Preparation containing lamotrigine self-microemulsion composition and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a preparation and application of a self-microemulsion composition containing lamotrigine. Comprising lamotrigine and a self-microemulsion (SMEDDS) carrier, the SMEDDS carrier is prepared from lamotrigine, an oil phase, an emulsifier and a co-emulsifier; the self-microemulsion composition comprises, by mass, 0.1%-18.7% of lamotrigine, 20%-33% of an oil phase and 67%-80% of an emulsion phase, the emulsion phase is composed of an emulsifier and a co-emulsifier, the mass ratio of the emulsifier to the co-emulsifier is 25.7%-32.9%: 67.1%-74.3%, and the mass concentration of the lamotrigine reaches 18.7%. The particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 50 nm or even less. The self-microemulsion composition can be prepared into soft capsules, hard capsules, tablets, granules, temperature-sensitive gels and other dosage forms to be applied to preparation of anti-epileptic drugs.

Description

[0001] This application is a divisional application of Chinese Patent CN 202211465735.2, filed on November 22, 2022, entitled "A self-microemulsion composition containing lamotrigine and its application thereto". Technical Field

[0002] This invention relates to the field of pharmaceutical technology, specifically to a formulation and application of a lamotrigine self-microemulsion composition. Background Technology

[0003] Epilepsy is a common chronic, recurrent neurological disorder caused by various etiologies. It is characterized by recurrent seizures due to abnormal neuronal discharges in the brain, with a prevalence of 5%. Currently, there are approximately 9 million epilepsy patients in my country, with about 600,000 new cases each year. Lamotrigine, chemically known as 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is a phenyltriazine antiepileptic drug with poor solubility, belonging to the BCSII class. Lamotrigine primarily acts on voltage-dependent sodium channels, inhibiting recurrent discharges, and may also act on glutamate-related neurotransmitters. It is an antiepileptic drug that inhibits glutamate and aspartate, stabilizing the presynaptic membrane and inhibiting the release of glutamate and aspartate. It is mainly used to treat refractory epilepsy. The dosage and administration instructions for lamotrigine tablets state: the initial dose is generally 25 mg / day, and the maintenance dose can be as high as 200 mg / day. Currently, the lamotrigine tablets commonly used in the Chinese market are ordinary tablets, while tablet formulations containing 25mg, 50mg, 100mg, and 150mg of active ingredient have been approved for sale.

[0004] Chinese invention patent CN111407725A discloses a lamotrigine emulsion and its preparation method, which includes 0.1-1% lamotrigine, an oil phase, an oil phase solubilizer, an emulsifier, etc. to form an emulsion system. The preparation method adopts a high-speed shearing method, and the droplet size is between 200-350nm. The original solution system is not stable enough during storage. In the optimal embodiment, the actual concentration of lamotrigine loaded in the original solution is 23mg / ml.

[0005] Rehab Abdelmonem et al. (Development, Characterization, and in-vivo Pharmacokinetic Study of Lamotrigine Solid Self-Nanoemulsifying Drug Delivery System. Drug Design, Development and Therapy 2020:144343–4362.) reported a lamotrigine-containing nanoemulsion system. Using 30% rose oil, 35% CR-EL, and 35% T80 or PEG400, the resulting nanoemulsion stock solution contained 5% lamotrigine, approximately 50 mg / ml. For clinical treatment maintenance doses of lamotrigine up to 200 mg / day, the drug loading capacity still needs further improvement.

[0006] S. Melane et al. (Formulation optimization of smartthermosettinglamotrigine loaded hydrogels using responsesurface methodology, Box Benhken design and artificial neural networks. Drug Development and Industrial Pharmacy. 2020. DOI:10.1080 / 03639045.2020.1791163) reported a nasal thermosensitive gel containing only 5 mg / ml of lamotrigine. Although nasal administration can improve bioavailability by about 2 times compared to oral administration, the concentration of lamotrigine loaded is still limited for daily doses or pediatric use. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a formulation and application of a lamotrigine self-microemulsion composition. This formulation not only effectively increases the lamotrigine loading in the self-microemulsion composition solution, but also remains stable at room temperature with or without the addition of pure water. Furthermore, the preparation process of the self-emulsifying composition system is simple, requiring only simple ultrasonic stirring without high-speed shearing. It exhibits short self-emulsification and dispersion time in aqueous media, and can be further prepared into a pharmaceutical formulation, effectively improving bioavailability.

[0008] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0009] On one hand, the present invention provides a self-microemulsion composition containing lamotrigine, comprising lamotrigine, an oil phase, an emulsifier, and a co-emulsifier; wherein, by mass ratio, the self-microemulsion composition comprises 0.1%–18.7% lamotrigine, 20%–33% oil phase, and 67%–80% emulsion phase, wherein the emulsion phase is composed of an emulsifier and a co-emulsifier, and the mass ratio of the emulsifier to the co-emulsifier is 25.7%–31.4%: 68.6%–74.3%.

[0010] Furthermore, the oil phase is glyceryl monolinoleate and / or medium-chain triglycerides, the emulsifier is one or two of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene castor oil, oleyl polyoxyethylene glyceryl ester, and polyoxyethylene-15 hydroxystearate (solutol HS15), and the co-emulsifier is one or two of Tween 80, PEG400, propylene glycol, diethylene glycol monoethyl ether, and ethanol.

[0011] Further, the oil phase consists of monolinoleic glycerol and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether. The mass ratio of the oil phase monolinoleic glycerol to medium-chain triglycerides is one of 1:1, 2:1, 3:1, 4:1, 5:1, 1:2, 1:3, 1:4, or 1:5; the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is one of 1:1, 2:1, 3:1, 1:2, or 1:3; and the mass ratio of the emulsifier to the co-emulsifier is one of 1.8:5.2, 2:5, or 2.2:4.8.

[0012] Furthermore, the mass ratio of the oil phase monolinoleic acid glyceride to the medium-chain triglyceride is 4:1, and the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is 4:1.

[0013] Furthermore, the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is 4:1, and the mass ratio of the emulsifier to the co-emulsifier is 2:5.

[0014] A method for preparing a self-microemulsion composition containing lamotrigine: Under conditions of 37°C and protection from light, emulsifier and co-emulsifier are weighed according to the prescribed amount of the self-microemulsion composition containing lamotrigine described above, and ultrasonically stirred and mixed evenly to obtain mixture one. Lamotrigine is added to mixture one and ultrasonically stirred and mixed evenly to obtain mixture two. Then, the mixed oil phase is added to mixture two and ultrasonically stirred to fully dissolve, thereby obtaining the self-microemulsion composition containing lamotrigine.

[0015] Furthermore, the prepared self-microemulsion composition contains 18.7% lamotrigine by mass, and the microemulsion formed by dispersing the self-microemulsion composition in an aqueous medium has a particle size of less than 50 nm, less than 20 nm, or even smaller.

[0016] Furthermore, the lamotrigine-containing self-microemulsion composition may also contain an appropriate amount of antioxidant (e.g., 0.1%, w / w). The antioxidant used is one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol), preferably vitamin E. The prepared lamotrigine-containing self-microemulsion composition stock solution is packaged into soft capsules or hard capsules to obtain self-microemulsion capsules. The obtained lamotrigine self-microemulsion capsules contain 16.7%–18.7% lamotrigine by mass, with a capsule size of 0.3 ml–0.5 ml / capsule, containing approximately 50.1–93.5 mg of lamotrigine / capsule.

[0017] Furthermore, the prepared lamotrigine-containing self-microemulsion composition stock solution is self-emulsified with ten times its volume of pure water, and then mixed with porous solid excipients to prepare a soft mass. This soft mass is then produced into tablets or granules according to conventional tablet or granule preparation procedures (soft mass preparation, granulation, drying, mixing, compression, packaging, etc.). The porous excipients include, for example, hydroxypropyl methylcellulose, silica, and cyclodextrin.

[0018] Furthermore, the self-microemulsion stock solution containing lamotrigine is self-emulsified with ten times the amount of pure water, and mixed with a porous solid excipient to prepare a soft material. This material is then granulated, dried, and packaged to form lamotrigine self-microemulsion granules, or granulated, dried, mixed, compressed, and packaged to form lamotrigine self-microemulsion tablets. The porous excipient is one, two, or three of hydroxypropyl methylcellulose, silica, and cyclodextrin.

[0019] Further, the prepared lamotrigine-containing self-microemulsion composition stock solution is supplemented with 0.1% antioxidant and 0.1% preservative. The antioxidant can be one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol), preferably vitamin E. The preservative is sodium benzoate, potassium sorbate, or a combination thereof. The antioxidant vitamin E can be added to the mixed oil phase and mixed thoroughly, and the preservative can be added to the co-emulsifier and mixed thoroughly.

[0020] Preparation process: Under light-protected conditions at 37°C, the emulsifier and co-emulsifier were weighed according to the prescription and ultrasonically stirred until homogeneous to obtain mixture one. Lamotrigine and preservative (sodium benzoate and potassium sorbate in a 1:1 mass ratio) were added to mixture one and ultrasonically stirred until homogeneous to obtain mixture two. Vitamin E was mixed with the mixed oil phase to obtain mixture three. Mixture three was then added to mixture two and ultrasonically stirred until fully dissolved to obtain a self-microemulsion solution. The prepared self-microemulsion solution was dispersed in 4 times its volume of pure water to form a self-emulsifying solution. The poralum composition was added to the self-emulsifying solution and stirred until homogeneous to form a gel solution. The pH of the gel solution was adjusted to between 5 and 6.5, mixed well, and stored at 4°C for 24 hours to allow for full swelling and removal of air bubbles.

[0021] The self-emulsifying solution and the poracillum composition were in a mass ratio of 4:1. The poracillum composition consisted of 21 parts of poracillum 407 and 2 parts of poracillum 188. The thermosensitive gel formulation prepared in Example 21 (lamotrigine mass concentration of 16.7%) had a concentration of 27.8 mg / g (approximately 27.8 mg / ml), which is more than five times the lamotrigine concentration of 5 mg / ml reported by S. Melane et al. for lamotrigine nasal thermosensitive gel. Furthermore, the self-microemulsifying system provided by this invention is more uniform and stable. This formulation can meet the needs of children with epilepsy, patients requiring rapid onset of action, and patients requiring transdermal administration of the thermosensitive gel.

[0022] The use of the formulation of the self-microemulsion composition containing lamotrigine in the preparation of a medicament for the prevention or treatment of epilepsy; the use of the thermosensitive gel formulation of the self-microemulsion composition containing lamotrigine in the preparation of a medicament for nasal or transdermal administration.

[0023] This invention, through the optimization of the types and combinations of oil phases, specific emulsifiers, co-emulsifiers, and the ratio of oil phase, emulsifiers, and co-emulsifiers, and the optimization of the preparation method of the self-microemulsion composition, provides a lamotrigine-containing self-microemulsion composition. The preparation method is simple, requiring no high-speed shearing; a clear and transparent self-microemulsion solution can be formed simply by ultrasonic stirring. The prepared self-microemulsion composition contains 18.7% lamotrigine by mass, i.e., 187 mg / g, meeting the clinical requirement of a maintenance dose of up to 200 mg / day for lamotrigine antiepileptic treatment. Compared with lamotrigine, the prepared lamotrigine-containing self-microemulsion composition has a higher concentration of lamotrigine. The AUC0-72h after administration of lamotrigine tablets increased by 2-fold, with a small inter-individual coefficient of variation (CV%), reducing the occurrence of adverse reactions from lamotrigine use. The prepared lamotrigine-containing self-microemulsion composition, when mixed with water, biologically relevant media (e.g., SGF, FessiF, and FassiF media), or gastrointestinal fluid, spontaneously forms clear, transparent, homogeneous, and stable O / W microemulsions with particle sizes less than 50 nm, 30 nm, or even 20 nm. The prepared lamotrigine-containing self-microemulsion composition, whether with or without added water, maintains a stable self-microemulsion solution form at room temperature or 4°C. The lamotrigine-containing self-microemulsion composition of this invention exhibits a high lamotrigine loading concentration and a homogeneous and stable self-microemulsion solution system. Attached Figure Description

[0024] Figure 1 A comparison of the pharmacokinetic data of the self-made soft capsules and the original lamotrigine tablets in beagle dogs (n=3, mean±SD). Detailed Implementation

[0025] To further describe the present invention, the following detailed description is provided in conjunction with embodiments, but the present invention is not limited to the specific embodiments thereon.

[0026] Experiment 1: The method for determining solubility is as follows:

[0027] Take 5 mL each of the oil phase, emulsifier, and co-emulsifier into test tubes, add an excess of equal amounts of lamotrigine to each, incubate at 37°C, shake for 24 hours, then centrifuge at high speed, take the supernatant, dilute with the mobile phase, and test the equilibrium solubility.

[0028] Tests revealed that lamotrigine has a solubility of approximately 41 mg / ml in rose oil, approximately 112 mg / ml in glyceryl monolinoleate, approximately 240 mg / ml in PEG400, and approximately 169 mg / ml in diethylene glycol monoethyl ether.

[0029] Experiment 2: Experiment on the selection of oil phase type and the mixing ratio of oil phases

[0030] The solubility of lamotrigine in monolinoleic acid glyceride was investigated by mixing it with rose oil or medium-chain triglycerides at different mass ratios (1:1, 2:1, 3:1, 4:1, 5:1, 1:2, 1:3, 1:4, 1:5). It was found that various combinations of monolinoleic acid glyceride and rose oil did not significantly improve the solubility of lamotrigine; however, the combination of monolinoleic acid glyceride and medium-chain triglycerides resulted in a greater loading of lamotrigine than when monolinoleic acid glyceride and medium-chain triglycerides were used alone. The highest solubility of lamotrigine was observed at mass ratios of 4:1 and 5:1. In subsequent studies combining emulsifier polyoxyethylene 40 hydrogenated castor oil and co-emulsifier, it was found that the self-microemulsification time in pure water was faster when the mass ratio of monolinoleic acid glyceride to medium-chain triglyceride was 4:1 compared to that when the mass ratio was 5:1. Therefore, a mass ratio of monolinoleic acid glyceride to medium-chain triglyceride of 4:1 is preferred.

[0031] Experiment 3: Transmittance Test of Emulsifier and Co-emulsifier

[0032] Using monolinoleic glycerol and medium-chain triglycerides (4:1) as the mixed oil phase, the transmittance of different emulsifiers and co-emulsifiers mixed with the mixed oil phase at a mass ratio of 1:1 was investigated. It was found that the microemulsion formed by polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene castor oil, oleyl polyoxyethylene glycerol, polyoxyethylene-15 hydroxystearate (solutol HS 15), Tween 80, PEG400, propylene glycol, diethylene glycol monoethyl ether, ethanol, and the mixed oil phase was clear and transparent, with a transmittance exceeding 90%.

[0033] Experiment 4: Optimal Selection of Emulsifiers and Co-emulsifiers

[0034] Based on the solubility of lamotrigine in various excipients, the properties of each excipient and the possible mutual solubilizing effects, as well as laboratory exploration and analysis, the composition and dosage of emulsifiers and co-emulsifiers were studied and analyzed. (See Table 1)

[0035] prescription:

[0036] Lamotrigine: appropriate amount; total mass of SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:2:5. The oil phase is composed of monolinoleic acid glyceride and medium-chain triglyceride (4:1).

[0037] Preparation process: Under the conditions of 37℃ and protection from light, the emulsifier and co-emulsifier were weighed according to the prescription and ultrasonically stirred to obtain mixture one. Lamotrigine was added to mixture one and mixed to obtain mixture two. The two oil phases were mixed to obtain mixture three. Mixture three was then added to mixture two and ultrasonically stirred to fully dissolve the mixture, thus obtaining SMEDDS stock solution. The solution was added to 10 times the amount of pure water, shaken slightly, and observed.

[0038] Table 1. Studies on formulations of different emulsifiers and co-emulsifiers

[0039]

[0040]

[0041] As can be seen from Examples 1-20 in the table above, under the condition that the amount of lamotrigine added is 170 mg (approximately 14.5% by mass), PEG400 and diethylene glycol monoethyl ether are used as co-emulsifiers, respectively. When polyoxyethylene 40 hydrogenated castor oil is used as an emulsifier in combination with the mixed oil, its emulsification effect is better than that of polyoxyethylene castor oil and oleoyl polyoxyethylene glycerol ester. This indicates that the combination of PEG400, diethylene glycol monoethyl ether, and a mixture of PEG400 and diethylene glycol monoethyl ether (3:1) as co-emulsifiers with polyoxyethylene 40 hydrogenated castor oil as an emulsifier has a good solubilizing and promoting effect on lamotrigine, and the self-microemulsion formed is transparent with a slightly pale blue opalescence.

[0042] Further research revealed that the combined use of PEG400 and diethylene glycol monoethyl ether as co-emulsifiers increased the loading capacity of the self-microemulsion system for lamotrigine, achieving a lamotrigine loading of 16% (w / w), which was higher than that achieved using PEG400 or diethylene glycol monoethyl ether alone. Furthermore, optimizing the PEG400:diethylene glycol monoethyl ether mass ratio to 3:1 and 4:1 resulted in a lamotrigine loading of 16.7% (w / w) in the self-microemulsion system, and further optimizing it to 4:1 resulted in a lamotrigine loading of 17.4% (w / w).

[0043] Experiment 5: Investigation of the ratio of oil phase to emulsion phase

[0044] The prescription is as follows:

[0045] Lamotrigine: 200mg;

[0046] The total mass of the SMEDDS carrier is 1000 mg: the mass ratio of the oil phase to the total mass of the carrier is shown in the table below.

[0047] The oil phase consists of monolinoleic acid glycerides and medium-chain triglycerides (4:1), and the emulsion phase consists of emulsifier: co-emulsifier = 2:5. The emulsifier is polyoxyethylene 40 hydrogenated castor oil; the co-emulsifier is PEG400: diethylene glycol monoethyl ether (4:1).

[0048] Table 2. Studies on different proportions of oil phase and emulsion phase

[0049] Oil phase / %(w / w) Milk phase / % (w / w) The emulsified state of 1 gram of self-emulsifying system after adding 100g of water 20 80 Clarity and transparency 25 75 Clarity and transparency 28 72 Clear and transparent, with a slightly bluish sheen. 30 70 Transparent with a slightly bluish luster 33 67 Blue opalescent 35 65 milky 38 62 Turbid, with API precipitate. 40 60 Turbid, with API precipitation and oil droplets.

[0050] As shown in the table above, the proportion of the oil phase in the lamotrigine self-microemulsion composition system should be less than or equal to 33%, and the total amount of the emulsion phase should be greater than or equal to 67%, resulting in better emulsification of the self-microemulsion system. To ensure emulsification and reduce the amount of emulsion phase used, the preferred oil phase:emulsion phase mass percentage is 20%–33%:80%–67%, more preferably 28%–30%:72%–70%, and even more preferably 30%:70%, considering minimizing the amount of emulsion phase used.

[0051] Experiment 6: Investigation of the ratio of emulsifier to co-emulsifier

[0052] The prescription is as follows:

[0053] Lamotrigine: 200mg;

[0054] The total mass of the SMEDDS carrier is 1000 mg: the mass ratio of oil phase to emulsion phase (emulsifier and co-emulsifier) ​​is 3:7;

[0055] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is 4:1. The mass ratios of emulsifier to co-emulsifier are 1:6, 1.5:5.5, 1.8:5.2, 2:5, 2.2:4.8, 2.4:4.6, 2.6:4.4, 3:4, and 4:3, respectively. The preparation process was carried out according to Experiment 4. It was found that as the emulsifier increased, the emulsification effect on the oil phase was enhanced, but the loading capacity of lamotrigine decreased. When the mass ratio of emulsifier to co-emulsifier was 1.8:5.2, 2:5, and 2.2:4.8, that is, when the mass ratio of emulsifier to co-emulsifier was 25.7%~31.4%:68.6%~74.3%, the self-microemulsion had a better emulsification effect in water and a good loading capacity of lamotrigine. Furthermore, when the mass ratio of emulsifier to co-emulsifier was 2:5, the self-microemulsion had a better emulsification effect in water and a superior loading capacity of lamotrigine.

[0056] Experiment 7: Investigation of Self-Microemulsion Preparation Methods

[0057] The prescription is as follows:

[0058] Lamotrigine: 200mg;

[0059] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:2:5.

[0060] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400: diethylene glycol monoethyl ether (4:1).

[0061] Preparation method (1): At 37°C and under light-protected conditions, lamotrigine was added to the co-emulsifier and ultrasonically mixed to obtain mixture one. The emulsifier was added to mixture one and ultrasonically mixed to obtain mixture two. The mixed oil phase was then added to mixture two and ultrasonically stirred to dissolve it completely, thus obtaining SMEDDS stock solution. After adding it to 10 times the amount of pure water and shaking it slightly, turbidity points were observed.

[0062] Preparation method (2): Under the conditions of 37°C and protection from light, weigh the oil phase and emulsifier according to the prescription and mix them with ultrasonically to obtain mixture one. Add lamotrigine to mixture one and mix with ultrasonically to obtain mixture two. Then add the co-emulsifier to mixture two and stir with ultrasonic to dissolve it completely to obtain SMEDDS stock solution. Add it to 10 times the amount of pure water, shake it slightly and observe. Lamotrigine precipitates out.

[0063] Compared with the two preparation methods above, the preparation method in Experiment 4 showed better loading effect on lamotrigine.

[0064] Experiment 8: Construction and Evaluation of Lamotrigine Self-Microemulsion System

[0065] Example 21

[0066] The prescription is as follows:

[0067] Lamotrigine: 200mg;

[0068] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:2:5.

[0069] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0070] Preparation process: Under the conditions of 37℃ and protection from light, the emulsifier and co-emulsifier were weighed according to the prescription and ultrasonically stirred and mixed evenly to obtain mixture one. Lamotrigine was added to mixture one and ultrasonically stirred and mixed evenly to obtain mixture two. Then, the mixed oil phase was added to mixture two and ultrasonically stirred to fully dissolve it, thus obtaining SMEDDS stock solution. It was added to 10 times the amount of pure water, shaken slightly, and observed.

[0071] The resulting lamotrigine self-microemulsion composition was transparent with a pale blue opalescence. After self-emulsification in pure water, the particle size was 18 nm, and the lamotrigine loading was 16.7% (w / w).

[0072] Example 22

[0073] The prescription is as follows:

[0074] Lamotrigine: 200mg;

[0075] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:2:5.

[0076] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0077] The preparation process was as described in Example 21: The resulting lamotrigine self-microemulsion composition was transparent with a pale blue opalescence. After self-emulsification in pure water, the particle size was 23 nm, and the lamotrigine loading was 16.7% (w / w).

[0078] Example 23

[0079] The prescription is as follows:

[0080] Lamotrigine: 200mg;

[0081] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:1.9:5.1.

[0082] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (1:1).

[0083] The preparation process was as described in Example 21: The resulting lamotrigine self-microemulsion composition was blue and opalescent. After self-emulsification in pure water, the particle size was 42 nm, and the lamotrigine loading was 16.7% (w / w).

[0084] Example 24

[0085] The prescription is as follows:

[0086] Lamotrigine: 200mg;

[0087] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:1.8:5.2.

[0088] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (1:1).

[0089] The preparation process was as described in Example 21: The resulting lamotrigine self-microemulsion composition was pale blue and opalescent. After self-emulsification in pure water, the particle size was 33 nm, and the lamotrigine loading was 16.7% (w / w).

[0090] Example 25

[0091] The prescription is as follows:

[0092] Lamotrigine: 210 mg;

[0093] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:1.9:5.1.

[0094] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (2:1).

[0095] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition is milky white.

[0096] Example 26

[0097] The prescription is as follows:

[0098] Lamotrigine: 210 mg;

[0099] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:1.8:5.2.

[0100] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0101] The preparation process was as described in Example 21: The resulting lamotrigine self-microemulsion composition was pale blue and opalescent. After self-emulsification in pure water, the particle size was 49 nm, and the lamotrigine loading was 17.4% (w / w).

[0102] Example 27

[0103] The prescription is as follows:

[0104] Lamotrigine: 220 mg;

[0105] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:1.8:5.2.

[0106] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0107] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition is blue and opalescent. The particle size after self-emulsification in pure water is 29 nm, and the lamotrigine loading is 18% (w / w).

[0108] Example 28

[0109] The prescription is as follows:

[0110] Lamotrigine: 220 mg;

[0111] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:1.7:5.3.

[0112] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0113] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition is blue and opalescent with cloud spots, and the lamotrigine loading is 18% (w / w).

[0114] Example 29

[0115] The prescription is as follows:

[0116] Lamotrigine: 220 mg;

[0117] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 2.9:2:5.1.

[0118] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0119] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition has a pale blue opalescence, and the particle size after self-emulsification in pure water is 25 nm, with a lamotrigine loading of 18% (w / w).

[0120] Example 30

[0121] The prescription is as follows:

[0122] Lamotrigine: 230 mg;

[0123] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 2.8:2:5.2.

[0124] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0125] The preparation process was as described in Example 21: The resulting lamotrigine self-microemulsion composition was blue and opalescent. After self-emulsification in pure water, the particle size was 23 nm, with slight API precipitation. The lamotrigine loading was 18.7% (w / w).

[0126] Example 31

[0127] The prescription is as follows:

[0128] Lamotrigine: 230 mg;

[0129] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 2.8:1.8:5.4.

[0130] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0131] The preparation process was as described in Example 21: The resulting lamotrigine self-microemulsion composition was pale blue and opalescent. After self-emulsification in pure water, the particle size was 25 nm, and the lamotrigine loading was 18.7% (w / w).

[0132] Example 32

[0133] The prescription is as follows:

[0134] Lamotrigine: 240 mg;

[0135] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 2.8:1.8:5.4.

[0136] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0137] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition is milky white.

[0138] Example 33

[0139] The prescription is as follows:

[0140] Lamotrigine: 0 mg;

[0141] The total mass of the SMEDDS carrier is 1000 mg; the mass ratio of oil phase: emulsifier: co-emulsifier is 3:2:5.

[0142] The oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0143] The preparation process is as described in Example 21: The resulting blank self-microemulsion composition without lamotrigine was a clear and transparent solution that formed a uniform self-emulsifying solution in pure water in 30 seconds, with a particle size of 17 nm.

[0144] Comparative Example 1

[0145] The prescription is as follows:

[0146] Lamotrigine: 110 mg;

[0147] The total mass of the SMEDDS carrier is 1000 mg: the oil phase is 300 mg of rose oil; the emulsifier is 350 mg of polyoxyethylene castor oil; and the co-emulsifier is 350 mg of PEG400.

[0148] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition has a pale blue opalescence and a particle size of 18 nm after dispersion in pure water.

[0149] Comparative Example 2

[0150] The prescription is as follows:

[0151] Lamotrigine: 140 mg;

[0152] The total mass of the SMEDDS carrier is 1000 mg: the oil phase is 300 mg of rose oil; the emulsifier is 350 mg of polyoxyethylene castor oil; and the co-emulsifier is 350 mg of PEG400.

[0153] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition is milky white and contains API precipitate after dispersion in pure water.

[0154] Comparative Example 3

[0155] The prescription is as follows:

[0156] Lamotrigine: 90 mg;

[0157] The total mass of the SMEDDS carrier is 1000 mg: the oil phase is 300 mg of rose oil; the emulsifier is 467 mg of polyoxyethylene castor oil; and the co-emulsifier is 233 mg of Tween 80.

[0158] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition has a pale blue opalescence and a particle size of 30 nm after dispersion in pure water.

[0159] Comparative Example 4

[0160] The prescription is as follows:

[0161] Lamotrigine: 110 mg;

[0162] The total mass of the SMEDDS carrier is 1000 mg: the oil phase is 300 mg of rose oil; the emulsifier is 467 mg of polyoxyethylene castor oil; and the co-emulsifier is 233 mg of Tween 80.

[0163] The preparation process is as described in Example 21: The resulting lamotrigine self-microemulsion composition is milky white with turbidity points, and API precipitates out after dispersion in pure water.

[0164] Analysis of Examples 21-33 and Comparative Examples 1-4 shows that the oil phase is composed of monolinoleic acid glyceride and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is diethylene glycol monoethyl ether and ethanol (1:1, 2:1, 3:1, 4:1). The lamotrigine self-microemulsion system is transparent, with a lamotrigine loading of 18.7%, and the particle size after self-emulsification in pure water is less than 50 nm.

[0165] Experiment 9: Stability Study

[0166] Stability tests were conducted on lamotrigine-containing self-microemulsion compositions prepared according to the formulations of Examples 21-33 and Comparative Examples 1-4. The compositions were placed at room temperature, 4°C, and room temperature with 15% water added for 24 hours, respectively, and the stability of the lamotrigine-containing self-microemulsion composition system was observed. The results are shown in the table below:

[0167] Table 3. Stability study of the self-microemulsions prepared in Examples 21-33 and Comparative Examples 1-4

[0168] Test conditions 4 degrees Celsius room temperature Room temperature and add 15% water Example 21 No precipitation No precipitation No precipitation Example 22 No precipitation No precipitation No precipitation Example 23 No precipitation No precipitation No precipitation Example 24 No precipitation No precipitation No precipitation Example 25 Slight precipitation Slight precipitation Precipitation Example 26 No precipitation No precipitation No precipitation Example 27 No precipitation No precipitation No precipitation Example 28 No precipitation No precipitation No precipitation Example 29 No precipitation No precipitation No precipitation Example 30 No precipitation No precipitation Precipitation Example 31 No precipitation No precipitation No precipitation Example 32 Slight precipitation Slight precipitation Precipitation Example 33 No precipitation No precipitation No precipitation Comparative Example 1 No precipitation No precipitation Slight precipitation Comparative Example 2 Precipitation Large amount of precipitation Large amount of precipitation Comparative Example 3 No precipitation No precipitation Precipitation Comparative Example 4 Precipitation Large amount of precipitation Large amount of precipitation

[0169] The stability test data above show that existing technologies use rose oil as the oil phase, CR-EL as the emulsifier, and PEG400 or Tween 80 as the co-emulsifier, with lamotrigine loading concentrations of 10% and 8%, respectively, and a maximum lamotrigine loading concentration of approximately 100 mg / g. Comparative Examples 2 and 4, when lamotrigine was added at concentrations of 12.3% and 10% at 140 nm and 110 nm, respectively, could not form a self-microemulsion system; the system was milky white, and a large amount of lamotrigine precipitated upon the addition of water. Therefore, the mixed oil phase, emulsifier, and co-emulsifier composition selected in this invention, and its preferred composition ratio, not only significantly increase the lamotrigine loading capacity (Example 31 contains up to 18.7% lamotrigine, w / w), but also form a stable self-microemulsion composition system.

[0170] Experiment 10: Pharmaceutical formulations containing lamotrigine self-microemulsion compositions

[0171] Example 22 Soft capsule or hard capsule formulation

[0172] Any of the self-microemulsion stock solutions prepared in Examples 1-33 above that can form self-microemulsion compositions are given an appropriate amount of antioxidant. The antioxidant used can be one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol), preferably vitamin E. The prepared self-microemulsion stock solution is then packaged into soft capsules or hard capsules to obtain self-microemulsion capsules. The lamotrigine self-microemulsion capsules prepared according to Example 21 contain 16.7% lamotrigine by mass, with a capsule size of 0.3 ml to 0.5 ml / capsule, containing approximately 50.1 to 83.5 mg of lamotrigine per capsule. The lamotrigine self-microemulsion capsules prepared according to Example 31 contain 18.7% lamotrigine by mass, with a capsule size of 0.3 ml to 0.5 ml / capsule, containing approximately 56.1 to 93.5 mg of lamotrigine per capsule.

[0173] Example 23 Tablets or Granules

[0174] The self-microemulsion stock solution prepared in any of the examples 1-33 above, capable of forming a self-microemulsion composition, is self-emulsified with ten times its volume of pure water. This stock solution is then mixed with a porous solid excipient to prepare a soft mass. Following conventional tablet or granule preparation procedures (soft mass preparation, granulation, drying, mixing, tableting, packaging, etc.), tablets or granules of the lamotrigine self-microemulsion system are produced. The porous excipients include, for example, hydroxypropyl methylcellulose, silica, and cyclodextrin.

[0175] Example 24 Thermosensitive Gel Formulation-1

[0176] Any of the self-microemulsion stock solutions prepared in Examples 1-33 above that can form a self-microemulsion composition were dispersed in 4 times the volume of pure water to form a self-emulsifying solution. The poracil composition was then added to the self-emulsifying solution and stirred until homogeneous to form a gel solution. The solution was stored at 4°C for 24 hours to allow for full swelling and removal of air bubbles, thus obtaining a thermosensitive gel containing the lamotrigine self-microemulsion composition. 0.1% of a preservative (sodium benzoate:potassium sorbate = 1:1) was then added, and the pH of the gel solution was adjusted to between 5 and 6.5 using a conventional acid-base solution. The gelation temperature of this example was measured to be 32.1°C using the inverted test tube method.

[0177] The poracil composition comprises 21 parts of poracil 407 and 2 parts of poracil 188, and the mass ratio of the self-emulsifying solution (self-microemulsion stock solution: pure water = 1:4) to the poracil composition is 4:1. The preservative may also be one or two of benzalkonium bromide, sodium benzoate, and potassium sorbate. The antioxidant may also be one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol). The preservative is one or two of benzalkonium bromide, sodium benzoate, and potassium sorbate, preferably sodium benzoate and potassium sorbate in a mass ratio of 1:1.

[0178] Example 24 Thermosensitive Gel Formulation-2

[0179] Preparation process: Under light-protected conditions at 37°C, the emulsifier and co-emulsifier were weighed according to the formulation amounts in Examples 1-33 that can form a self-microemulsion, and ultrasonically stirred to obtain mixture one. Lamotrigine and 0.1% preservative (sodium benzoate and potassium sorbate in a mass ratio of 1:1) were added to mixture one and ultrasonically stirred to obtain mixture two. 0.1% antioxidant vitamin E was mixed with the mixed oil phase to obtain mixture three. Mixture three was then added to mixture two and ultrasonically stirred until fully dissolved, thus obtaining the self-microemulsion solution. The prepared self-microemulsion solution was dispersed with 4 times the amount of pure water to form a self-emulsifying solution. The poracil composition was added to the self-emulsifying solution and stirred until uniform to form a gel solution. The gel solution was stored at 4°C for 24 hours to allow full swelling and removal of air bubbles, thus obtaining a thermosensitive gel containing the lamotrigine self-microemulsion composition. The pH of the gel solution was adjusted to between 5 and 6.5 using conventional acid-base solutions. The gelation temperature of this example was measured to be 32.0°C using the inverted test tube method.

[0180] The self-emulsifying solution (self-microemulsion stock solution: pure water = 1:4) and the porasarm composition have a mass ratio of 4:1. The porasarm composition consists of 21 parts of porasarm 407 and 2 parts of porasarm 188. The antioxidant may also be one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol). The preservative may also be one or two of benzalkonium bromide, sodium benzoate, and potassium sorbate, preferably sodium benzoate and potassium sorbate in a mass ratio of 1:1.

[0181] Taking the thermosensitive gel formulation prepared from the self-microemulsion composition containing lamotrigine as an example (prepared in Example 21 with a lamotrigine mass concentration of 16.7%), the concentration of lamotrigine in the thermosensitive gel formulation is 27.8 mg / g, approximately 27.8 mg / ml. Nasal administration is 0.1 ml per dose, and the nasal administration dose of lamotrigine is approximately 2.78 mg per dose, which can meet the needs of children with epilepsy and patients requiring rapid onset of action.

[0182] Combining the thermosensitive gels containing lamotrigine self-microemulsion compositions prepared in Examples 23 and 24, this invention overcomes the problems of lamotrigine, as a BCSII, being highly lipid-soluble and poorly soluble in aqueous media, as well as the need for rapid onset of action and reaching an effective dosage for the prevention and treatment of epileptic seizures. Combining the advantages of both the self-microemulsion system and the thermosensitive gel, the self-microemulsion system improves the solubility of lamotrigine in aqueous media, achieving a drug loading of 18.7% in the self-microemulsion stock solution. Furthermore, it forms microemulsions in aqueous media with particle sizes less than 50 nm or even less than 20 nm, resulting in better dissolution and absorption and higher bioavailability. The thermosensitive gel formulation, administered via nasal administration, allows the drug to reach the brain more rapidly for the prevention and treatment of epileptic seizures. Moreover, the thermosensitive gel prepared by this invention can also be used as a transdermal thermosensitive gel. The thermosensitive gel formulation containing the lamotrigine self-microemulsion composition prepared in Example 21 (lamotrigine mass concentration of 16.7%) has a concentration of 27.8 mg / g, approximately 27.8 mg / ml. The nasal administration dose is 0.1 ml per dose, while the nasal administration dose of lamotrigine is approximately 2.78 mg per dose, which can meet the needs of children with epilepsy and patients who require rapid onset of action.

[0183] Experiment 11: Pharmacokinetic Study in Beagle Dogs

[0184] This experimental example provides pharmacokinetic tests of the soft capsules (0.3 ml / capsule, containing approximately 50.1 mg / capsule of lamotrigine, calculated as 50 mg / capsule) prepared in Example 21 and the original lamotrigine tablets (Lipitor).

[0185] Test methods and targets:

[0186] Six healthy beagle dogs were randomly divided into three groups of two each for a fasting test. The dogs were fasted for 10 hours before the test, administered the drug on an empty stomach, and were fed 4 hours after administration.

[0187] The reference formulation is the original lamotrigine tablet (Lipitor), containing 50 mg of lamotrigine per tablet;

[0188] The homemade soft capsule is the lamotrigine soft capsule provided in Example 21, containing 50 mg of lamotrigine per capsule.

[0189] Sampling Design: Blood samples (2 mL each) were collected at 0.25 h, 0.5 h, 1 h, 1.5 h, 2.0 h, 2.5 h, 3 h, 3.5 h, 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 h after drug administration. Plasma was separated by centrifugation. Blood drug concentration was measured, and pharmacokinetic parameters were statistically analyzed. See the table below:

[0190] Among them, T max To reach peak time, C max The maximum plasma concentration (peak concentration) is AUC. 0-72h AUC (area of ​​the drug-time curve) is the duration from the start of drug administration to the last point.

[0191] The results are attached. Figure 1 The figure shows the drug-time curves of lamotrigine soft capsules (self-made soft capsule preparation, containing 50 mg / capsule of lamotrigine) and the original lamotrigine tablets (Lipitor, containing 50 mg / tablet of lamotrigine) provided in Example 21 in the fasting test in beagle dogs under fasting conditions.

[0192] Table 4. Pharmacokinetic statistical analysis of self-made capsules and reference lamotrigine tablets (Mean±SD(CV%))

[0193] Pharmacokinetic parameters Test formulation (T) (N=3) Reference formulation (R) (N=3) <![CDATA[T max (h)]]> 0.25(0.25，1.00) 1.00(0.5，3.50) <![CDATA[C max (ng / mL)]]> 3705.931±98.025(7.23) 1925.871±214.368(25.05) <![CDATA[AUC 0-72h (h.ng / mL)]]> 52902.4±752.0(6.34) 26933.9±4085.8(21.17)

[0194] Note: T max Represented by median (minimum, maximum)

[0195] As shown in the table above, the time to peak concentration (Tmax) of lamotrigine soft capsules (self-made) administered orally on an empty stomach in beagles was faster than that of the original lamotrigine tablets, indicating that the self-made lamotrigine soft capsules were absorbed more quickly; the maximum plasma concentration (Cmax) of the self-made lamotrigine soft capsules was... max It has 1.9 times the AUC of the original lamotrigine tablets and the self-made lamotrigine soft capsules. 0-72h Converted to 50mg, it is approximately twice the dose of the original lamotrigine tablets; furthermore, from C max AUC 0-72hThe coefficient of variation (CV%) of the self-made lamotrigine soft capsules was significantly lower than that of the original lamotrigine tablets. The coefficient of variation among individuals taking the self-made lamotrigine soft capsules was also lower, effectively reducing adverse reactions caused by individual differences.

[0196] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A formulation containing a lamotrigine self-microemulsion composition, characterized in that: The self-microemulsion composition containing lamotrigine consists of lamotrigine, an oil phase, an emulsifier, and a co-emulsifier; the oil phase is glyceryl monolinoleate and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether. The self-microemulsion composition containing lamotrigine contains 18.7% or less lamotrigine by mass ratio, and the ratio of oil phase: emulsifier: co-emulsifier is (2.8-3.0): (1.7-2.0): (5.0-5.4). The mass ratio of the oil phase monolinoleic acid glyceride to the medium-chain triglyceride is 4:1, and the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is one of 1:1, 3:1, or 4:

1. The preparation method of the self-microemulsion composition containing lamotrigine is as follows: Under the conditions of 37°C and protection from light, the emulsifier and co-emulsifier are weighed according to the prescribed amount of the self-microemulsion composition containing lamotrigine and ultrasonically stirred and mixed evenly to obtain mixture one. Lamotrigine is added to mixture one and ultrasonically stirred and mixed evenly to obtain mixture two. Then, the mixed oil phase is added to mixture two and ultrasonically stirred to fully dissolve it, thereby obtaining the self-microemulsion composition containing lamotrigine, i.e., the self-microemulsion stock solution. The formulation containing the lamotrigine self-microemulsion composition is a soft capsule. The self-microemulsion stock solution containing the lamotrigine self-microemulsion composition is mixed with an appropriate amount of antioxidant and then encapsulated in a soft capsule to obtain a self-microemulsion capsule. The antioxidant used is one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E.

2. The formulation containing the lamotrigine self-microemulsion composition according to claim 1, characterized in that: The antioxidant used is vitamin E.

3. A formulation containing a lamotrigine self-microemulsion composition, characterized in that: The self-microemulsion composition containing lamotrigine consists of lamotrigine, an oil phase, an emulsifier, and a co-emulsifier; the oil phase is glyceryl monolinoleate and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether. The self-microemulsion composition containing lamotrigine contains 18.7% or less lamotrigine by mass ratio, and the ratio of oil phase: emulsifier: co-emulsifier is (2.8-3.0): (1.7-2.0): (5.0-5.4). The mass ratio of the oil phase monolinoleic acid glyceride to the medium-chain triglyceride is 4:1, and the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is one of 1:1, 3:1, or 4:

1. The preparation method of the self-microemulsion composition containing lamotrigine is as follows: Under the conditions of 37°C and protection from light, the emulsifier and co-emulsifier are weighed according to the prescribed amount of the self-microemulsion composition containing lamotrigine and ultrasonically stirred and mixed evenly to obtain mixture one. Lamotrigine is added to mixture one and ultrasonically stirred and mixed evenly to obtain mixture two. Then, the mixed oil phase is added to mixture two and ultrasonically stirred to fully dissolve it, thereby obtaining the self-microemulsion composition containing lamotrigine, i.e., the self-microemulsion stock solution. The formulation containing the lamotrigine self-microemulsion composition is a tablet or granule. The self-microemulsion stock solution containing the lamotrigine is self-emulsified with ten times the amount of pure water, mixed with a porous solid excipient to prepare a soft mass, and then granulated, dried, and packaged to form lamotrigine self-microemulsion system granules or granulated, dried, mixed, compressed, and packaged to form lamotrigine self-microemulsion system tablets. The porous excipient is one, two, or three of hydroxypropyl methylcellulose, silica, and cyclodextrin.

4. A formulation containing a lamotrigine self-microemulsion composition, characterized in that: The self-microemulsion composition containing lamotrigine consists of lamotrigine, an oil phase, an emulsifier, and a co-emulsifier; the oil phase is glyceryl monolinoleate and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether. The self-microemulsion composition containing lamotrigine contains 18.7% or less lamotrigine by mass ratio, and the ratio of oil phase: emulsifier: co-emulsifier is (2.8-3.0): (1.7-2.0): (5.0-5.4). The mass ratio of the oil phase monolinoleic acid glyceride to the medium-chain triglyceride is 4:1, and the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is one of 1:1, 3:1, or 4:

1. The preparation method of the self-microemulsion composition containing lamotrigine is as follows: Under the conditions of 37°C and protection from light, the emulsifier and co-emulsifier are weighed according to the prescribed amount of the self-microemulsion composition containing lamotrigine and ultrasonically stirred and mixed evenly to obtain mixture one. Lamotrigine is added to mixture one and ultrasonically stirred and mixed evenly to obtain mixture two. Then, the mixed oil phase is added to mixture two and ultrasonically stirred to fully dissolve it, thereby obtaining the self-microemulsion composition containing lamotrigine, i.e., the self-microemulsion stock solution. The formulation containing the lamotrigine self-microemulsion composition is a thermosensitive gel formulation. The self-microemulsion stock solution containing the lamotrigine is dispersed with 4 times the amount of pure water to form a self-emulsifying solution. The poracil composition is added to the self-emulsifying solution and stirred evenly to form a gel solution. The solution is stored at 4 degrees Celsius to allow it to fully swell and remove air bubbles, thus obtaining a thermosensitive gel containing the lamotrigine self-microemulsion composition. The self-emulsifying solution (self-microemulsion stock solution: pure water = 1:4) and the poracil composition have a mass ratio of 4:

1. The poracil composition consists of 21 parts of poracil 407 and 2 parts of poracil 188.

5. The formulation containing the lamotrigine self-microemulsion composition according to claim 4, characterized in that: The preparation process of the lamotrigine self-microemulsion composition formulation is as follows: Under light-protected conditions at 37°C, the emulsifier and co-emulsifier are weighed according to the formula of the self-microemulsion as described in claim 4 and ultrasonically stirred and mixed evenly to obtain mixture one. Lamotrigine and preservative are added to mixture one and ultrasonically stirred and mixed evenly to obtain mixture two. Antioxidant is mixed with the mixed oil phase to obtain mixture three. Mixture three is then added to mixture two and ultrasonically stirred to fully dissolve, thus obtaining the self-microemulsion solution. The prepared self-microemulsion solution is dispersed with 4 times the amount of pure water to form a self-emulsifying solution. The poracil composition is added to the self-emulsifying solution and stirred evenly to form a gel solution. The solution is stored at 4°C to allow it to fully swell and remove air bubbles, thus obtaining a thermosensitive gel containing the lamotrigine self-microemulsion composition. The pH value of the gel solution is adjusted to between 5 and 6.5 with an acid or alkali solution to obtain a thermosensitive gel containing the lamotrigine self-microemulsion composition. The antioxidant is one or two of tert-butyl-p-hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E; the preservative is one or two of benzalkonium bromide, sodium benzoate, and potassium sorbate.

6. The formulation containing the lamotrigine self-microemulsion composition according to claim 5, characterized in that: The preservative is 0.1% preservative, which is sodium benzoate and potassium sorbate in a mass ratio of 1:1; the antioxidant is 0.1% vitamin E.

7. The formulation containing the lamotrigine self-microemulsion composition according to any one of claims 1-6, characterized in that: The mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is 4:1, and the mass ratio of the emulsifier to the co-emulsifier is 2:

5.

8. A formulation containing a lamotrigine self-microemulsion composition according to claim 7, characterized in that: The microemulsions formed by dispersing the microemulsion composition into an aqueous medium have a particle size of less than 50 nm or even less than 20 nm.

9. Use of the formulation of the self-microemulsion composition containing lamotrigine according to any one of claims 1-8 in the preparation of a medicament for the prevention or treatment of epilepsy.

10. The use of the thermosensitive gel formulation of the self-microemulsion composition containing lamotrigine according to any one of claims 4-8 in the preparation of a medicament for nasal or transdermal administration.

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