A formulation containing a lamotrigine self-microemulsifying composition and use thereof

Abstract

The present application relates to the technical field of medicine, in particular to a kind of preparation and application of self-microemulsifying composition containing lamotrigine.The self-microemulsifying composition includes lamotrigine and self-microemulsifying drug delivery system (SMEDDS) carrier;The SMEDDS carrier includes: by lamotrigine, oil phase, emulsifier and co-emulsifier;The self-microemulsifying composition, by mass ratio, lamotrigine is 0.1% to 18.7%, oil phase is 20% to 33%, milk phase is 67% to 80%, the milk phase is by emulsifier and co-emulsifier, and the mass ratio of emulsifier and co-emulsifier is 25.7 to 32.9%:67.1% to 74.3%, and the mass concentration of lamotrigine reaches 18.7%.The particle size of microemulsion formed by the self-microemulsifying composition dispersed in aqueous medium is less than 50nm or even smaller.The self-microemulsifying composition is prepared into soft capsule, hard capsule, tablet, granule, temperature-sensitive gel and other dosage forms, and is applied in the preparation of antiepileptic drugs.

Description

[0001] This application is a divisional application of Chinese Patent Application No. CN 202211465735.2, filed on November 22, 2022, entitled "Self-microemulsion composition containing lamotrigine and application thereof". TECHNICAL FIELD

[0002] The present application relates to the field of medicine, in particular to a self-microemulsion composition containing lamotrigine and its application. BACKGROUND

[0003] Epilepsy is a chronic recurrent neurological disease caused by various causes, characterized by recurrent seizures caused by abnormal discharge of brain neurons, with a prevalence of 5%. There are currently about 9 million epilepsy patients in China, with about 600,000 new cases each year. Lamotrigine, with the chemical name of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is a phenyltriazine antiepileptic drug with poor solubility, belonging to BCSII. Lamotrigine mainly acts on voltage-dependent sodium channels and has an inhibitory effect on repetitive discharge, and may also act on glutamate-related neurotransmitters. It can inhibit glutamate and aspartate and can stabilize the presynaptic membrane and inhibit the release of glutamate and aspartate. It is mainly used for the treatment of intractable epilepsy. The dosage of lamotrigine in the instructions for use is generally 25 mg / day, and the maintenance dose is as high as 200 mg / day. The commonly used lamotrigine tablets on the Chinese market are ordinary tablets, and tablet formulations containing 25 mg, 50 mg, 100 mg, and 150 mg of active ingredients have been approved for sale.

[0004] Chinese Invention Patent CN111407725A discloses a lamotrigine emulsion and its preparation method, which comprises 0.1-1% lamotrigine, an oil phase, an oil phase solubilizer, an emulsifier, and an emulsification system. The preparation method uses high-speed shearing, the emulsion droplet size is between 200-350 nm, the original liquid system is not stable enough, and the actual concentration of lamotrigine in the original liquid system in the optimal example is 23 mg / 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 nanoemulsion system containing lamotrigine, with 30% rose oil, 35% CR-EL, 35% T80 or PEG400, the mass concentration of lamotrigine in the nanoemulsion stock solution was 5%, about 50mg / ml, and the drug loading amount still needs to be improved for the clinical treatment of lamotrigine with a high maintenance dose of up to 200mg / day.

[0006] S. Melamane et al (Formulation optimization of smart thermosetting lamotrigine loaded hydrogels using response surface methodology, Box Benhken design and artificial neural networks. Drug Development and Industrial Pharmacy. 2020. DOI: 10.1080 / 03639045.2020.1791163) reported a lamotrigine nasal warm-sensitive gel, which loaded lamotrigine at a concentration of only 5mg / ml, although nasal administration can improve the bioavailability by about 2 times compared with oral administration, but for the daily dosage of lamotrigine or children's medication, the loaded lamotrigine concentration is still limited. SUMMARY

[0007] In view of the deficiencies of the prior art, the purpose of the present application is to provide a lamotrigine self-microemulsion composition formulation and application, which can effectively increase the drug loading amount of lamotrigine in the self-microemulsion composition solution, and can stably exist at room temperature with or without pure water, and the preparation process of the self-emulsifying composition system is simple, which does not need high-speed shearing, but only needs simple ultrasonic stirring, the self-emulsifying and dispersing time in aqueous medium is short, and the further preparation into a pharmaceutical preparation effectively improves the bioavailability.

[0008] In order to solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0009] In one aspect, the present application provides a self-microemulsifying composition containing lamotrigine, comprising lamotrigine, oil phase, emulsifier and co-emulsifier; the self-microemulsifying composition contains 0.1% to 18.7% of lamotrigine, 20% to 33% of oil phase, 67% to 80% of emulsion phase, and the emulsion phase is composed of emulsifier and co-emulsifier, and the mass ratio of emulsifier to co-emulsifier is 25.7% to 31.4%: 68.6% to 74.3%.

[0010] Further, the oil phase is glyceryl monolinoleate and or medium-chain triglyceride, the emulsifier is one or both of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene castor oil, oleoyl polyoxyethylene glycerol, and polyoxyethylene-15 hydroxystearate (solutol HS15), and the co-emulsifier is one or both of tween 80, PEG400, propylene glycol, and diethylene glycol monoethyl ether.

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

[0012] Further, the mass ratio of glyceryl monolinoleate to medium-chain triglyceride in the oil phase is 4:1, and the mass ratio of PEG400 to diethylene glycol monoethyl ether in the co-emulsifier is 4:1.

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

[0014] A preparation method of a self-microemulsifying composition containing lamotrigine: under the conditions of 37℃ and avoiding light, the emulsifier and co-emulsifier are weighed according to the prescription amount of the self-microemulsifying composition containing lamotrigine described above, and are mixed uniformly by ultrasonic stirring to obtain a mixture one, lamotrigine is added to the mixture one, and is mixed uniformly by ultrasonic stirring to obtain a mixture two, and then a mixed oil phase is added to the mixture two, and is dissolved sufficiently by ultrasonic stirring, thereby obtaining the self-microemulsifying composition containing lamotrigine.

[0015] Further, the mass percentage of lamotrigine in the prepared self-microemulsifying composition is less than or equal to 18.7%, and the particle size of the microemulsion formed by dispersing the self-microemulsifying composition into an aqueous medium is less than 50 nm or less than 20 nm or even smaller.

[0016] Further, the self-microemulsifying composition containing lamotrigine can be added with an appropriate amount of antioxidant (e.g. 0.1%, w / w), and the antioxidant used can be one or two of t-butyl hydroxy anisole (BHA), butylated hydroxytoluene (BHT), vitamin C, vitamin E (dl-alpha-tocopherol), preferably vitamin E, and the self-microemulsifying composition containing lamotrigine prepared from the stock solution is filled into soft capsules or hard capsules to obtain self-microemulsifying capsules. The self-microemulsifying lamotrigine capsules prepared have a mass concentration of lamotrigine of 16.7% to 18.7%, a capsule size of 0.3 ml to 0.5 ml per capsule, and contain about 50.1 to 93.5 mg of lamotrigine per capsule.

[0017] Further, the self-microemulsifying composition containing lamotrigine prepared from the stock solution is self-emulsified with ten times the amount of purified water, mixed with a solid excipient having pores to prepare a soft material, and the self-microemulsifying lamotrigine system is prepared into tablets or granules according to the conventional preparation process (preparation of a soft material, granulation, drying, total mixing, tabletting, and packaging, etc.) for tablets or granules. The excipient having pores can be an excipient such as hydroxypropyl methylcellulose, silicon dioxide, or cyclodextrin.

[0018] Further, the self-microemulsifying composition containing lamotrigine is self-emulsified with ten times the amount of purified water, mixed with a solid excipient having pores to prepare a soft material, and the self-microemulsifying lamotrigine system is prepared into granules by granulation, drying, and packaging or into tablets by granulation, drying, total mixing, tabletting, and packaging. The excipient having pores can be one or two or three of hydroxypropyl methylcellulose, silicon dioxide, and cyclodextrin.

[0019] Further, the self-microemulsifying composition containing lamotrigine prepared from the stock solution is added with 0.1% of an antioxidant and 0.1% of a preservative, and the antioxidant used can be one or two of t-butyl hydroxy anisole (BHA), butylated hydroxytoluene (BHT), vitamin C, vitamin E (dl-alpha-tocopherol), preferably vitamin E, and the preservative used can be sodium benzoate, potassium sorbate, or a combination thereof. The antioxidant vitamin E can be added to the oil phase and mixed, and the preservative can be added to the co-emulsifier and mixed.

[0020] Preparation process: at 37℃ and in the dark, the emulsifier and co-emulsifier were weighed according to the prescription amount, and then were mixed uniformly by ultrasonic stirring to obtain mixture one; the lamotrigine, preservative (sodium benzoate and potassium sorbate with a mass ratio of 1:1) were added to mixture one and mixed uniformly by ultrasonic stirring to obtain mixture two; vitamin E was mixed with the mixed oil to obtain mixture three; mixture three was added to mixture two, and ultrasonic stirring was performed to make it fully dissolved, thereby obtaining the self-microemulsion solution. The prepared self-microemulsion solution was dispersed into 4 times of pure water to form a self-emulsifying solution, the poloxamer composition was added to the self-emulsifying solution and stirred uniformly to form a gel solution, the pH value of the gel solution was adjusted to 5-6.5, and then the mixture was stirred uniformly and stored at 4℃ for 24 hours to make it fully swell and exhaust air bubbles, thereby obtaining the self-microemulsion solution.

[0021] The mass ratio of the self-emulsifying solution to the poloxamer composition is 4:1, and the poloxamer composition is composed of 21 parts of poloxamer 407 and 2 parts of poloxamer 188. The temperature-sensitive gel preparation prepared in Example 21 (the mass concentration of lamotrigine is 16.7%) is 27.8 mg / g, about 27.8 mg / ml, which is more than 5 times of the lamotrigine concentration 5 mg / ml in the lamotrigine nasal temperature-sensitive gel reported by S. Melamane et al., and the self-microemulsion system provided by the present application is more uniform and stable. It can meet the needs of children with epilepsy and patients who need rapid effect, and the temperature-sensitive gel transdermal drug delivery.

[0022] The self-microemulsion composition containing lamotrigine is used for preparing a drug for preventing or treating epilepsy; the temperature-sensitive gel preparation of the self-microemulsion composition containing lamotrigine is used for preparing a drug for nasal administration or transdermal administration.

[0023] The self-microemulsion composition containing lamotrigine provided by the application is prepared by optimizing the type and combination of the oil phase, the type and combination of the specific emulsifier and the co-emulsifier, and the ratio of the oil phase, the emulsifier and the co-emulsifier, and the preparation method of the self-microemulsion composition, and the preparation method is simple, does not need high-speed shearing, and can form a clear and transparent self-microemulsion solution by simple ultrasonic stirring; the self-microemulsion composition prepared contains lamotrigine with a mass ratio as high as 18.7%, that is, 187 mg / g, which meets the requirement of the maintenance dose of lamotrigine for anti-epilepsy treatment in the clinic as high as 200 mg / day; the preparation of the self-microemulsion composition containing lamotrigine has an AUC0-72h that is 2 times higher than that of the common lamotrigine tablet after administration, and the coefficient of variation CV% among individuals is small, thereby reducing the occurrence of adverse reactions of lamotrigine; the self-microemulsion composition containing lamotrigine prepared can spontaneously form a clear, transparent, uniform and stable O / W microemulsion with a particle size of less than 50 nm or less than 30 nm or even less than 20 nm when mixed with water, a biologically related medium (for example, SGF, SGF, FessiF and FassiF medium) or a gastrointestinal fluid; the self-microemulsion composition containing lamotrigine prepared can be stored with or without water at room temperature or 4 degrees Celsius, and the self-microemulsion solution system can exist in the form of a stable solution. The self-microemulsion composition containing lamotrigine of the application has a high concentration of lamotrigine and a uniform and stable self-microemulsion solution system. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 Figure 2 is a graph (n=3, mean±SD) for the pharmacokinetic comparison of the self-made soft capsule and the original lamotrigine tablet in beagle dogs. DETAILED DESCRIPTION

[0025] In order to further describe the application, the application will be further described in detail in combination with the examples below, but the application is not limited to the specific examples.

[0026] Test one: the solubility determination method is as follows:

[0027] 5 mL of the oil phase, the emulsifier and the co-emulsifier were respectively taken in test tubes, and an excess amount of equal amount of lamotrigine was respectively added, 37℃ was kept, and shaking was performed for 24 hours, then high-speed centrifugation was performed, the supernatant was taken, diluted with the mobile phase, and the equilibrium solubility was detected.

[0028] It is found by the test that the solubility of lamotrigine in rose oil is about 41 mg / ml, the solubility in monolinolein is about 112 mg / ml, the solubility in PEG400 is about 240 mg / ml, and the solubility in diethylene glycol monoethyl ether is about 169 mg / ml.

[0029] Test two: test of oil phase type selection and mixed oil phase ratio

[0030] The solubility of lamotrigine was investigated by mixing monolinolein and rose oil or medium-chain triglyceride at different mass ratios (1:1, 2:1, 3:1, 4:1, 5:1, 1:2, 1:3, 1:4, 1:5) respectively. It was found that the various combinations of monolinolein and rose oil did not significantly improve the solubility of lamotrigine; however, the combination of monolinolein and medium-chain triglyceride resulted in a larger amount of lamotrigine being loaded than when monolinolein or medium-chain triglyceride was used alone, and the solubility of lamotrigine was the largest when the mass ratio of monolinolein to medium-chain triglyceride was 4:1 or 5:1. In subsequent studies on the combination of emulsifiers polyoxyethylene 40 hydrogenated castor oil and co-emulsifiers, it was found that the self-emulsification time of the self-microemulsion system prepared using monolinolein and medium-chain triglyceride at a mass ratio of 4:1 was faster than that of the system prepared using monolinolein and medium-chain triglyceride at a mass ratio of 5:1 in pure water, so the mass ratio of monolinolein to medium-chain triglyceride was preferably 4:1.

[0031] Test three: transmittance test of emulsifiers and co-emulsifiers

[0032] The transmittance of the mixture of different emulsifiers, co-emulsifiers and mixed oil phase (monolinolein and medium-chain triglyceride at a mass ratio of 4:1) at a mass ratio of 1:1 was investigated. It was found that the microemulsions formed by polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene castor oil, oleoyl polyoxyethylene glycerol, polyoxyethylene-15 hydroxystearate (solutol HS 15), Tween 80, PEG400, propylene glycol, diethylene glycol monoethyl ether and ethanol and the mixed oil phase were clear and transparent, with a transmittance of more than 90%.

[0033] Test four: selection of emulsifiers and co-emulsifiers

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

[0035] Prescription:

[0036] Lamotrigine: appropriate amount; the total mass of the SMEDDS carrier is 1000 mg: the mass ratio of the oil phase, emulsifier and co-emulsifier is 3:2:5. The oil phase is monolinolein 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) Emulsion phase / % (w / w) Emulsification state after 1 gram of self-emulsifying system was added to 100 g of water 20 80 Clear and transparent 25 75 Clear and transparent 28 72 Clear and transparent, slightly bluish opalescence 30 70 Transparent with slightly bluish opalescence 33 67 Bluish opalescence 35 65 Opalescent 38 62 Hazy, with API precipitation, 40 60 Hazy, with API precipitation, with 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 with 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) T max (h)]]> 0.25(0.25，1.00) 1.00(0.5，3.50) C max (ng / mL) 3705.931±98.025(7.23) 1925.871±214.368(25.05) 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 comprising a self-microemulsifying composition of lamotrigine, characterized in that: The self-microemulsion composition containing lamotrigine is composed of lamotrigine, an oil phase, an emulsifier and a co-emulsifier; the oil phase is glyceryl monolinoleate and medium-chain triglyceride, 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 lamotrigine less than or equal to 18.7% by mass ratio, and the 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 glyceryl monolinoleate and medium-chain triglyceride is 4:1, and the mass ratio of the co-emulsifier PEG400:diethylene glycol monoethyl ether is one of 1:1, 3:1 and 4:

1. The preparation method of the self-microemulsion composition containing lamotrigine is as follows: under the conditions of 37 DEG C and light avoidance, the emulsifier and the co-emulsifier are weighed according to the prescription amount of the self-microemulsion composition containing lamotrigine, and then are uniformly mixed by ultrasonic stirring to obtain a mixture one; lamotrigine is added into the mixture one and uniformly mixed by ultrasonic stirring to obtain a mixture two; and then the mixed oil phase is added into the mixture two and is fully dissolved by ultrasonic stirring, so that the self-microemulsion composition containing lamotrigine, i.e. the self-microemulsion stock solution, is obtained. The preparation of the self-microemulsion composition containing lamotrigine is a soft capsule, the self-microemulsion stock solution of the self-microemulsion composition containing lamotrigine is added with an appropriate amount of antioxidant, and then is filled into a soft capsule to obtain a self-microemulsion capsule; the antioxidant used is one or two of tert-butyl hydroxyanisole BHA, butylated hydroxytoluene BHT, vitamin C and vitamin E.

2. The formulation containing lamotrigine self-microemulsifying composition according to claim 1, characterized by: The antioxidant used is vitamin E.

3. A formulation comprising a self-microemulsifying composition of lamotrigine, characterized in that: The self-microemulsion composition containing lamotrigine is composed of lamotrigine, an oil phase, an emulsifier and a co-emulsifier; the oil phase is glyceryl monolinoleate and medium-chain triglyceride, 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 lamotrigine less than or equal to 18.7% by mass ratio, and the 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 glyceryl monolinoleate and medium-chain triglyceride is 4:1, and the mass ratio of the co-emulsifier PEG400:diethylene glycol monoethyl ether is one of 1:1, 3:1 and 4:

1. The preparation method of the self-microemulsion composition containing lamotrigine is as follows: under the conditions of 37 DEG C and light avoidance, the emulsifier and the co-emulsifier are weighed according to the prescription amount of the self-microemulsion composition containing lamotrigine, and then are uniformly mixed by ultrasonic stirring to obtain a mixture one; lamotrigine is added into the mixture one and uniformly mixed by ultrasonic stirring to obtain a mixture two; and then the mixed oil phase is added into the mixture two and is fully dissolved by ultrasonic stirring, so that the self-microemulsion composition containing lamotrigine, i.e. the self-microemulsion stock solution, is obtained. 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 comprising a self-microemulsifying composition of lamotrigine, characterized by: 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, 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°C for 24 hours 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) has a mass ratio of 4:1 to the porasarm composition, which consists of 21 parts of porasarm 407 and 2 parts of porasarm 188.

5. The formulation containing the lamotrigine self-microemulsion composition according to claim 4, characterized in that: The preparation process of the self-microemulsion composition containing lamotrigine: at 37℃ and in the dark, the emulsifier and co-emulsifier are weighed according to the prescription amount of the self-microemulsion of claim 4, and are mixed uniformly by ultrasonic stirring to obtain mixture one, lamotrigine and preservative are added to mixture one and are mixed uniformly by ultrasonic stirring to obtain mixture two, vitamin E and mixed oil phase are mixed to obtain mixture three, and mixture three is added to mixture two and is dissolved sufficiently by ultrasonic stirring, thereby obtaining a self-microemulsion solution; the prepared self-microemulsion solution is dispersed into 4 times of pure water to form a self-emulsifying solution, the poloxamer composition is added to the self-emulsifying solution and is stirred uniformly to form a gel solution, the gel solution is stored at 4℃ for 24 hours, is allowed to swell sufficiently and is deaerated, thereby obtaining a warm-sensitive gel of the self-microemulsion composition containing lamotrigine; the pH value of the gel solution is adjusted to 5-6.5 by an acid-alkali solution, thereby obtaining the warm-sensitive gel of the self-microemulsion composition containing lamotrigine. The preservative is one or two of benzalkonium bromide, sodium benzoate and potassium sorbate.

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

7. The formulation comprising a lamotrigine self-microemulsifying composition according to any one of claims 1 to 6, characterized by: 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 comprising a self-microemulsifying composition of lamotrigine according to claim 7, characterized by: The particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 50 nm.

9. A formulation comprising a self-microemulsifying composition of lamotrigine according to claim 7, characterized by: The particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 20 nm.

10. Use of the self-microemulsion composition containing lamotrigine according to any one of claims 1-9 in the preparation of a medicament for preventing or treating epilepsy.

11. Use of the warm-sensitive gel preparation of the self-microemulsion composition containing lamotrigine according to any one of claims 4-9 in the preparation of a medicament for nasal administration or transdermal administration.

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