Composition containing lamotrigine as well as preparation method and application thereof

Abstract

The invention discloses a dry pharmaceutical composition, which comprises one or more lamotrigine hydrate crystals with a therapeutically effective amount and one or more pharmaceutically acceptable auxiliary materials, and the auxiliary materials comprise a thickening agent; the dry pharmaceutical composition is preferably a dry suspension, which can be formulated as a suspension for administration, which can be stably used for at least 1-3 months. The invention also discloses a preparation method of the dry pharmaceutical composition and the dry suspension and application of the dry pharmaceutical composition and the dry suspension to treatment of nervous system diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a dried composition containing lamotrigine, a dry suspension, its preparation method, and its use in treating diseases. Background Technology

[0002] Epilepsy is one of the most common neurological disorders. Epileptic seizures can lead to a progressive decline in brain function, causing cognitive impairment and intellectual decline. Sudden seizures can easily cause accidental injuries, and status epilepticus can be life-threatening, severely impacting a patient's quality of life and generally requiring lifelong medication.

[0003] Lamotrigine (trade name Lamictal) exerts its antiepileptic effect primarily by blocking voltage-gated sodium channels, reducing sodium influx, and increasing neuronal stability. Lamotrigine was launched in Europe in 1991 and in the United States in 1994. Currently, lamotrigine is used as monotherapy or adjunctive therapy for various types of epilepsy, particularly in infants, adolescents, and elderly patients, with efficacy comparable to phenytoin and carbamazepine.

[0004] Currently, there are four dosage forms of lamotrigine approved for marketing both domestically and internationally: immediate-release tablets, chewable tablets, orally disintegrating tablets, and extended-release tablets. There is no commercially available oral liquid formulation of lamotrigine. Therefore, it is often necessary to crush lamotrigine tablets to prepare a liquid formulation for easier administration to children and patients with swallowing difficulties. However, this hastily prepared formulation can easily lead to inaccurate dosage and drug contamination.

[0005] Lamotrigine is a Class II drug molecule in the Biopharmaceutics Classification System (BCS). It has poor solubility in aqueous media; lowering the pH can increase solubility to some extent, but the effect is limited. Chinese patent applications CN201510288845.X and CN201510350210.8 disclose the formulation and preparation method of lamotrigine oral solution, but the drug concentration of this formulation is less than 2 mg / mL, which cannot meet clinical needs. For higher concentration formulations, organic solvents need to be added, which is not suitable for children.

[0006] Single-dose products developed with anhydrous lamotrigine also have many unavoidable drawbacks. For example, if the patient is underweight, there may be a large amount of product remaining after each use, leading to medication waste and repeated doses. Furthermore, single-dose dry suspensions require reconstitution with water before each use, causing inconvenience and poor patient compliance. Multi-dose products, on the other hand, significantly improve patient compliance and virtually eliminate medication waste and the phenomenon of patients continuing to take medication beyond the expiration date due to concerns about waste. Moreover, multi-dose dry suspensions only require reconstitution before the first dose; subsequent doses can be taken as directed by the pharmacist, making it more convenient and quick, and significantly increasing patient compliance.

[0007] Developing multi-dose suspensions using anhydrous lamotrigine is not ideal. The inventors of this invention discovered through experiments that while conventional methods for preparing lamotrigine suspensions do not produce lumpy crystals immediately after preparation, a large number of lumpy crystals appear after three days at room temperature. Furthermore, the crystals tend to increase in size over time, which can lead to inaccurate medication administration for patients. Chinese patent application CN106491539B discloses a method for inhibiting hydrates, but this inhibition only lasts for 24 hours, causing inconvenience for long-term patient use.

[0008] For active pharmaceutical ingredients, their crystallization state can affect many of their properties, such as melting point, solubility, stability, and bioavailability. Drug cocrystals or hydrates can utilize hydrogen bonds or other non-covalent interactions to effectively improve the crystallinity and physicochemical properties of the drug without destroying its active ingredients, making them a hot area in the research and development of solid pharmaceutical dosage forms.

[0009] To date, various lamotrigine cocrystals have been reported. Reported lamotrigine salts include: 1:1 lamotrigine-4-hydroxybenzoic acid, 1:1 lamotrigine-saccharin, 1:3 lamotrigine-acetic acid, 1:1 lamotrigine-propionic acid, 2:1 lamotrigine-adipic acid, 2:1 lamotrigine-malic acid, 1:1 lamotrigine-methylparaben, 1:1 lamotrigine-nicotine, 1:1:1 lamotrigine-nicotine-hydrate, and 1:1 lamotrigine-acetamide. Reported lamotrigine solvates include: 1:2 lamotrigine methanol solvate and 1:1:1 lamotrigine-ethanol-hydrate. However, none of these cocrystals have been further investigated to develop liquid dosage forms, failing to address the issue of dosage accuracy in multi-dose liquid formulations of lamotrigine.

[0010] WO 2022 / 218437 discloses a crystalline form of lamotrigine hydrate, its preparation method, and compositions comprising the same. However, the inventors have found that suspensions formulated from the aforementioned compositions have poor stability in water and cannot adequately meet drug administration requirements. Summary of the Invention

[0011] The inventors of this invention conducted extensive and in-depth research on this topic, thereby completing this invention.

[0012] In a first aspect, the present invention provides a dried pharmaceutical composition comprising a therapeutically effective amount of one or more lamotrigine hydrate crystals and one or more pharmaceutically acceptable excipients, said excipients including a thickener.

[0013] The lamotrigine hydrate crystallizer and thickener in the dried pharmaceutical composition enable the final dry suspension to be reconstituted into a uniform suspension that remains stable for a long time; the oral suspension prepared from the dry suspension can be used stably for at least 1-3 months.

[0014] In some specific embodiments, the pharmaceutical composition further includes a pH adjuster.

[0015] In some specific embodiments, the dried pharmaceutical composition is a dried suspension. Preferably, the dried suspension further includes fillers, preservatives, flow aids, defoamers, and / or flavoring agents.

[0016] In some specific embodiments, the particle size (D90) of the lamotrigine hydrate crystals is about 1-200 μm.

[0017] In some specific implementations, the weight ratio of the lamotrigine hydrate crystals to the thickener is approximately from 10:1 to 10:7.

[0018] In some specific embodiments, when the pharmaceutical composition further comprises a pH adjuster, the weight ratio of the lamotrigine hydrate crystals to the pH adjuster is approximately from 10:0.1 to 10:8.

[0019] In some specific embodiments, the thickener is selected from hydrolyzed colloids such as xanthan gum, guar gum, locust bean gum, and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides such as starch and pregelatinized starch; alginates such as sodium alginate; acrylic copolymers such as carbomer; povidone; and magnesium aluminum silicate and combinations thereof. Preferably, xanthan gum, povidone, sodium carboxymethyl cellulose, sodium alginate, magnesium aluminum silicate, and / or carbomer are used.

[0020] In some specific embodiments, the pharmaceutical composition comprises the following excipients:

[0021] Approximately 1-5 parts by weight of xanthan gum;

[0022] Approximately 10-80 parts by weight of mannitol;

[0023] Approximately 10-80 parts by weight of microcrystalline cellulose;

[0024] Approximately 10-80 parts by weight of lactose;

[0025] Approximately 1-5 parts by weight of sucralose;

[0026] Approximately 1-5 parts by weight of orange flavoring;

[0027] A combination of approximately 1-3 parts by weight of sodium methylparaben and sodium propylparaben, wherein the weight ratio of sodium methylparaben to sodium propylparaben is approximately 9:1;

[0028] Approximately 0.1-5 parts by weight of silicon dioxide;

[0029] Approximately 0.01-3 parts by weight of simethicone emulsion.

[0030] In some embodiments, the composition further comprises one or more other drugs selected from oxcarbazepine, carbamazepine, topiramate, and lacoamide.

[0031] In some embodiments, the composition can also be used to prepare formulations such as tablets, capsules, powders, granules, and suspensions.

[0032] In a second aspect, the present invention provides a method for preparing a dried pharmaceutical composition, comprising:

[0033] (a) Provides an anhydrous lamotrigine compound that, when added to water, transforms into lamotrigine hydrate crystals;

[0034] (b) The above-mentioned lamotrigine hydrate crystals are mixed with pharmaceutically acceptable first-series excipients, wet-granulated, and dried in a fluidized bed or oven to obtain granules;

[0035] (c) The particles are crushed to a particle size (D90) of about 1-400 μm; preferably, about 30 μm, 70 μm, or 110 μm.

[0036] (d) The pulverized particles are mixed with a second series of excipients to obtain a dried pharmaceutical composition, wherein the second series of excipients contains at least one thickener that enables the dried pharmaceutical composition, such as a dry suspension, to be reconstituted into a homogeneous suspension.

[0037] The dried pharmaceutical composition can be prepared into the dried suspension using conventional techniques in the art.

[0038] Therefore, in another aspect, the present invention provides a method for preparing the dried suspension, wherein...

[0039] The pharmaceutically acceptable excipients in step (b) above are excipients of the first series, which are selected from one or more combinations of fillers, sweeteners, pH adjusters, preservatives, flow aids, defoamers, flavoring agents and surfactants.

[0040] In some specific implementations, the particles in step (c) are mainly composed of lamotrigine hydrate crystals.

[0041] In some specific implementations, the second series of excipients further includes one or more excipients selected from thickeners, sweeteners, pH adjusters, preservatives, flow aids, defoamers, and flavoring agents.

[0042] In some specific embodiments, the weight ratio of the lamotrigine hydrate crystallizer to the pH adjuster is approximately from 10:0.1 to 10:8 and / or the weight ratio of the lamotrigine hydrate crystallizer to the thickener is approximately from 10:1 to 10:7.

[0043] In some specific embodiments, the thickener is selected from hydrolyzed colloids such as xanthan gum, guar gum, locust bean gum, and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides such as starch and pregelatinized starch; alginates such as sodium alginate; acrylic copolymers such as carbomer; povidone; and magnesium aluminum silicate and combinations thereof.

[0044] In some specific embodiments, the lamotrigine hydrate crystals account for 1% to 80% of the composition.

[0045] In some specific implementations, the dried pharmaceutical composition is prepared as a suspension, wherein the suspension can be used for at least 1-3 months.

[0046] This invention also provides other methods for preparing lamotrigine dry suspensions, as shown in the following technical solutions.

[0047] A method for preparing lamotrigine dry suspension, wherein the method comprises the following steps: first, forming a lamotrigine hydrate suspension from lamotrigine; then, adding this lamotrigine suspension as a slurry to a filler for wet granulation; drying the granules, pulverizing them, and then mixing them with pharmaceutically acceptable excipients to obtain a lamotrigine dry suspension composition.

[0048] In some embodiments, the particle size D90 of the lamotrigine particles is not greater than 200 μm.

[0049] In some embodiments, the lamotrigine hydrate crystal form can be a specific hydrate crystal or a combination of multiple hydrate crystals.

[0050] In some implementations, the pulverization includes needle pulverization, hammer pulverization, and cutter pulverization.

[0051] In some embodiments, the filler (or diluent) is selected from starches, such as corn starch; sugar alcohols, such as sucrose, lactose, and mannitol; celluloses, such as microcrystalline cellulose; and inorganic salts, such as calcium sulfate and calcium hydrogen phosphate.

[0052] This invention provides another method for preparing lamotrigine dry suspension, wherein the method includes the following steps: first forming a lamotrigine hydrate suspension with lamotrigine, filtering and drying it, pulverizing the dried lamotrigine hydrate crystals, and then mixing the pulverized material with pharmaceutically acceptable excipients to obtain a lamotrigine dry suspension composition.

[0053] In some embodiments, the lamotrigine hydrate crystals include all lamotrigine hydrate crystalline forms.

[0054] In some embodiments, the particle size D90 of the lamotrigine hydrate crystals is not greater than 200 μm.

[0055] In some embodiments, the particle size D90 of the pulverized lamotrigine hydrate crystals is not greater than 400 μm.

[0056] In some embodiments, the lamotrigine hydrate crystal form can be a specific hydrate crystal or a combination of multiple hydrate crystals.

[0057] In some implementations, the pulverization includes needle pulverization, hammer pulverization, and cutter pulverization.

[0058] The present invention provides another method for preparing lamotrigine dry suspension, wherein the method includes the following steps: directly mixing lamotrigine hydrate crystals with pharmaceutically acceptable excipients to obtain a lamotrigine dry suspension composition.

[0059] In some embodiments, the lamotrigine hydrate crystal form can be a specific hydrate crystal or a combination of multiple hydrate crystals.

[0060] In some embodiments, the particle size D90 of the lamotrigine hydrate crystals is not greater than 200 μm.

[0061] In a third aspect, the present invention provides a method for treating a neurological disorder, comprising administering to an individual in need a therapeutically effective amount of the lamotrigine dry composition of the present invention.

[0062] In some specific implementations, the neurological disease is selected from one or more of Alzheimer's disease, depression, multiple sclerosis, Parkinson's disease, and epilepsy.

[0063] In some specific implementations, the medications available for patient use may be further selected from one or more of oxcarbazepine, carbamazepine, phenytoin, valproic acid, ethosuximide, felbamate, gabapentin, levetiracetam, thiogabin, prugabalin, phenobarbital, zonisamide, clonazepam, phenytoin sodium, sodium valproate, clonazan, vigabatrin, topiramate, and lacaramide.

[0064] In a fourth aspect, the present invention provides the use of the lamotrigine dried composition of the present invention in the preparation of a medicament for treating nervous system diseases.

[0065] In some specific implementations, the neurological disease is selected from one or more of Alzheimer's disease, depression, multiple sclerosis, Parkinson's disease, and epilepsy.

[0066] In some specific implementations, the medications available for patient use may be further selected from one or more of oxcarbazepine, carbamazepine, phenytoin, valproic acid, ethosuximide, felbamate, gabapentin, levetiracetam, thiogabin, prugabalin, phenobarbital, zonisamide, clonazepam, phenytoin sodium, sodium valproate, clonazan, vigabatrin, topiramate, and lacaramide.

[0067] In a fifth aspect, the present invention provides the lamotrigine dried composition of the present invention for the treatment of nervous system diseases.

[0068] In some implementations, the neurological disease is selected from one or more of Alzheimer's disease, depression, multiple sclerosis, Parkinson's disease, and epilepsy.

[0069] In some implementations, the drug is used in combination with other drugs to treat the neurological disease.

[0070] In some implementations, the drug is in the form of a dry suspension or a suspension concentrate.

[0071] In some embodiments, more than about 80% of the lamotrigine in the drug is present in the form of lamotrigine hydrate crystals. Detailed Implementation

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail.

[0073] The terms “including,” “comprising,” “having,” “containing,” or “involving,” as used herein, and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0074] As used herein, the term “about” means that a person skilled in the art would consider the value to be within an acceptable standard error, such as ±0.05, ±0.1, ±0.2, ±0.3, ±0.5, ±1, ±2, or ±3.

[0075] As used herein, the term "suspension" refers to the distribution of a solid drug product in the form of microparticles within a liquid formulation. As used herein, the term "dry suspension" refers to a powdered substance made from a solid drug product and suitable pharmaceutical excipients. This powdered substance, when mixed with a solvent, such as an aqueous phase, can be dispersed to form a suspension for administration to a patient, such as orally. In this document, lamotrigine dry suspension refers to a powdered substance containing lamotrigine particles.

[0076] As used herein, the term "D90" means that 90% of the lamotrigine particles have a diameter smaller than the stated particle size.

[0077] The first series of excipients may include one or more of the following: fillers, sweeteners, pH adjusters, preservatives, flow aids, defoamers, and flavoring agents.

[0078] The second series of excipients generally includes thickeners and, optionally, one or more of the following: sweeteners, pH adjusters, preservatives, flow aids, defoamers, and flavoring agents.

[0079] Lamotrigine hydrate may be in any hydrate form. The particles in step (a) may include one or more forms of hydrate.

[0080] The pulverization process in step (b) may include stirring, sieving, cutting, grinding, pressurizing, and any other suitable method or method to control particle size. In some embodiments, the particle size D90 of the pulverized material is less than 400 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 180 μm, less than 150 μm, less than 100 μm, less than 80 μm, less than 50 μm, less than 30 μm, less than 20 μm, and less than 10 μm. This includes, but is not limited to, particles with D90 of approximately 1 μm, approximately 2 μm, approximately 5 μm, approximately 10 μm, approximately 20 μm, approximately 50 μm, approximately 60 μm, approximately 80 μm, approximately 100 μm, approximately 110 μm, approximately 120 μm, approximately 150 μm, approximately 200 μm, approximately 250 μm, and any D90 particle size within the above two particle size ranges.

[0081] In step (a), the lamotrigine hydrate particles, before or after mixing with the excipients, can be pulverized into particles of a suitable size. In some embodiments, the lamotrigine hydrate particles in step (a) are mixed with the first series of excipients. In some embodiments, the lamotrigine hydrate particles in step (a) are not mixed with the first series of excipients, and the lamotrigine hydrate in step (a) directly undergoes the operation in step (b). In some embodiments, the particles in step (a) are mainly composed of or consist of lamotrigine hydrate.

[0082] The first and / or second series of excipients may include a pH adjuster. The weight ratio of lamotrigine to the pH adjuster ranges from about 10:0.1 to 10:8, including but not limited to ratios within any two of the above ranges: 10:0.1, 10:0.2, 10:0.5, 10:0.8, 10:1, 10:1.5, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8. The pH range of the suspension includes about 3.0 to 8.0, including but not limited to about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, and about 8.0. A more preferred pH range is 4.0 to 6.0.

[0083] The thickener serves to stabilize lamotrigine hydrate crystal particles in the suspension. Suitable thickeners include, but are not limited to, xanthan gum, sodium carboxymethyl cellulose, sodium alginate, and magnesium aluminum silicate. The weight ratio between lamotrigine hydrate crystals and the pH adjuster ranges from about 10:1 to 10:8, including but not limited to about 10:1, about 10:2, about 10:3, about 10:4, about 10:5, about 10:6, about 10:7, about 10:8, and any ratio between two of the above ranges.

[0084] In some embodiments, the method further includes, prior to step (a), preparing anhydrous lamotrigine into hydrated lamotrigine, including adding anhydrous lamotrigine to water to obtain a hydrated lamotrigine suspension. Then, the hydrated lamotrigine is separated from the suspension, excess water is removed and the particles are dried, and the resulting particles are processed to a suitable particle size with a D90 as specified above. In some embodiments, the initial anhydrous lamotrigine used has a particle size D90 of less than 800 μm, less than 600 μm, less than 500 μm, less than 400 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 180 μm, less than 150 μm, less than 100 μm, less than 80 μm, less than 50 μm, less than 30 μm, less than 20 μm, and less than 10 μm. The particle size D90 of the anhydrous lamotrigine used in some embodiments includes, but is not limited to, about 1 μm, about 2 μm, about 3 μm, about 1 μm, about 2 μm, about 3 μm, about 5 μm, about 10 μm, about 20 μm, about 50 μm, about 60 μm, about 80 μm, about 100 μm, about 110 μm, about 120 μm, about 150 μm, about 200 μm, about 250 μm, and any D90 particle size between the two ranges mentioned above.

[0085] Optionally, the wet granules obtained by mixing the suspension containing lamotrigine hydrate and the first series of excipients are further dried after removing excess water to obtain lamotrigine hydrate granules mixed with the first series of excipients. In some embodiments, the isolated lamotrigine hydrate can be mixed with the first series of excipients to prepare wet granules, which are then dried to obtain lamotrigine hydrate granules with the appropriate D90 particle size mentioned above.

[0086] The granules, processed to a suitable D90 particle size, are mixed with a thickener and one or more optional excipients, such as sweeteners, pH adjusters, preservatives, flow aids, defoamers, and flavoring agents. The mixture is then homogenized by shaking or other processing steps. The mixture is then passed through a sieve with an aperture less than 2000 μm, less than 1500 μm, less than 1000 μm, less than 800 μm, less than 600 μm, less than 500 μm, less than 400 μm, less than 300 μm, or less than 200 μm, including but not limited to sieves with apertures of approximately 800 μm, approximately 700 μm, approximately 600 μm, approximately 500 μm, approximately 450 μm, approximately 400 μm, approximately 350 μm, approximately 300 μm, approximately 200 μm, approximately 100 μm, and any of the above two ranges.

[0087] A method for preparing a composition or particles is provided, which, after mixing with water, forms a stable lamotrigine hydrate suspension, wherein the particle size D90 of the lamotrigine hydrate particles is less than a certain value for a period of time. Specific preparation methods and steps are described in the above method. In some embodiments, after mixing the particles and water, the particle size D90 of the lamotrigine hydrate in the reconstituted suspension used for administration is less than 400 μm, less than 300 μm, less than 200 μm, less than 180 μm, less than 150 μm, less than 100 μm, less than 80 μm, less than 50 μm, less than 30 μm, less than 20 μm, or less than 10 μm, including but not limited to particle sizes D90 of about 1 μm, about 2 μm, about 3 μm, about 5 μm, about 10 μm, about 20 μm, about 50 μm, about 60 μm, about 80 μm, about 100 μm, about 110 μm, about 120 μm, 150 μm, about 200 μm, and any of the above two ranges. In some embodiments, the lamotrigine hydrate particles in the reconstituted suspension after mixing the powder with water can maintain a stable particle size range for at least 1 day, at least 2 days, at least 5 days, at least 7 days, at least 10 days, at least 20 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, or at least 12 months. The D90 and / or particle stability of the reconstituted suspension particles can be controlled by adjusting one or two parameters during the operation (e.g., the initial lamotrigine hydrate particle size before mixing with other materials in different proportions).

[0088] On the other hand, lamotrigine hydrate particles and compositions for preparing suspensions are provided. The particles can be prepared according to the methods disclosed herein.

[0089] On the other hand, this patent provides a method for treating a neurological disorder, comprising preparing a suspension from a dried composition prepared according to a portion disclosed herein. In some embodiments, the neurological disorder is selected from one or more of Alzheimer's disease, depression, multiple sclerosis, Parkinson's disease, and epilepsy. In some embodiments, the medication for patient administration may further be selected from oxcarbazepine, carbamazepine, phenytoin, valproic acid, ethosuximide, felbamate, gabapentin, levetiracetam, thiogabenin, prugabalin, phenobarbital, zonisamide, clonazepam, phenytoin sodium, sodium valproate, clobazine, vigabatrin, topiramate, and lactamase.

[0090] The following examples are for further illustration of the invention and do not limit the scope of the invention to these examples. The raw materials and reagents used in the invention may be commercially available.

[0091] Experimental Example---1 Preparation of Dry Suspension by Different Processes

[0092] Method (Group 1) of the present invention: 10 parts by weight of anhydrous lamotrigine with a D90 of 8 μm are added to 30 parts by weight of purified water and stirred and dispersed. The stirring speed is set to 800 rpm and stirred at room temperature for 3 hours.

[0093] The mixture was added as a slurry to a mixture of 20 parts by weight of mannitol, 20 parts by weight of lactose, and 20 parts by weight of microcrystalline cellulose for wet granulation. The stirring speed was set at 150 rpm and the shearing speed at 1500 rpm. After completion, the wet granules were passed through a 6250 μm sieve. The wet granules were then dried using a fluidized bed with an inlet air temperature of 60°C. Finally, the granules were pulverized to a particle size of approximately 70 μm with a D90.

[0094] Place the above-mentioned pulverized materials and other materials (parts by weight) in Table 5 below into a hopper of appropriate size, mix at 20 rpm for 5 minutes, pass through a 457 μm sieve, and then continue to mix in the hopper for 10 minutes to obtain a dry suspension powder that can be bottled.

[0095] Existing technology WO 2022 / 218437, method (group 2): 10 parts by weight of anhydrous lamotrigine with a D90 of 8 μm, as per Table 5. All materials in the formulation are placed in a suitably sized hopper and mixed at 20 rpm for 5 min. The mixture is then passed through a 457 μm sieve and mixed again in the hopper for 10 min to obtain a canned dry suspension powder.

[0096] The dry suspension particles prepared by the two methods described above were weighed out in appropriate amounts and added to 500ml glass bottles respectively. Stability tests were conducted in stability chambers at 25℃ / 60%RH and 30℃ / 65%RH. After 6 months, the bottles were removed, water was added, and the suspensions were shaken to prepare suspensions. The content and impurities were then analyzed, as shown in the table below.

[0097] Table 5

[0098]

[0099] Table 6. Stability Content Data

[0100]

[0101] Table 7. Stability Impurity Data

[0102]

[0103] Note: ND indicates that no impurities were detected or the impurity content was extremely low, less than the detection range.

[0104] Following the above method, lamotrigine dry suspensions were prepared using two different processes with the formulation in Table 5. According to the results in Table 6, the dry suspension prepared using the previous patent method showed uneven content in the reconstituted suspension, with an RSD > 5%, failing to meet the standard for suspension content uniformity. In contrast, the dry suspension prepared using the process in this patent showed uniform content in the reconstituted suspension, with an RSD < 1.0. According to the results in Table 7, the impurities in the lamotrigine dry suspensions prepared using both different processes were within the normal range. Therefore, based on the stability results of the above examples, the lamotrigine dry suspension product prepared using the process of this patent is more stable.

[0105] Example 1---Preparation of dry suspensions using wet granulation with anhydrous lamotrigine of different particle sizes.

[0106] Ten parts by weight (D90) of anhydrous lamotrigine with concentrations of 4 μm, 60 μm, and 150 μm were added to 30 parts by weight of purified water and stirred to disperse. The stirring speed was set to 800 rpm and stirred at room temperature for 3 h to obtain lamotrigine hydrate crystals. The characteristic peaks of the anhydrous lamotrigine at diffraction angles (2θ) of 12.3±0.2, 13.7±0.2, 16.5±0.2, 17.3±0.2, and 17.8±0.2 degrees in the XRPD spectrum were not clearly shown in the hydrate crystals. The characteristic peaks of the hydrate at diffraction angles (2θ) of 10.69±0.2, 13.12±0.2, and 15.73±0.2 degrees were also observed, indicating that the anhydrous lamotrigine transformed into hydrate crystals.

[0107] The mixture was added as a slurry to a mixture of 20 parts by weight of mannitol, 20 parts by weight of lactose, and 20 parts by weight of microcrystalline cellulose for wet granulation. The stirring speed was set at 150 rpm and the shearing speed at 1500 rpm. After completion, the wet granules were passed through a 6250 μm sieve. The wet granules were then dried using a fluidized bed with an inlet air temperature of 60°C. Finally, the granules were pulverized to a particle size of approximately 70 μm with a D90.

[0108] The above-mentioned pulverized materials and other materials (parts by weight) in Table 1 were placed in a hopper of appropriate size and mixed at 20 rpm for 5 minutes. After passing through a 475 μm sieve, the mixture was then placed in the hopper and mixed for another 10 minutes to obtain a canned dry suspension powder. Table 1

[0109] Group 1 2 3 Lamotrigine D90 particle size (µm) 4.4 60.6 150.0 Lamotrigine 10 10 10 Mannitol 20 20 20 Lactose monohydrate 20 20 20 microcrystalline cellulose 20 20 20 Sucralose 1 1 1 Xanthan Gum 3 3 3 silicon dioxide 1 1 1 Orange flavoring 0.5 0.5 0.5 Citric acid 2.5 2.5 2.5 Sodium hydrogen phosphate 1.5 1.5 1.5 Simethicone emulsion 1.6 1.6 1.6 Sodium methylparaben 2 2 2 Sodium hydroxypropyl ester 0.2 0.2 0.2

[0110] Following the above method, dry suspensions prepared using lamotrigine with three different particle sizes according to the formulation in Table 1 exhibit physicochemical stability in terms of content and related substances. The physicochemical properties of the reconstituted suspension remain stable for at least 3 months, meaning that patients can use the product continuously for at least 3 months after reconstitution and opening. The lamotrigine dry suspension prepared using this method has broad requirements for the particle size of the active pharmaceutical ingredient (API), essentially covering all particle sizes of lamotrigine shipped from the factory. According to the above examples, the particle size D90 of the API lamotrigine can cover 1-200 μm.

[0111] Example 2---Preparation of dry suspensions using anhydrous lamotrigine with different particle sizes via hydrate filtration

[0112] Ten parts by weight (D90) of anhydrous lamotrigine with concentrations of 4 μm, 60 μm, and 150 μm were added to 100 parts by weight of purified water and dispersed by stirring at 800 rpm for 3 hours at room temperature to obtain lamotrigine hydrate crystals. The XRPD spectra of the anhydrous lamotrigine showed a series of characteristic peaks at diffraction angles (2θ) of 12.3±0.2, 13.7±0.2, 16.5±0.2, 17.3±0.2, and 17.8±0.2 degrees, which were not clearly visible in the hydrate crystals. Furthermore, the hydrate crystals exhibited a series of characteristic peaks at diffraction angles (2θ) of 10.69±0.2, 13.12±0.2, and 15.73±0.2 degrees, indicating that the anhydrous lamotrigine transformed into hydrate crystals. This suspension was filtered to obtain wet lamotrigine particles. The lamotrigine was dried in a fluidized bed with an inlet air temperature of 60°C. The dried lamotrigine granules were then pulverized to a particle size of approximately 30 μm with a D90 value using a pulverizer.

[0113] The formula is shown in Table 2. The above-mentioned pulverized lamotrigine hydrate and other materials (parts by weight) in Table 2 are placed in a hopper of appropriate size and mixed at a speed of 20 rpm for 5 min. After passing through a 475 μm sieve, the mixture is then placed in the hopper and mixed for another 10 min to obtain a dry suspension powder that can be bottled.

[0114] Using lamotrigine raw materials with three different particle sizes, the dry suspension prepared according to the method described above and the formulation in Table 2 was physicochemically stable in terms of content and related substances. After filtration, the wet particles were dried, and crystallization was detected. A series of characteristic peaks of hydrates at diffraction angles (2θ) of 10.69±0.2, 13.12±0.2, and 15.73±0.2 degrees were still present in the XRPD spectrum, indicating that the lamotrigine crystals in the formulation suspension prepared by this process are still hydrate crystals. The physicochemical properties of the reconstituted suspension are stable for at least 3 months, meaning that patients can use the product continuously for at least 3 months after opening and reconstitution. The lamotrigine dry suspension prepared using this method has broad requirements for the particle size of the lamotrigine raw material, basically covering all particle sizes of lamotrigine. According to the above examples, the particle size D90 of the lamotrigine raw material can cover 1-200 μm.

[0115] Table 2

[0116] Group 1 2 3 Lamotrigine D90 particle size (µm) 4.4 60.6 150.0 Lamotrigine 10 10 10 Mannitol 20 20 20 Sucralose 1 1 1 Xanthan Gum 3 3 3 silicon dioxide 1 1 1 Orange flavoring 0.5 0.5 0.5 Citric acid 2.5 2.5 2.5 Sodium hydrogen phosphate 1.5 1.5 1.5 Sodium methylparaben 2 2 2 Sodium hydroxypropyl ester 0.2 0.2 0.2

[0117] Example 3---Preparation of dry suspensions using lamotrigine hydrates of different particle sizes

[0118] Ten parts by weight (D90) of lamotrigine hydrate crystals with values ​​of 4 μm, 60 μm, and 110 μm were crystallized. Their XRPD spectra showed a series of characteristic peaks of the hydrate at diffraction angles (2θ) of 10.69 ± 0.2, 13.12 ± 0.2, and 15.73 ± 0.2 degrees. The formulation was the same as in Table 2. All materials in the formulation were placed in a suitably sized hopper and mixed at 20 rpm for 5 min. The mixture was then passed through a 475 μm sieve and continued mixing in the hopper for 10 min to obtain a canned dry suspension powder.

[0119] The dry suspension prepared according to the above method is physicochemically stable in terms of content and related substances. The physicochemical properties of the reconstituted suspension remain stable for at least 3 months, meaning that patients can use the product continuously for at least 3 months after opening and reconstitution.

[0120] Example 4---Pulverizing intermediates to different particle sizes to prepare dry suspensions

[0121] Ten parts by weight of anhydrous lamotrigine with a D90 of 8 μm were added to 30 parts by weight of purified water and stirred to disperse. The stirring speed was set to 800 rpm and stirred at room temperature for 3 h to obtain lamotrigine hydrate crystals. The XRPD spectrum showed a series of characteristic peaks of hydrate at diffraction angles (2θ) of 10.69±0.2, 13.12±0.2, and 15.73±0.2 degrees, indicating that lamotrigine had been transformed from anhydrous lamotrigine to hydrate crystals.

[0122] The mixture was added as a slurry to a mixture of 20 parts by weight of mannitol, 20 parts by weight of lactose, and 20 parts by weight of microcrystalline cellulose for wet granulation. The stirring speed was set at 150 rpm and the shearing speed at 1500 rpm. After completion, the wet granules were passed through a 6250 μm sieve. The wet granules were then dried using a fluidized bed dryer with an inlet air temperature of 60 °C. The dried granules were then divided into three equal portions and pulverized using a pulverizer to obtain intermediate materials with D90 values ​​of approximately 30 μm, 70 μm, 110 μm, and 320 μm, respectively.

[0123] The above-mentioned pulverized materials and other materials (parts by weight) in Table 3 below are placed in a hopper of appropriate size and mixed at 20 rpm for 5 minutes. After passing through a 475 μm sieve, they are then placed in the hopper and mixed for another 10 minutes to obtain a dry suspension powder that can be bottled.

[0124] Table 3

[0125]

[0126] Following the above method, the dry suspensions prepared using three different particle size pulverized intermediates according to the prescription in Table 3 showed physicochemical stability in terms of content and related substances. The physicochemical properties of the reconstituted suspension remained stable for at least 3 months, meaning the product could be used continuously by patients for at least 3 months after opening and reconstitution. This indicates that the particle size of the pulverized intermediates was acceptable, at least within the range of 20–400 μm.

[0127] Example 5---Preparation of dry suspension from mixtures of different crystalline hydrate crystals

[0128] Solid particles of different lamotrigine hydrate crystal forms were prepared and pulverized to a particle size D90 of no more than 110 μm. According to Table 4, lamotrigine hydrate of different crystal forms was placed together with other materials (parts by weight) in a hopper of appropriate size and mixed at 20 rpm for 5 min. After passing through a 475 μm sieve, it was continued to be placed in the hopper and mixed for 10 min to obtain a dry suspension powder that can be bottled.

[0129] Table 4

[0130]

[0131]

[0132] Following the above method and the formulation in Table 4, two different crystal forms of lamotrigine hydrate were used. The XRPD spectrum of crystal form II showed a series of characteristic peaks of the hydrate at diffraction angles (2θ) of 10.69±0.2, 13.12±0.2, and 15.73±0.2 degrees. The XRPD spectrum of crystal form A showed a series of characteristic peaks of the hydrate at diffraction angles (2θ) of 11.44±0.2, 13.302±0.2, and 14.90±0.2 degrees. Dry suspensions prepared with different proportions of hydrate showed stable content and physical properties such as related substances. The inventors also found that when the reconstituted suspensions were placed at high temperatures of 40℃ and 60℃, the suspension at 2M at 40℃ showed characteristic peaks for both crystal forms, while the suspension at 2M at 60℃ only showed characteristic peaks for crystal form II, with no obvious characteristic peaks for crystal form A.

[0133] Equal masses of the two crystal forms of lamotrigine were mixed in pure water and placed at high temperatures of 40°C and 60°C. At 2M, only the characteristic peak of crystal form II was detected in the suspensions under both temperature conditions, and no obvious characteristic peak of crystal form A was observed.

[0134] Based on the above experimental results, it can also be concluded that crystal form A is an intermediate form of crystal form II, and crystal form II is a more stable crystal form.

[0135] Example 6---Preparation of dry suspensions using different drying methods

[0136] Ten parts by weight of anhydrous lamotrigine with a D90 of 4 μm were added to 30 parts by weight of purified water and stirred to disperse. The stirring speed was set to 800 rpm and stirred at room temperature for 3 h to obtain lamotrigine hydrate crystals. The XRPD spectrum of the anhydrous lamotrigine showed a series of characteristic peaks at diffraction angles (2θ) of 12.3±0.2, 13.7±0.2, 16.5±0.2, 17.3±0.2, and 17.8±0.2 degrees, which were not clearly shown in the hydrate crystals. The hydrate crystals showed a series of characteristic peaks at diffraction angles (2θ) of 10.69±0.2, 13.12±0.2, and 15.73±0.2 degrees, indicating that the anhydrous lamotrigine had been transformed into hydrate crystals.

[0137] The mixture was added as a slurry to a mixture of 20 parts by weight of mannitol, 20 parts by weight of lactose, and 20 parts by weight of microcrystalline cellulose for wet granulation. The stirring speed was set at 150 rpm and the shearing speed at 1500 rpm. After completion, the wet soft material was passed through a 6250 μm sieve. The material was divided into two halves. One half was dried using a fluidized bed (Group 1) with an inlet air temperature of 60°C. The other half was dried using an oven (Group 2) with an oven temperature of 50°C. Drying was stopped when the LOD (Level of Drying) reached ≤2.0%. The material was then pulverized to a D90 of approximately 70 μm using a pulverizer.

[0138] Place the above-mentioned pulverized materials and other materials (parts by weight) in Table 8 below into a hopper of appropriate size, mix at 20 rpm for 5 minutes, pass through a 475 μm sieve, and then continue to mix in the hopper for 10 minutes to obtain a dry suspension powder that can be bottled.

[0139] Table 8

[0140] Group 1 2 Material drying methods Fluidized bed drying Oven drying Lamotrigine D90 particle size (µm) 4.4 4.4 Lamotrigine 10 10 Mannitol 20 20 Lactose monohydrate 20 20 microcrystalline cellulose 20 20 Sucralose 1 1 Xanthan Gum 3 3 silicon dioxide 1 1 Orange flavoring 0.5 0.5 Citric acid 2.5 2.5 Sodium hydrogen phosphate 1.5 1.5 Simethicone emulsion 1.6 1.6 Sodium methylparaben 2 2 Sodium hydroxypropyl ester 0.2 0.2

[0141] Following the above method, using the formulation in Table 8, the lamotrigine dry suspensions prepared using two different drying processes showed stable physicochemical properties, including content and related substances. The physicochemical properties of the reconstituted suspensions were also stable for at least 3M, meaning that both fluidized bed drying and oven drying methods could produce compliant lamotrigine dry suspensions from the wet granulated material.

[0142] The above-described embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and alterations without departing from the concept of the present invention, and these modifications and alterations all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent is determined by the appended claims.

Claims

1. A dried pharmaceutical composition comprising a therapeutically effective amount of one or more lamotrigine hydrate crystals and one or more pharmaceutically acceptable excipients, said excipients including thickeners; preferably a dried suspension, wherein said dried suspension is formulated as an oral suspension.

2. The dried pharmaceutical composition according to claim 1, wherein the suspension prepared by the dried suspension can be used stably for at least 1-3 months.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a pH adjuster.

4. The pharmaceutical composition according to any one of claims 1-3, further comprising a filler, a preservative, a flow aid, an antifoaming agent, and / or a flavoring agent.

5. The pharmaceutical composition according to any one of claims 1-3, wherein the particle size (D90) of the lamotrigine hydrate crystals is about 1-200 μm.

6. The pharmaceutical composition according to claim 1, wherein the weight ratio of the lamotrigine hydrate crystals and the thickener is from about 10:1 to 10:

7.

7. The pharmaceutical composition according to claim 3, wherein the weight ratio of the lamotrigine hydrate crystals and the pH adjuster is from about 10:0.1 to 10:

8.

8. The pharmaceutical composition according to claim 1, wherein the thickener is selected from hydrolyzed colloids, such as xanthan gum, guar gum, locust bean gum, and carrageenan; cellulose derivatives, such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides, such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic copolymers, such as carbomer; povidone; and magnesium aluminum silicate and combinations thereof; preferably xanthan gum, povidone, sodium carboxymethyl cellulose, sodium alginate, magnesium aluminum silicate, and / or carbomer.

9. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition comprises the following excipients: Approximately 1-5 parts by weight of xanthan gum; Approximately 10-80 parts by weight of mannitol; Approximately 10-80 parts by weight of microcrystalline cellulose; Approximately 10-80 parts by weight of lactose; Approximately 1-5 parts by weight of sucralose; Approximately 1-5 parts by weight of orange flavoring; A combination of approximately 1-3 parts by weight of sodium methylparaben and sodium propylparaben, wherein the weight ratio of sodium methylparaben to sodium propylparaben is approximately 9:1; Approximately 0.1-5 parts by weight of silicon dioxide; Approximately 0.01-3 parts by weight of simethicone emulsion.

10. A method for preparing a dried pharmaceutical composition according to any one of claims 1-9, comprising: (a) Provide an anhydrous lamotrigine that is converted into lamotrigine hydrate crystals upon addition to water and / or directly provide lamotrigine hydrate crystals; (b) The above-mentioned lamotrigine hydrate crystals are mixed with pharmaceutically acceptable first-series excipients, wet-granulated, and dried in a fluidized bed or oven to obtain granules; (c) The particles are crushed to a particle size (D90) of about 1-400 μm; preferably, about 30 μm, 70 μm, or 110 μm. (d) The pulverized particles are mixed with a second series of excipients to obtain a dried pharmaceutical composition, wherein the second series of excipients contains at least one thickener that enables the dried pharmaceutical composition, such as a dry suspension, to be reconstituted into a homogeneous suspension.

11. A method for preparing a dried pharmaceutical composition according to any one of claims 1-9, comprising: (e) Provide an anhydrous lamotrigine that is converted into lamotrigine hydrate crystals upon addition to water and / or directly provide lamotrigine hydrate crystals; (f) Crystallize the above-mentioned lamotrigine hydrate and dry it to obtain lamotrigine hydrate crystalline particles; (g) The particles are crushed to a particle size (D90) of about 1-200 μm; preferably, about 10 μm, 30 μm, or 70 μm. (h) The pulverized particles are mixed with a first series and / or a second series of excipients to obtain a dried pharmaceutical composition, wherein the second series of excipients contains at least one thickener that enables the dried pharmaceutical composition, such as a dry suspension, to be reconstituted into a homogeneous suspension.

12. A method for preparing the dry suspension of claim 10 or 11, wherein... The pharmaceutically acceptable excipients in steps (b) and (h) are excipients of the first series, which are selected from one or more combinations of fillers, sweeteners, pH adjusters, preservatives, flow aids, defoamers, flavoring agents and surfactants.

13. The method according to claim 10 or 11, wherein the particles in step (a) consist primarily of lamotrigine hydrate crystals.

14. The method of claim 10 or 11, wherein the second series of excipients further comprises one or more excipients selected from thickeners, sweeteners, pH adjusters, preservatives, flow aids, defoamers, and flavoring agents.

15. The method of claim 10 or 11, wherein the weight ratio of the lamotrigine hydrate crystallizer and the pH adjuster is about 10:0.1 to 10:8 and / or the weight ratio of the lamotrigine hydrate crystallizer and the thickener is about 10:1 to 10:

7.

16. The method of claim 10 or 11, wherein the thickener is selected from hydrolyzed colloids such as xanthan gum, guar gum, locust bean gum, and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose; polysaccharides such as starch and pregelatinized starch; alginates such as sodium alginate; acrylic copolymers such as carbomer; povidone; and magnesium aluminum silicate and combinations thereof.

17. The method according to claim 10 or 11, wherein the lamotrigine hydrate crystals constitute 1% to 80% of the composition by weight.

18. The method of claim 10 or 11, wherein the dried pharmaceutical composition is formulated into an oral suspension that is stable for use for at least 1-3 months.

19. Use of the lamotrigine dry composition of any one of claims 1-9 in the preparation of a medicament for treating nervous system diseases.

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

21. The use according to claim 19, wherein the drug is used in combination with one or more drugs selected from oxcarbazepine, carbamazepine, phenytoin, valproic acid, ethosuximide, felbamate, gabapentin, levetiracetam, thiogabin, prugabalin, phenobarbital, zonisamide, clonazepam, phenytoin sodium, sodium valproate, clobazine, vigabatrin, topiramate, and lacaramide.

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