising filtering the suspension to obtain the lamotrigine hydrate form a; optionally, the method further comprises washing the crystals with water during filtration to remove the thickener adhering to the crystals.

19. Suspension according to any one of claims 1-18, the suitable pH modifier (type and/or content) being selected to provide a pH range such that lamotrigine hydrate form a has an increase in particle size selected from the group consisting of: the particle size increase is less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

20. The suspension according to any one of claims 1-19, the lamotrigine water particle size (D90) being selected to provide a lamotrigine hydrate form a having a range of particle size increases in the suspension selected from the group consisting of: the particle size increases by less than 150%, less than 100%, less than 80%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5% over a range of about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks.

Technical scheme group H:

1. a process for preparing a suspension comprising lamotrigine hydrate form a, wherein the lamotrigine hydrate form a has a particle size selected from the group consisting of: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm,

wherein the method comprises the steps of:

(a) Adding lamotrigine particles and a thickener to the aqueous phase, wherein the particle size (D90) of the lamotrigine particles is selected from one or more of the following: 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.3 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.9 μm and 8.0 μm, and a particle size range (90D) consisting of any two of the foregoing particle sizes (D90); and

(b) Uniformly dispersing lamotrigine particles having the particle diameter (D90) and a thickener in an aqueous phase; the aqueous phase is cooled to a temperature below about 25 ℃ to obtain a suspension comprising lamotrigine hydrate form a.

2. The process according to claim 1, further comprising adding a pH adjuster, wherein the suitable pH adjuster (type and/or content) is selected to control such that the suspension of lamotrigine particles after reconstitution in the aqueous phase has a pH selected from one or more of the following: 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85 and 6.9, and a pH range consisting of any two of the foregoing pH values;

optionally, a suitable pH adjuster (type and/or content) is selected to control such that the suspension of lamotrigine particles reconstituted in the aqueous phase has the stability defined by the previous scheme.

3. The method according to claim 1 or 2, further comprising adding a preservative.

4. According to the process of claims 1 to 3, the aqueous phase is cooled to a temperature of less than about 20 ℃, less than about 10 ℃, less than about 4 ℃, or less than about 0 ℃ to obtain a suspension comprising lamotrigine hydrate form a.

5. The process according to claims 1 to 4, wherein more than 80%, 85%, 90% or 95% of the lamotrigine in the suspension is present in the form of lamotrigine hydrate form a.

Technical scheme group I:

1. a process for preparing a suspension of lamotrigine hydrate form a, wherein the lamotrigine hydrate form a remains having a particle size in the range of 20-80 μm for at least one week and has an antimicrobial stability of at least one month according to USP <51>, wherein the process comprises the steps of:

(a) Adding lamotrigine particles having a particle size (D90) of 1-30 μm, a pH adjuster and a preservative to the aqueous phase; and

(b) Uniformly dispersing the lamotrigine particles, a pH regulator and a preservative in an aqueous phase; the aqueous phase is cooled to a temperature below about 25 ℃ to obtain a suspension comprising lamotrigine hydrate form a.

Technical scheme group J:

1. a process for preparing a suspension comprising lamotrigine hydrate form a, the process comprising the steps of: adding lamotrigine particles and a thickener to an aqueous phase, dispersing uniformly, and standing at a low temperature to obtain the suspension comprising lamotrigine hydrate form a, wherein the lamotrigine particles have a particle size (D90) of about 1-30 μm, wherein the low temperature is below about 25 ℃; and is also provided with

Wherein the XRPD pattern of lamotrigine hydrate form a comprises characteristic peaks at diffraction angles (2θ) of about 11.5±0.2, 13.4±0.2, 15.0±0.2, 16.5±0.2, 19.2±0.2, 26.9±0.2, and 27.7±0.2 degrees, and no characteristic peaks at one or more of diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees, or the XRPD pattern of lamotrigine hydrate form a has no characteristic peak at diffraction angles (2θ) of about 15.9±0.2, 20.5±0.2, 23.5±0.2, 28.2±0.2, and 30.7±0.2 degrees; or alternatively

The XRPD pattern of lamotrigine hydrate form a is substantially the same as shown in figure 1;

alternatively, the lamotrigine hydrate form a is at least about 80%, at least about 90%, at least about 95%, or substantially pure.

2. The process according to claim 1, comprising selecting the particle size (D90) of the lamotrigine particles such that lamotrigine hydrate form a in the suspension has a particle size selected from one or more of the following ranges: 20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-80 μm, 40-70 μm, 40-60 μm, 40-50 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-80 μm, 60-70 μm and 70-80 μm.

3. A process for preparing lamotrigine hydrate form a comprising filtering the suspension of claim 1 to obtain the lamotrigine hydrate form a.

4. The method of any one of claims 1-3, wherein the lamotrigine particles have a particle size (D90) of about 4.5 to 30 μιη, about 4.5 to 20 μιη, about 8 to 12 μιη, 4.5 to 8 μιη, or 12 to 13 μιη;

alternatively, the process may be carried out in a single-stage,

wherein the pH of the suspension is 4.6-6.9, 5.8-6.9 or 5.5-6.5; or alternatively

The suspension has a pH selected from one or more of the following: 4.6, 4.7, 4.8, 4.9, 5.3, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.85 and 6.9, and a pH range consisting of any two of the foregoing pH values.

5. The method according to any one of claims 1-4, wherein the thickener is selected from the group consisting of hydrocolloids, such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

Preferably, the thickener is selected from xanthan gum, povidone, colloidal microcrystalline cellulose, sodium alginate and combinations thereof;

preferably, the thickener is xanthan gum; and is also provided with

Preferably, the thickener is about 1 to 7 parts by weight, more preferably about 1 to 5 parts by weight, based on about 10 parts by weight of the lamotrigine particles.

6. The method of any one of claims 1-5, wherein the aqueous phase is purified water or comprises purified water and one or more of a flavor, a pH adjuster, and a sweetener; and is also provided with

Preferably, the aqueous phase is about 100 to 5000 parts by weight, more preferably about 500 to 2000 parts by weight, based on about 10 parts by weight of the lamotrigine particles.

7. The method according to any one of claims 1-6, wherein the uniform dispersion is achieved by mechanical stirring, magnetic stirring and/or manual shaking for about 1-120 minutes, preferably about 3-15 minutes.

8. The method of any one of claims 1-7, wherein the low temperature is less than about 25 ℃, preferably less than about 20 ℃;

preferably, the time of the incubation at low temperature is at least about 30 minutes, more preferably at least about 2 hours.

9. The method according to any one of claims 1-8, wherein the interval between uniform dispersion and placement at low temperature is at most about 12 hours, preferably at most about 1 minute, more preferably 0.

10. The method according to any one of claims 1-9, wherein the suspension is applicable as a suspension; and is also provided with

Preferably, the method further comprises preparing the lamotrigine particles and thickener together with one or more of a filler, sweetener, pH adjuster and preservative into a dry suspension before adding to the aqueous phase;

preferably, the dry suspension is prepared by direct mixing.

11. The method of claim 10, wherein the filler is one or more of mannitol, microcrystalline cellulose, sucrose, lactose, and preferably the filler is about 20-60 parts by weight based on about 10 parts by weight of the lamotrigine particles;

the sweetener is one or more combinations of sucralose, aspartame, sodium saccharin, and preferably, the sweetener is about 1-3 parts by weight based on about 10 parts by weight of the lamotrigine particles;

the pH adjustor is one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, and preferably, the pH adjustor is about 0.5-8 parts by weight, about 0.5-5.1 parts by weight, about 3-8 parts by weight, or about 2-5 parts by weight, based on about 10 parts by weight of the lamotrigine particles; and is also provided with

The preservative is one or more of sodium propylparaben, sodium methylparaben, sodium benzoate, potassium sorbate, and preferably the preservative is about 1-3 parts by weight based on about 10 parts by weight of the lamotrigine particles.

12. The process according to any one of claims 1-11, wherein more than about 80% of the lamotrigine is present in the form of lamotrigine hydrate form a, preferably more than about 90% of the lamotrigine is present in the form of lamotrigine hydrate form a, and more preferably more than about 95% of the lamotrigine is present in the form of lamotrigine hydrate form a, and most preferably more than about 97% of the lamotrigine is present in the form of lamotrigine hydrate form a.

13. A composition comprising a suspension comprising lamotrigine hydrate form a prepared by the process of any one of claims 1-12 and one or more pharmaceutically acceptable excipients.

14. The composition of claim 13, wherein the composition further comprises one or more additional drugs selected from oxcarbazepine (oxcarbazpin), carbamazepine (carbazpin), phenytoin (phnitin), valproic acid (valproic acid), ethosuximide (thospormid), febrile urethane (flbamate), gabapentin (gabapntin), levetiracetam (lvtiramt), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbital), zonisamid (zonisamid), clonazepam (clomazpam), phenytoin sodium (phnitin), valproat (valproat), clobazam (clobazin), vigabapin (topiramate) and lacamide (lacd).

15. The composition according to claim 13 or 14, wherein the composition is in the form of a formulation selected from the group consisting of tablets, capsules, powders and suspensions, and preferably is a suspension.

16. The composition according to any one of claims 13-15, wherein more than about 80% of the lamotrigine in the composition is present in the form of lamotrigine hydrate form a, preferably more than about 90% of the lamotrigine is present in the form of lamotrigine hydrate form a, and more preferably more than about 95% of the lamotrigine is present in the form of lamotrigine hydrate form a.

17. The composition according to any one of claims 13-16, wherein the pharmaceutically acceptable excipient is selected from one or more of a thickener, a filler, a sweetener, a pH adjuster, and a preservative;

preferably, the thickener is selected from one or more of xanthan gum, povidone, colloidal microcrystalline cellulose and sodium alginate, more preferably xanthan gum; and preferably the thickener is present in an amount of about 1 to 7 parts by weight, preferably about 1 to 5 parts by weight, based on about 10 parts by weight of lamotrigine hydrate form a;

preferably, the filler is selected from one or more of mannitol, microcrystalline cellulose, sucrose and lactose; and preferably the filler is present in an amount of about 20 to 60 parts by weight, based on about 10 parts by weight of lamotrigine hydrate form a;

Preferably, the sweetener is selected from one or more of sucralose, aspartame, and sodium saccharin; and preferably the sweetener is present in an amount of about 1 to 3 parts by weight, based on about 10 parts by weight of lamotrigine hydrate form a;

preferably, the pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid and sodium citrate; and preferably the pH adjuster is present in an amount of about 0.5 to 8 parts by weight, about 0.5 to 5.1 parts by weight, about 3 to 8 parts by weight, or about 2 to 5 parts by weight, based on about 10 parts by weight of lamotrigine hydrate form a; and

preferably, the preservative is selected from one or more of sodium propyl hydroxybenzoate, sodium methyl hydroxybenzoate, sodium benzoate and potassium sorbate; and preferably the preservative is present in an amount of about 1 to 3 parts by weight based on about 10 parts by weight of lamotrigine hydrate form a.

18. The composition according to any one of claims 13-17, comprising:

about 10 parts by weight lamotrigine hydrate form a;

about 1 to about 5 parts by weight of xanthan gum;

about 20 to 60 parts by weight mannitol;

about 1 to about 3 parts by weight of sucralose;

about 2-5 parts by weight of sodium dihydrogen phosphate, about 2-5 parts by weight of disodium hydrogen phosphate, and/or about 2-5 parts by weight of citric acid; and

About 1 to 3 parts by weight of a combination of sodium methylparaben and sodium propylparaben, wherein the weight ratio of sodium methylparaben to sodium propylparaben is about 9:1.

19. Use of a composition according to any one of claims 13-18 in the manufacture of a medicament for the treatment of a neurological disorder.

20. The use according to claim 19, wherein the neurological disease is selected from one or more of alzheimer's disease, depression, multiple sclerosis, parkinson's disease and epilepsy.

21. The use according to claim 19 or 20, wherein the medicament is for use in combination with other medicaments for the treatment of the neurological disease, preferably the other medicaments are selected from one or more of oxcarbazepine (oxcarbazpin), carbamazepine (carbamazepin), phenytoin (phnitin), valproic acid (valproic acid), ethosuximide (thoximid), febanamate (flbamate), gabapentin (gabapntin), levetiracetam (lvtiramm), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbitial), zonisamide (zonisamide), clonazepam (clonazepam), phenytoin sodium (phnitin), valproic acid sodium (valvular), clobazam), aminohexenoic acid (vigabalin), topiramate (topiramate) and lacamide (lac).

22. The use according to any one of claims 19-21, wherein the medicament is in the form of a suspension.

23. The use according to any one of claims 19-22, wherein more than about 80% of the lamotrigine in the medicament is present in the form of lamotrigine hydrate form a, preferably more than about 90% of the lamotrigine is present in the form of lamotrigine hydrate form a, and more preferably more than about 95% of the lamotrigine is present in the form of lamotrigine hydrate form a.

Technical scheme group K:

1. a kit comprising a pharmaceutical composition according to claim set A, B and C, a suspension according to claim set D and E, a dry suspension prepared by the method according to claim set F, a suspension prepared by the method according to claim set G, H, I and J, wherein

Lamotrigine and other ingredients of the foregoing technical set (e.g., one or more selected from pH adjusters, preservatives, thickeners, bulking agents, sweeteners, etc.) are contained in the same container;

or alternatively

Lamotrigine and other ingredients mentioned in the foregoing technical group (e.g., one or more selected from pH adjusters, preservatives, thickeners, fillers, sweeteners, etc.) are contained in one or more different containers;

Optionally, lamotrigine particles in the kit may be mixed with other ingredients (e.g., one or more selected from pH adjusters, preservatives, thickeners, fillers, sweeteners, etc.) and added to water to make a suspension; or lamotrigine particles in the kit may be mixed with an aqueous solution comprising other ingredients (e.g., one or more selected from pH adjusters, preservatives, thickeners, fillers, sweeteners, etc.) to prepare a suspension;

optionally, the suspension, the dry suspension, the lamotrigine, and the type, content, D90 particle size, microscope particle size, antimicrobial stability, etc., of, for example, pH modifiers, preservatives, thickeners, fillers, sweeteners, etc., are as described in the previous section herein.

Technical scheme group L:

1. use of a pharmaceutical composition according to claim set A, B and C, a suspension according to claim set D and E, a dry suspension prepared by a method according to claim set F, a suspension prepared by a method according to claim set G, H, I and J for the preparation of a medicament or a kit for the treatment of a neurological disorder.

2. The use according to claim 1, wherein the neurological disease is selected from one or more of alzheimer's disease, depression, multiple sclerosis, parkinson's disease and epilepsy.

3. The use according to claim 1 or 2, wherein the medicament is for use in combination with other medicaments for the treatment of the neurological disease; optionally, the other drug is selected from one or more of oxcarbazepine (oxcarbazpin), carbamazepine (carbamazepin), phenytoin (phtin), valproic acid (valproic acid), ethosuximide (thospormid), febrile amine (flbamate), gabapentin (gabapntin), levetiracetam (lvtiractam), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbital), zonisamide (zonisamid), clonazepam (clonazepam), phenytoin sodium (phtomin), valproate (valproat), clobazam (clobazam), vigabatrin (topiramate) and lacamamide (lacamide).

Technical scheme group M:

1. a method of treating a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim set A, B and C, the suspension of claim set D and E, the dry suspension prepared by the method of claim set F, the suspension prepared by the method of claim set G, H, I and J.

2. The method according to claim 1, wherein the neurological disease is selected from one or more of alzheimer's disease, depression, multiple sclerosis, parkinson's disease and epilepsy.

3. The method according to claim 1 or 2, further comprising administering to a subject in need thereof a therapeutically effective amount of an additional agent for treating the neurological disease; optionally, the other drug is selected from one or more of oxcarbazepine (oxcarbazpin), carbamazepine (carbamazepin), phenytoin (phtin), valproic acid (valproic acid), ethosuximide (thospormid), febrile amine (flbamate), gabapentin (gabapntin), levetiracetam (lvtiractam), tiagabine (tiagabin), pregabalin (prgabalin), phenobarbital (phnobarbital), zonisamide (zonisamid), clonazepam (clonazepam), phenytoin sodium (phtomin), valproate (valproat), clobazam (clobazam), vigabatrin (topiramate) and lacamamide (lacamide).

4. The method according to any one of claims 1-3, wherein the mode of administration is selected from one or more of the following: (a) Administration by the oral route, including capsules, tablets, granules, sprays, syrups or other such forms of dosage forms; (b) Non-oral routes of administration, such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraaural administration, including aqueous suspensions, oily formulations and the like or drops, sprays, suppositories, ointments, salves and the like; (c) Administration by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal, intrasternal injection, etc.; and d) topical administration, including inhalation solutions, nasal sprays, implants, and the like;

Alternatively, the mode of administration is oral.

5. The method according to any one of claims 1-4, wherein the pharmaceutical compositions of claim set A, B and C, the suspensions of claim set D and E, the dry suspension prepared by the method of claim set F, the suspensions prepared by the method of claim set G, H, I and J are administered in a single dose or multiple doses one to four times a day.

6. The method according to any one of claims 1-5, wherein the pharmaceutical composition of claim set A, B and C, the suspension of claim set D and E, the dry suspension prepared by the method of claim set F, the suspension prepared by the method of claim set G, H, I and J is administered in a dosage range of 0.1mg lamotrigine hydrate form a/kg patient body weight to 1000mg lamotrigine hydrate form a/kg patient body weight.

7. The method according to any one of claims 1-6, wherein the mode of administration is oral route of administration and the oral dose is 1mg to 500mg, or 5mg to 200mg; or the mode of administration is intravenous, subcutaneous or intramuscular injection, and the intravenous, subcutaneous or intramuscular injection dose is 0.01mg to 100mg, or 0.1mg to 60mg.

8. The method according to any one of claims 1-8, wherein the pharmaceutical composition of claim set A, B and C, the suspension of claim set D and E, the dry suspension prepared by the method of claim set F, the suspension prepared by the method of claim set G, H, I and J, is released for a period of 1 hour to 12 hours, 3 hours to 12 hours, or 6 hours to 12 hours after administration.

9. The method according to any one of claims 1-8, wherein the pharmaceutical compositions of claim set A, B and C, the suspensions of claim set D and E, the dry suspension prepared by the method of claim set F, the suspensions prepared by the method of claim set G, H, I and J are packaged with the other drugs in one kit, or are packaged separately.

10. The method according to any one of claims 1-9, wherein the pharmaceutical composition of claim set A, B and C, the suspension of claim set D and E, the dry suspension prepared by the method of claim set F, the suspension prepared by the method of claim set G, H, I and J are administered to the patient simultaneously or sequentially with the other drug.

Claims

3. The pharmaceutical composition according to claims 1-2, wherein the pH adjusting agent is selected from one or more combinations of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate; and/or

6. The pharmaceutical composition according to any one of claims 1-5, wherein the lamotrigine particles have a particle size (D90) of about 4.5-8 μm and the amount of the pH adjusting agent is such that the pH of the suspension is about 4.6-6.9; and/or the number of the groups of groups,

the pH adjuster is about 0.5 to 5.1 parts by weight based on about 10 parts by weight of the lamotrigine particles; and/or the number of the groups of groups,

7. The pharmaceutical composition according to any one of claims 1-5, wherein the lamotrigine particles have a particle size (D90) of about 12-13 μm and the amount of the pH adjusting agent is such that the pH of the suspension is about 5.8-6.9; and/or the number of the groups of groups,

the pH adjuster is about 3-8 parts by weight based on about 10 parts by weight of the lamotrigine particles; and/or the number of the groups of groups,

8. Pharmaceutical composition according to any one of claims 1 to 5, the suitable lamotrigine water particle size (D90) being selected such that lamotrigine hydrate form a formed by the dry suspension after formulation into a suspension has in suspension a pH range selected from the following particle size increases: at about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, the particle size increases by less than 100%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5%.

9. Pharmaceutical composition according to any one of claims 1 to 5, the pH range for which the suitable pH adjusting agent corresponds being selected such that lamotrigine hydrate form a formed by the dry suspension after formulation into a suspension has in suspension a pH range selected from the following particle size increases: at about 1 day, about 2 days, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, the particle size increases by less than 100%, less than 50%, less than 30%, less than 20%, less than 10%, or less than 5%.

10. Pharmaceutical composition according to any one of claims 1 to 9, wherein the thickening agent is selected from the group consisting of hydrocolloids such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers such as carbomers; and magnesium aluminum silicate and combinations thereof;

optionally, the thickener is xanthan gum; and/or

14. The pharmaceutical composition according to any one of claims 1-13, wherein the pharmaceutical composition further comprises a preservative, a sweetener and a filler;

15. The pharmaceutical composition according to any one of claims 1-14, wherein the lamotrigine particles have a particle size (D90) of 4.5 μm or 8 μm, and wherein the thickener is xanthan gum, the xanthan gum being 3 parts by weight based on 10 parts by weight of the lamotrigine particles; the pH adjuster is a combination of disodium hydrogen phosphate and citric acid, 4 parts by weight of the pH adjuster (optionally 1.5 parts by weight of the disodium hydrogen phosphate, and 2.5 parts by weight of the citric acid) based on 10 parts by weight of the lamotrigine particles; the preservative is a combination of sodium propyl paraben and sodium methyl paraben, wherein the preservative is 2.2 parts by weight (optionally the sodium propyl paraben is 0.2 parts by weight and the sodium methyl paraben is 2.0 parts by weight) based on 10 parts by weight of the lamotrigine particles; the filler is mannitol, and the filler is 20 parts by weight based on 10 parts by weight of the lamotrigine particles; and the sweetener is sucralose, and the sweetener is 1 part by weight based on 10 parts by weight of the lamotrigine particles.

17. A suspension prepared from the pharmaceutical composition according to any one of claims 1-16, wherein the suspension is obtained by mixing the pharmaceutical composition according to any one of claims 1-16 with water.

18. Use of a pharmaceutical composition according to any one of claims 1-16 or a suspension according to claim 17 for the preparation of a kit for the treatment of neurological diseases; optionally, the neurological disease is selected from one or more of alzheimer's disease, depression, multiple sclerosis, parkinson's disease, and epilepsy.