A self-microemulsifying composition containing lamotrigine and its application

Abstract

The present invention relates to the field of pharmaceutical technology, specifically to a self-microemulsifying composition containing lamotrigine, its preparation, and application. The self-microemulsifying composition comprises lamotrigine, an oil phase, an emulsifier, and a co-emulsifier. The oil phase comprises monolinolein and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifiers are PEG400 and diethylene glycol monoethyl ether. Calculated by weight, the composition contains less than or equal to 18.7% lamotrigine, and the oil phase: emulsifier: co-emulsifier ratio is (2.8-3.0): (1.7-2.0): (5.0-5.4). When the self-microemulsifying composition is dispersed in an aqueous medium, the microemulsion formed has a particle size of less than 50 nm or even smaller. The self-microemulsifying composition can be prepared into dosage forms such as capsules, tablets, granules, and thermosensitive gels, and its application in the preparation of anti-epileptic drugs is also discussed.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a self-microemulsifying composition containing lamotrigine, a preparation thereof and an application thereof. Background Art

[0002] Epilepsy is a common, chronic, recurrent neurological disorder caused by a variety of etiologies, characterized by recurrent epileptic seizures caused by abnormal brain neuronal discharges. Its prevalence is 5%. Currently, approximately 9 million people with epilepsy live in my country, with approximately 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 BCS class II. Lamotrigine primarily acts on voltage-dependent sodium channels, inhibiting recurrent discharges. It may also act on glutamate-related neurotransmitters. As an antiepileptic drug that inhibits glutamate and aspartate, it stabilizes presynaptic membranes and inhibits the release of glutamate and aspartate. It is primarily used to treat intractable epilepsy. The instructions for use of lamotrigine tablets state that the starting dose of lamotrigine is generally 25 mg / day, with a maintenance dose of up to 200 mg / day. Currently, the lamotrigine tablets commonly used in the Chinese market are regular tablets, and tablet preparations containing 25mg, 50mg, 100mg, and 150mg of active ingredients have been approved for sale.

[0003] Chinese invention patent CN111407725A discloses a lamotrigine emulsion and a preparation method thereof, which comprises 0.1-1% lamotrigine, an oil phase, an oil phase solubilizer, an emulsifier, etc. to form an emulsification system, and adopts a high-speed shear preparation method. The droplet size thereof is between 200-350nm. The stock solution system is not stable enough during storage. In the optimal embodiment, the actual loaded lamotrigine concentration of the stock solution is 23mg / ml.

[0004] Rehab Abdelmonem et al. (Development, Characterization, and in-vivoPharmacokinetic Study of Lamotrigine Solid Self-Nanoemulsifying Drug Delivery System. Drug Design, Development and Therapy 2020:14 4343–4362.) reported a nanoemulsion system containing lamotrigine. The mass concentration of lamotrigine in the prepared nanoemulsion solution was 5%, about 50 mg / ml, using 30% rose oil, 35% CR-EL, and 35% T80 or PEG400. For the clinical treatment maintenance dose of lamotrigine as high as 200 mg / day, the drug loading capacity needs to be further improved.

[0005] S. Melamane et al. (Formulation optimization of smartthermosettinglamotrigine loaded hydrogels using responsesurface methodology,Box Benhken design andartificial neural networks. Drug Development andIndustrial Pharmacy.2020. DOI: 10.1080 / 03639045.2020.1791163) reported a nasal thermosensitive gel of lamotrigine with a loaded lamotrigine concentration of only 5 mg / ml. Although nasal administration can increase the bioavailability by about 2 times compared with oral administration, the loaded lamotrigine concentration is still limited for daily lamotrigine dosage or pediatric use. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention aims to provide a self-microemulsifying composition of lamotrigine, a preparation method thereof, and an application thereof. The composition can not only effectively increase the drug loading of lamotrigine in the self-microemulsifying composition solution, but also can be stably present at room temperature with or without the addition of purified water. In addition, the preparation process of the self-emulsifying composition system is simple, does not require high-speed shearing, and only requires simple ultrasonic stirring. The self-emulsification and dispersion time in the aqueous medium is short.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] In one aspect, the present invention provides a self-microemulsifying composition containing lamotrigine, comprising lamotrigine, an oil phase, an emulsifier, and a co-emulsifier; the self-microemulsifying composition comprises, by mass, 0.1% to 18.7% lamotrigine, 20% to 33% oil phase, and 67% to 80% emulsion phase; 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% to 31.4%:68.6% to 74.3%.

[0009] Furthermore, the oil phase is monolinoleyl glyceryl and / or medium-chain triglyceride, the emulsifier is one or two of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene castor oil, oleoyl polyoxyethylene glyceride, 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.

[0010] Furthermore, the oil phase comprises monolinolein and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifiers are PEG400 and diethylene glycol monoethyl ether. The mass ratio of the oil phase monolinolein and medium-chain triglycerides 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 the co-emulsifier PEG400 and diethylene glycol monoethyl ether is one of 1:1, 2:1, 3:1, 1:2, and 1:3, and the mass ratio of the emulsifier to the co-emulsifier is one of 1.8:5.2, 2:5, and 2.2:4.8.

[0011] Furthermore, the mass ratio of the oil phase monolinoleyl glycerol to medium-chain triglycerides is 4:1, and the mass ratio of the co-emulsifier PEG400 to diethylene glycol monoethyl ether is 4:1.

[0012] Furthermore, the mass ratio of the co-emulsifier PEG400:diethylene glycol monoethyl ether is 4:1, and the mass ratio of the emulsifier to the co-emulsifier is 2:5.

[0013] A method for preparing a self-microemulsifying composition containing lamotrigine comprises: weighing an emulsifier and an emulsifier according to the prescription of the self-microemulsifying composition containing lamotrigine described above, mixing them uniformly with ultrasonic stirring at 37° C. and in the dark, obtaining a first mixture; adding lamotrigine to the first mixture, mixing them uniformly with ultrasonic stirring to obtain a second mixture; and then adding a mixed oil phase to the second mixture, stirring them ultrasonically to fully dissolve them, thereby obtaining a self-microemulsifying composition containing lamotrigine.

[0014] Furthermore, the prepared self-microemulsifying composition contains lamotrigine in a mass percentage of less than or equal to 18.7%, and the particle size of the microemulsion formed when the self-microemulsifying composition is dispersed in an aqueous medium is less than 50 nm, less than 20 nm, or even smaller.

[0015] Furthermore, the self-microemulsifying composition containing lamotrigine may also contain an appropriate amount of an antioxidant (e.g., 0.1%, w / w). The antioxidant used is one or two of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol), preferably vitamin E. The prepared self-microemulsifying composition containing lamotrigine is packaged in soft or hard capsules to obtain microemulsified capsules. The prepared lamotrigine self-microemulsifying capsules have a lamotrigine concentration of 16.7% to 18.7%, a capsule size of 0.3 ml to 0.5 ml per capsule, and contain approximately 50.1 to 93.5 mg of lamotrigine per capsule.

[0016] Furthermore, the prepared lamotrigine-containing self-microemulsifying composition stock solution is self-emulsified by adding ten times the amount of pure water, and then mixed with a porous solid excipient to prepare a soft material. The lamotrigine self-microemulsifying system tablets or granules are prepared according to conventional tablet or granule preparation procedures (soft material preparation, granulation, drying, mixing, tableting, packaging, etc.). The porous excipients include, for example, hypromellose, silicon dioxide, and cyclodextrin.

[0017] Furthermore, 0.1% of an antioxidant and 0.1% of a preservative are added to the prepared lamotrigine-containing self-microemulsifying composition stock solution. The antioxidant may be one or two of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol), preferably vitamin E. The preservative may be sodium benzoate, potassium sorbate, or a combination thereof. The antioxidant vitamin E may be added to the mixed oil phase and mixed evenly, and the preservative may be added to the co-emulsifier and mixed evenly.

[0018] Preparation process: At 37°C in the dark, weigh the emulsifier and co-emulsifier according to the prescribed amount and mix them uniformly with ultrasonic stirring to obtain Mixture 1. Lamotrigine and a preservative (sodium benzoate and potassium sorbate in a 1:1 weight ratio) are added to Mixture 1 and mixed uniformly with ultrasonic stirring to obtain Mixture 2. Vitamin E is mixed with the mixed oil phase to obtain Mixture 3. Mixture 3 is then added to Mixture 2 and mixed with ultrasonic stirring to fully dissolve, thereby obtaining a self-microemulsification solution. The prepared self-microemulsification solution is dispersed in 4 times pure water to form a self-emulsifying solution. The polaxamer composition is added to the self-emulsifying solution and stirred uniformly to form a gel solution. The pH of the gel solution is adjusted to between 5 and 6.5, mixed uniformly, and stored at 4°C for 24 hours to allow for full swelling and expel all bubbles.

[0019] The mass ratio of the self-emulsifying solution to the polaxamer composition is 4:1, and the polaxamer composition is composed of 21 parts of Polaxamer 407 and 2 parts of Polaxamer 188. The thermosensitive gel preparation prepared in Example 21 (lamotrigine concentration of 16.7%) has a concentration of 27.8 mg / g, approximately 27.8 mg / ml, more than five times the 5 mg / ml lamotrigine concentration of the thermosensitive nasal lamotrigine gel reported by S. Melamane et al. Furthermore, the self-microemulsifying system provided by the present invention is more uniform and stable. It can meet the needs of children with epilepsy and those requiring rapid onset of action, as well as transdermal administration of thermosensitive gels.

[0020] The present invention optimizes the types and combinations of oil phases, the types and combinations of specific emulsifiers and co-emulsifiers, the ratios of the oil phase, the emulsifiers, and the co-emulsifiers, and optimizes the preparation method of the self-microemulsifying composition. The self-microemulsifying composition containing lamotrigine is simple to prepare and does not require high-speed shearing. A clear and transparent self-microemulsifying solution can be formed by simple ultrasonic stirring. The prepared self-microemulsifying composition contains 18.7% by weight of lamotrigine, i.e., 187 mg / g, which meets the requirement of a maintenance dose of up to 200 mg / day for clinical anti-epileptic treatment with lamotrigine. The prepared self-microemulsifying composition containing lamotrigine is superior to lamotrigine in the preparation of the self-microemulsifying composition. The AUC0-72h after administration of lamotrigine ordinary tablets is increased by 2 times, and the inter-individual coefficient of variation CV% is small, reducing the occurrence of adverse reactions caused by the use of lamotrigine; the prepared self-microemulsifying composition containing lamotrigine is mixed with water, biologically relevant media (such as SGF, SGF, FessiF and FassiF media) or gastrointestinal fluid to spontaneously form clear, transparent, uniform and stable O / W microemulsions with a particle size of less than 50nm, less than 30nm or even less than 20nm; the prepared self-microemulsifying composition containing lamotrigine is stored at room temperature or 4 degrees Celsius with or without water, and its self-microemulsifying solution system can exist in the form of a stable solution. The self-microemulsifying composition containing lamotrigine of the present invention has a high concentration of lamotrigine loaded and the self-microemulsifying solution system is uniform and stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Comparative graph of the pharmacokinetics of homemade soft capsules and original lamotrigine tablets in beagle dogs (n=3, mean±SD). DETAILED DESCRIPTION

[0022] To further describe the present invention, the present invention will be further described in detail below with reference to the embodiments, but the present invention is not limited to the specific embodiments.

[0023] Test 1: The solubility was determined as follows:

[0024] Take 5 mL each of oil phase, emulsifier and co-emulsifier in a test tube, add excess equal amount of lamotrigine, keep warm at 37℃, shake for 24 hours, then centrifuge at high speed, take the supernatant, dilute with mobile phase, and detect equilibrium solubility.

[0025] Through testing, it was found that the solubility concentration of lamotrigine in rose oil is about 41 mg / ml, the solubility in monolinoleyl glycerol 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.

[0026] Test 2: Test on oil phase type selection and mixed oil ratio

[0027] The solubility of lamotrigine was investigated by mixing monolinolein 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, and 1:5). 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 triglycerides showed a greater loading of lamotrigine than monolinolein or medium-chain triglycerides alone, with the highest solubility of lamotrigine achieved at mass ratios of 4:1 and 5:1. In subsequent studies on combinations with the emulsifier polyoxyethylene 40 hydrogenated castor oil and co-emulsifiers, it was found that the self-emulsification time of the self-microemulsifying system prepared when the mass ratio of monolinolein to medium-chain triglycerides was 4:1 was faster in pure water than that of the mass ratio of 5:1, so the preferred mass ratio of monolinolein to medium-chain triglycerides was 4:1.

[0028] Test 3: Transmittance test of emulsifier and co-emulsifier

[0029] Using a 4:1 mixed oil phase of monolinoleyl glycerol and medium-chain triglycerides, the transmittance of various emulsifiers and co-emulsifiers mixed with the mixed oil phase at a mass ratio of 1:1 was investigated. Microemulsions formed with polyoxyl 40 hydrogenated castor oil, polyoxyethylene castor oil, oleoyl polyoxyethylene glycerides, polyoxyethylene-15 hydroxystearate (solutol HS 15), Tween 80, PEG 400, propylene glycol, diethylene glycol monoethyl ether, and ethanol were clear and transparent, with transmittance exceeding 90%.

[0030] Test 4: Optimization of emulsifiers and co-emulsifiers

[0031] Based on the solubility of lamotrigine in various excipients, the properties of each excipient and the possible mutual promotion of dissolution, as well as laboratory exploration and summary analysis, the composition and dosage of emulsifiers and co-emulsifiers were studied and analyzed. (See Table 1)

[0032] prescription:

[0033] 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 monolinoleylglycerol and medium-chain triglycerides (4:1).

[0034] Preparation process: At 37°C and in the dark, weigh the emulsifier and co-emulsifier according to the prescription amount and mix them evenly with ultrasonic stirring to obtain mixture 1. Add lamotrigine to mixture 1 and mix evenly to obtain mixture 2. Mix the two oil phases to obtain mixture 3. Then add mixture 3 to mixture 2 and stir ultrasonically to fully dissolve it to obtain SMEDDS stock solution. Add it into 10 times pure water, shake it slightly and observe.

[0035] Table 1. Research on different emulsifier and co-emulsifier formulations

[0036]

[0037]

[0038] As can be seen from Examples 1-20 in the table above, when 170 mg (approximately 14.5% by mass) of lamotrigine was added, PEG400 and diethylene glycol monoethyl ether were used as co-emulsifiers. When polyoxyethylene 40 hydrogenated castor oil was used as an emulsifier in combination with the mixed oil, its emulsification effect was better than that of polyoxyethylene castor oil and oleoyl polyoxyethylene glyceride. This indicates that the combination of PEG400, diethylene glycol monoethyl ether, or a mixture of PEG400 and diethylene glycol monoethyl ether (3:1) as a co-emulsifier with polyoxyethylene 40 hydrogenated castor oil as an emulsifier effectively promoted the solubilization of lamotrigine, and the resulting self-microemulsion was transparent with a slightly bluish opalescence.

[0039] Further research revealed that when PEG400 and diethylene glycol monoethyl ether were used together as co-emulsifiers, the loading capacity of the self-microemulsifying system for lamotrigine was increased, reaching 16% (w / w) of lamotrigine, which was higher than the loading capacity of PEG400 or diethylene glycol monoethyl ether alone. Furthermore, when the PEG400:diethylene glycol monoethyl ether mass ratio was optimized to 3:1 and 4:1, the loading capacity of the self-microemulsifying system for lamotrigine reached 16.7% (w / w). Furthermore, when the PEG400:diethylene glycol monoethyl ether mass ratio was 4:1, the loading capacity of the self-microemulsifying system for lamotrigine reached 17.4% (w / w).

[0040] Experiment 5: Investigation of the ratio of oil phase to emulsion phase

[0041] The prescription is as follows:

[0042] Lamotrigine: 200 mg;

[0043] The total mass of SMEDDS carrier is 1000 mg: the mass ratio of oil phase is shown in the table below.

[0044] The oil phase is composed of monolinoleyl glycerol and medium-chain triglycerides (4:1), and the emulsion phase (emulsifier: co-emulsifier = 2:5). The emulsifier is polyoxyethylene 40 hydrogenated castor oil; the co-emulsifier is PEG400: diethylene glycol monoethyl ether (4:1).

[0045] Table 2. Studies on different ratios of oil phase to emulsion phase

[0046]

[0047] As can be seen from the test results in the table above, the proportion of the oil phase in the lamotrigine self-microemulsifying 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%, and the self-microemulsifying system has a good emulsification effect. In order to ensure the emulsification effect and reduce the amount of the emulsion phase, the preferred mass ratio of oil phase: emulsion phase is 20% to 33%:80% to 67%, more preferably 28% to 30%:72% to 70%, and in order to minimize the amount of the emulsion phase, 30%:70% is more preferred.

[0048] Experiment 6: Investigation of the ratio of emulsifier to co-emulsifier

[0049] The prescription is as follows:

[0050] Lamotrigine: 200 mg;

[0051] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsion phase (emulsifier and co-emulsifier) was 3:7;

[0052] The oil phase consists of monolinolein and medium-chain triglycerides (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and 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 referred to Experiment 4, and it was found that with the increase of emulsifier, 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 emulsification effect of the self-microemulsion in water was better, and the ability to load lamotrigine was good; further, when the mass ratio of emulsifier to co-emulsifier was 2:5, the emulsification effect of the self-microemulsion in water was better, and the ability to load lamotrigine was better.

[0053] Experiment 7: Investigation of the preparation method of self-microemulsion

[0054] The prescription is as follows:

[0055] Lamotrigine: 200 mg;

[0056] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:2:5;

[0057] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400:diethylene glycol monoethyl ether (4:1).

[0058] Preparation method (1): At 37°C and in the dark, add lamotrigine to the emulsifier and mix them ultrasonically to obtain mixture 1. Add the emulsifier to mixture 1 and mix them ultrasonically to obtain mixture 2. Then add the mixed oil phase to mixture 2 and stir ultrasonically to fully dissolve it to obtain SMEDDS stock solution. Add it into 10 times pure water and shake it slightly to observe whether there is a turbidity point.

[0059] Preparation method (2): At 37°C and in the dark, weigh the oil phase and emulsifier according to the prescribed amount and mix them ultrasonically to obtain mixture 1. Add lamotrigine to mixture 1 and mix them ultrasonically to obtain mixture 2. Then add the co-emulsifier to mixture 2 and stir ultrasonically to fully dissolve it to obtain SMEDDS stock solution. Add it into 10 times pure water and shake it slightly to observe whether lamotrigine is precipitated.

[0060] Compared with the above two preparation methods, the preparation method in Experiment 4 has a better loading effect on lamotrigine.

[0061] Experiment 8: Construction and evaluation of lamotrigine self-microemulsification system

[0062] Example 21

[0063] The prescription is as follows:

[0064] Lamotrigine: 200 mg;

[0065] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:2:5;

[0066] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0067] Preparation process: At 37°C and in the dark, weigh the emulsifier and co-emulsifier according to the prescription amount and mix them evenly with ultrasonic stirring to obtain mixture 1. Add lamotrigine to mixture 1 and mix evenly with ultrasonic stirring to obtain mixture 2. Then add the mixed oil phase to mixture 2 and stir ultrasonically to fully dissolve it to obtain SMEDDS stock solution, add it into 10 times pure water, shake it slightly and observe.

[0068] The obtained lamotrigine self-microemulsification composition was transparent with light blue opalescence, had a particle size of 18 nm after self-emulsification in pure water, and had a lamotrigine drug loading of 16.7% (w / w).

[0069] Example 22

[0070] The prescription is as follows:

[0071] Lamotrigine: 200 mg;

[0072] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:2:5;

[0073] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0074] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition was transparent with a light blue opalescence, had a particle size of 23 nm after self-emulsification in pure water, and had a lamotrigine drug loading of 16.7% (w / w).

[0075] Example 23

[0076] The prescription is as follows:

[0077] Lamotrigine: 200 mg;

[0078] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:1.9:5.1;

[0079] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (1:1).

[0080] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a blue opalescence, a particle size of 42 nm after self-emulsification in pure water, and a lamotrigine drug loading of 16.7% (w / w).

[0081] Example 24

[0082] The prescription is as follows:

[0083] Lamotrigine: 200 mg;

[0084] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:1.8:5.2;

[0085] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (1:1).

[0086] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a light blue opalescence, a particle size of 33 nm after self-emulsification in pure water, and a lamotrigine drug loading of 16.7% (w / w).

[0087] Example 25

[0088] The prescription is as follows:

[0089] Lamotrigine: 210 mg;

[0090] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:1.9:5.1;

[0091] The oil phase is monolinoleic acid glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (2:1).

[0092] The preparation process refers to Example 21: The obtained lamotrigine self-microemulsification composition is milky white.

[0093] Example 26

[0094] The prescription is as follows:

[0095] Lamotrigine: 210 mg;

[0096] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:1.8:5.2;

[0097] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0098] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a light blue opalescence, a particle size of 49 nm after self-emulsification in pure water, and a lamotrigine drug loading of 17.4% (w / w).

[0099] Example 27

[0100] The prescription is as follows:

[0101] Lamotrigine: 220 mg;

[0102] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:1.8:5.2;

[0103] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0104] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a blue opalescence, a particle size of 29 nm after self-emulsification in pure water, and a lamotrigine drug loading of 18% (w / w).

[0105] Example 28

[0106] The prescription is as follows:

[0107] Lamotrigine: 220 mg;

[0108] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:1.7:5.3;

[0109] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0110] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had blue opalescence, a cloud point, and a lamotrigine drug loading of 18% (w / w).

[0111] Example 29

[0112] The prescription is as follows:

[0113] Lamotrigine: 220 mg;

[0114] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 2.9:2:5.1;

[0115] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0116] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a light blue opalescence, a particle size of 25 nm after self-emulsification in pure water, and a lamotrigine drug loading of 18% (w / w).

[0117] Example 30

[0118] The prescription is as follows:

[0119] Lamotrigine: 230 mg;

[0120] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 2.8:2:5.2;

[0121] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0122] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a blue opalescence, a particle size of 23 nm after self-emulsification in pure water, slight API precipitation, and a lamotrigine drug loading of 18.7% (w / w).

[0123] Example 31

[0124] The prescription is as follows:

[0125] Lamotrigine: 230 mg;

[0126] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 2.8:1.8:5.4;

[0127] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0128] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a light blue opalescence, a particle size of 25 nm after self-emulsification in pure water, and a lamotrigine drug loading of 18.7% (w / w).

[0129] Example 32

[0130] The prescription is as follows:

[0131] Lamotrigine: 240 mg;

[0132] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 2.8:1.8:5.4;

[0133] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (4:1).

[0134] The preparation process refers to Example 21: The obtained lamotrigine self-microemulsification composition is milky white.

[0135] Example 33

[0136] The prescription is as follows:

[0137] Lamotrigine: 0 mg;

[0138] The total mass of SMEDDS carrier was 1000 mg: the mass ratio of oil phase:emulsifier:co-emulsifier was 3:2:5;

[0139] The oil phase is monolinoleyl glyceride and medium-chain triglyceride (4:1); the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier is PEG400 and diethylene glycol monoethyl ether (3:1).

[0140] The preparation process was similar to that of Example 21: the obtained blank self-microemulsifying composition without lamotrigine was a clear and transparent solution, which formed a uniform self-emulsifying solution in pure water within 30 seconds with a particle size of 17 nm.

[0141] Comparative Example 1

[0142] The prescription is as follows:

[0143] Lamotrigine: 110 mg;

[0144] 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.

[0145] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a light blue opalescence and a particle size of 18 nm after being dispersed in pure water.

[0146] Comparative Example 2

[0147] The prescription is as follows:

[0148] Lamotrigine: 140 mg;

[0149] 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.

[0150] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition was milky white, and API precipitated after being dispersed in pure water.

[0151] Comparative Example 3

[0152] The prescription is as follows:

[0153] Lamotrigine: 90 mg;

[0154] 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.

[0155] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition had a light blue opalescence and a particle size of 30 nm after being dispersed in pure water.

[0156] Comparative Example 4

[0157] The prescription is as follows:

[0158] Lamotrigine: 110 mg;

[0159] 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.

[0160] The preparation process was similar to that of Example 21: the obtained lamotrigine self-microemulsification composition was milky white with a cloud point, and the API precipitated after being dispersed in pure water.

[0161] From the analysis of Examples 21-33 and Comparative Examples 1-4, it can be seen that the lamotrigine self-microemulsification system prepared by the oil phase comprising monolinoleyl glycerol and medium-chain triglycerides (4:1); the emulsifier being polyoxyethylene 40 hydrogenated castor oil; and the co-emulsifier being diethylene glycol monoethyl ether and ethanol (1:1, 2:1, 3:1, 4:1) is transparent, the lamotrigine loading reaches 18.7%, and the particle size after self-emulsification in pure water is less than 50 nm.

[0162] Test 9: Stability test

[0163] According to the formula ratios of Examples 21-33 and Comparative Examples 1-4, self-microemulsifying compositions containing lamotrigine were prepared and subjected to stability tests: the compositions were placed at room temperature, 4 degrees Celsius, and room temperature with 15% water added for 24 hours, and the stability of the self-microemulsifying compositions containing lamotrigine was observed. The results are shown in the following table:

[0164] Table 3. Stability of self-microemulsions prepared in Examples 21-33 and Comparative Examples 1-4

[0165]

[0166] As can be seen from the above stability study data, prior art reports use rose oil as the oil phase, CR-EL as the emulsifier, and PEG400 or Tween 80 as co-emulsifiers, with lamotrigine loading concentrations of 10% and 8%, respectively, and a maximum lamotrigine loading concentration of approximately 100 mg / g. In Comparative Examples 2 and 4, when lamotrigine 140nm and 110nm were added at concentrations of 12.3% and 10%, respectively, a self-microemulsifying system could not be produced, resulting in a milky white appearance. Upon addition of water, a large amount of lamotrigine precipitated. This indicates that the present invention's combination of mixed oil phase, emulsifier, and co-emulsifier, and their preferred composition ratio, not only significantly increases lamotrigine loading capacity (Example 31 contains up to 18.7% lamotrigine, w / w), but also results in a stable self-microemulsifying composition system.

[0167] Test 10: Pharmaceutical preparations containing a self-microemulsifying composition system containing lamotrigine

[0168] Example 22 Soft capsule or hard capsule preparation

[0169] Any of the self-microemulsifying solutions prepared in Examples 1-33 above that can form a self-microemulsifying composition is added with an appropriate amount of an antioxidant. The antioxidant used can be one or two of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, or vitamin E (dl-α-tocopherol), preferably vitamin E. The prepared self-microemulsifying solution is placed in soft or hard capsules to obtain self-microemulsifying capsules. The lamotrigine self-microemulsifying capsules prepared in Example 21 have a lamotrigine concentration of 16.7%, a capsule size of 0.3 ml to 0.5 ml per capsule, and contain approximately 50.1 to 83.5 mg of lamotrigine per capsule. The lamotrigine self-microemulsifying capsules prepared in Example 31 have a lamotrigine concentration of 18.7%, a capsule size of 0.3 ml to 0.5 ml per capsule, and contain approximately 56.1 to 93.5 mg of lamotrigine per capsule.

[0170] Example 23 Tablets or granules

[0171] Any of the self-microemulsifying solutions capable of forming a self-microemulsifying composition prepared in Examples 1-33 above is self-emulsified by adding ten times the amount of pure water. The solution is then mixed with a porous solid excipient to prepare a soft material. Lamotrigine self-microemulsifying tablets or granules are prepared according to conventional tablet or granule preparation procedures (soft material preparation, granulation, drying, mixing, tableting, packaging, etc.). Porous excipients such as hypromellose, silicon dioxide, and cyclodextrin can be used.

[0172] Example 24 Thermosensitive Gel Preparation-1

[0173] Any of the self-microemulsifying compositions prepared in Examples 1-33 was dispersed in 4 times the amount of pure water to form a self-emulsifying solution. The polaxamer composition was then added to the self-emulsifying solution and stirred to form a gel solution. The solution was then stored at 4°C for 24 hours to allow for full swelling and expel all bubbles, thereby obtaining a temperature-sensitive gel containing the lamotrigine self-microemulsifying 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 using the test tube inversion method to be 32.1°C.

[0174] The polaxamer composition comprises 21 parts of Polaxamer 407 and 2 parts of Polaxamer 188. The mass ratio of the self-emulsifying solution (self-microemulsifying stock solution: pure water = 1:4) to the polaxamer composition is 4:1. The preservative may also be one or both of benzalkonium bromide, sodium benzoate, and potassium sorbate. The antioxidant may also be one or both of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin C, and vitamin E (dl-α-tocopherol). The preservative may be one or both of benzalkonium bromide, sodium benzoate, and potassium sorbate, preferably with a mass ratio of sodium benzoate to potassium sorbate of 1:1.

[0175] Example 24 Thermosensitive Gel Preparation-2

[0176] Preparation process: At 37°C and protected from light, weigh the emulsifier and co-emulsifier according to the self-microemulsifying amount prescribed in Examples 1-33, and mix them uniformly with ultrasonic stirring to obtain Mixture 1. Lamotrigine and 0.1% preservative (sodium benzoate and potassium sorbate in a 1:1 weight ratio) are added to Mixture 1 and mixed uniformly with ultrasonic stirring to obtain Mixture 2. 0.1% antioxidant vitamin E is mixed with the mixed oil phase to obtain Mixture 3. Mixture 3 is then added to Mixture 2 and ultrasonically stirred to dissolve thoroughly, thereby obtaining a self-microemulsifying solution. The prepared self-microemulsifying solution is dispersed in 4 times pure water to form a self-emulsifying solution. The polaxamer composition is added to the self-emulsifying solution and stirred uniformly to form a gel solution. The solution is then stored at 4°C for 24 hours to allow for full swelling and expel air bubbles, thereby obtaining a temperature-sensitive gel containing the lamotrigine self-microemulsifying composition. The pH of the gel solution is adjusted to between 5 and 6.5 using a conventional acid-base solution. The gelation temperature of this example, measured by the test tube inversion method, is 32.0°C.

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

[0178] Taking the thermosensitive gel preparation prepared from the self-microemulsifying composition containing lamotrigine prepared in Example 21 (lamotrigine concentration of 16.7%) as an example, the concentration of lamotrigine in the thermosensitive gel preparation is 27.8 mg / g, or approximately 27.8 mg / ml. With a nasal administration of 0.1 ml / time, the nasal dose of lamotrigine is approximately 2.78 mg / time, which meets the needs of children with epilepsy and those requiring rapid onset of action.

[0179] The thermosensitive gel containing the lamotrigine self-microemulsifying composition prepared in Examples 23 and 24 overcomes the problems of lamotrigine's high lipid solubility as a BCSII, making it difficult to dissolve in aqueous media, and the need for rapid onset of action and achieving an effective dosage for preventing and treating epileptic seizures. Combining the advantages of both the self-microemulsifying system and the thermosensitive gel, the self-microemulsifying system improves lamotrigine's solubility in aqueous media. The self-microemulsifying system achieves a drug loading of 18.7% in the original solution, and forms microemulsions in aqueous media with particle sizes less than 50 nm or even less than 20 nm, resulting in improved dissolution and absorption, and higher bioavailability. Formulated into a thermosensitive gel formulation and administered nasally, the drug can reach the brain more quickly to prevent and treat epileptic seizures. Furthermore, the thermosensitive gel prepared in this invention can also be used as a thermosensitive gel for transdermal administration. The thermosensitive gel formulation containing the lamotrigine self-microemulsifying composition prepared in Example 21 (lamotrigine concentration of 16.7%) achieved a concentration of 27.8 mg / g, approximately 27.8 mg / ml. The nasal administration dose is 0.1 ml / time, and the nasal administration dose of lamotrigine is about 2.78 mg / time, which can meet the medication needs of children with epilepsy and patients who need rapid onset of action.

[0180] Experiment 11: Pharmacokinetic study in beagle dogs

[0181] This test example provides a pharmacokinetic test of the soft capsules prepared in Example 21 (0.3 ml / capsule, containing approximately 50.1 mg / capsule of lamotrigine, calculated as 50 mg / capsule) and the original lamotrigine tablets (Lamictal).

[0182] Test methods and objects:

[0183] Six healthy beagle dogs were randomly divided into three groups, with two dogs in each group, and fasting experiments were performed. The dogs were fasted for 10 hours before the experiment, and then given the drug on an empty stomach. The dogs were fed 4 hours after the drug was given.

[0184] The reference preparation was the original lamotrigine tablet (Lamictal), containing 50 mg of lamotrigine per tablet;

[0185] The homemade soft capsules were the lamotrigine soft capsules provided in Example 21, containing 50 mg of lamotrigine per capsule.

[0186] Sampling Design: 2 mL of blood samples 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 administration, and plasma was separated by centrifugation. Blood drug concentrations were measured and pharmacokinetic parameters were statistically analyzed. See the table below:

[0187] Among them, T max is the peak time, C max is the maximum plasma concentration (peak concentration), AUC 0-72h AUC (area under the curve) is the duration from the start of drug administration to the last point.

[0188] The results are as attached Figure 1 Shown are the drug-time curves of the lamotrigine soft capsules (homemade soft capsule preparation, containing 50 mg of lamotrigine per capsule) and the original lamotrigine tablets (Lamictal, containing 50 mg of lamotrigine per tablet) provided in Example 21 in the fasting test in beagle dogs.

[0189]

[0190] As shown in the table above, the time to peak Tmax of lamotrigine soft capsules (homemade) taken orally on an empty stomach in beagle dogs is faster than that of the original drug lamotrigine tablets, indicating that the homemade lamotrigine soft capsules are absorbed faster; the maximum blood drug concentration C max The AUC of the homemade lamotrigine soft capsule is 1.9 times that of the original lamotrigine tablets. 0-72h Converted to 50mg, it is about twice the original lamotrigine tablet; In addition, from C max , AUC 0-72h Judging from the coefficient of variation, the CV% value of the homemade lamotrigine soft capsules was significantly lower than the CV% value of the original lamotrigine tablets. The coefficient of variation between individuals taking the homemade lamotrigine soft capsules was lower, which effectively reduced the adverse reactions caused by individual differences.

[0191] The above embodiments are preferred implementations of the present invention, but the implementation of the present invention is not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A self-microemulsifying composition containing lamotrigine, characterized in that: The invention is composed of lamotrigine, an oil phase, an emulsifier and a co-emulsifier; the oil phase is monolinoleic acid glyceryl ester 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-microemulsifying composition contains lamotrigine less than or equal to 18.7% by mass, and the oil phase: emulsifier: co-emulsifier are (2.8-3.0): (1.7-2.0): (5.0-5.4); The mass ratio of the oil phase monolinoleyl glycerol and medium-chain triglycerides 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.

2. A self-microemulsifying composition containing lamotrigine according to claim 1, characterized in that: The mass ratio of the co-emulsifier PEG400:diethylene glycol monoethyl ether is 4:1, and the mass ratio of the emulsifier to the co-emulsifier is 2:

5.

3. A self-microemulsifying composition containing lamotrigine according to claim 1, characterized in that: The particle size of the microemulsion formed by dispersing the self-microemulsifying composition into an aqueous medium is less than 50 nm.

4. A self-microemulsifying composition containing lamotrigine according to claim 3, characterized in that: The particle size of the microemulsion formed by dispersing the self-microemulsifying composition into an aqueous medium is less than 20 nm.

5. A method for preparing a self-microemulsifying composition containing lamotrigine, characterized in that: At 37° C. and in the dark, an emulsifier and a co-emulsifier are weighed according to the prescription amount of the self-microemulsifying composition containing lamotrigine according to any one of claims 1 to 4, and ultrasonic stirring is performed to mix uniformly to obtain a first mixture; lamotrigine is added to the first mixture and ultrasonic stirring is performed to mix uniformly to obtain a second mixture; and then the mixed oil phase is added to the second mixture and ultrasonic stirring is performed to fully dissolve, thereby obtaining a self-microemulsifying composition containing lamotrigine.

6. A pharmaceutical preparation, characterized in that: The self-microemulsifying composition containing lamotrigine according to any one of claims 1 to 4 is filled into soft capsules or hard capsules, or is added with porous excipients to prepare solid tablets or granules, or is stirred and mixed with a mixed matrix of polaxamer 407 and polaxamer 188 to prepare a thermosensitive gel preparation.

7. Use of the self-microemulsifying composition containing lamotrigine according to any one of claims 1 to 4 or the preparation according to claim 6 in the preparation of a medicament for preventing or treating epilepsy.

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