Untitled record

Lamotrigine orally disintegrating tablet formulations

Orally Disintegrating Tablet Compositions of Lamotrigine

Full description

Background of the invention

The present invention relates to a pleasant-tasting tablet composition that disintegrates or dissolves in the mouth and includes lamotrigine.

This combination is used to treat epilepsy and mood disorders such as bipolar disorder.

Dysphagia resulting from fear or choking is a common condition among all groups of people of all ages.

For example, this condition is seen in about 35% of the general population, with an additional 30% to 40% of elderly patients, and 18% to 22% of all long-term hospital residents. , who need to take medications at regular intervals in order to maintain a certain lifestyle. This leads to a low degree of compliance in these patients or a lack of response to treatment when giving medications orally, which negatively affects the effectiveness of oral treatment.

The main goal of treatment for patients with epilepsy is to maintain adequate levels of anti-epileptic drug and prevent subsequent recurrence of the disease. In patients with mood disorders such as bipolar disorder, the goal here is to prevent relapses and stabilize the mood. In both cases, compliance with treatment is one of the basic matters necessary to maintain therapeutic levels of the drug in the blood.

Lamotrigine is known as an anticonvulsant drug, and is used to treat epilepsy, epilepsy and bipolar disorder, and partial seizures associated with Lennox-Gastaut syndrome. Chemically, lamotrigine is a compound 3,5-diamino-6-(2,3,-dichlorophenyl)-1,2,4-triazine, with the numerical formula C9H7N5Cl2, a molecular weight of 256.09, and the following general formula: :

The process of preparing lamotrigine is described in US Patent No. 460, 2017, which is used herein as a technical reference for this invention for all its purposes. Lamotrigine is very slightly soluble in water (about 0.17 mg/mL at 25°C, about 0.57 mg/mL at 37°C), but is more highly soluble in HCl (0.01 A) (about 3 mg/mL at 37°C). 25°C) and in HCl (0.1 p) (about 4 mg/mL at 25°C).

General description of the invention

In one embodiment, the present invention relates to an orally disintegrating tablet composition comprising a therapeutically effective amount of lamotrigine, such that when such composition is ingested, it is substantially disintegrated in the oral cavity and lamotrigine is released in a manner substantially similar to that in which lamotrigine is released from the immediate-release compositions. immediate release.

In another embodiment, the present invention relates to a composition of oral disintegrant tablets comprising a therapeutically effective amount of lamotrigine coated with a coating of acceptable taste, in combination with granules comprising a disintegrant, a sugar alcohol, and/or a saccharide, such that after Ingestion of the formulation is largely disintegrated in the oral cavity and lamotrigine is released in a manner substantially similar to that of lamotrigine from immediate-release formulations.

In another embodiment, the present invention relates to a method for preparing compositions comprising particles of lamotrigine, with granules comprising a disintegrant, a sugar alcohol, and/or a saccharide. This method includes:

(a) Coating lamotrigine-containing particles with a taste-blocking coating;

(b) Preparation of granules comprising a disintegrant, a sugar alcohol, and/or a saccharide;

(c) mixing the coated particles obtained in step (a) with the granules in step (b) and with other optional pharmaceutically acceptable components;

(d) Compress the resulting mixture in step (c) into tablets.

In still another embodiment, the present invention relates to a method for treating mood disorders, or for treating or preventing epileptic seizures. This method involves administering to a patient in need of treatment a therapeutically effective amount of a formulation containing lamotrigine particles, in combination with granules containing a disintegrant and/or sugar alcohol and/or saccharide.

Those embodiments, features and advantages associated with the present invention will become clearer through the detailed description and examples contained in the following sections of the invention.

Brief explanation of the drawings

Figure 1: Illustrating aspects of the dissolution process for oral disintegrating tablet formulations containing small pellets of lamotrigine in Example 3.

Figure 2: Illustrating the dissolution aspects of oral disintegrating tablet formulations including lamotrigine microcapsules in Example 3.

Figure 3: A comparison of the in-oral (in vivo) disintegration times for formulations containing lamotrigine microbeads and the microcapsules in Example 3.

Figure 4: A comparison of taste/flavor score results for formulations containing lamotrigine microbeads and the microcapsules in Example 3.

Figure 5: A comparison of post-taste scores for a formulation containing lamotrigine microbeads and the microcapsules in Example 3.

Figure 6: A comparison of plasma concentration profiles over time for lamotrigine-coated microparticles and LamictalIR in Example 5.

Figure 7: A comparison between the average Cmax results for a oral disintegrating tablet formulation containing lamotrigine with fine particles coated with a taste-blocking substance, and LamictalIR in Example 5.

Figure 8: A comparison between the AUC(0-24) results for a tablet formulation that disintegrates in the mouth and contains lamotrigine particles coated with a taste-blocking substance, and LamictalIR in Example 5.

Detailed description:

As used in this text, the terms “drug”, “active” or “active pharmaceutical ingredient” include a pharmacologically acceptable and therapeutically effective compound (such as lamotrigine), the pharmacologically acceptable salts of that compound, and/or dimers and mixtures. Such dimers, soluble substances (including hydrates) and/or compound esters (such as lamotrigine).

The terms “orodispersing tablet” or “orodispersing tablet” or “ODT” refer to a solid dose of the compound of the present invention that rapidly disintegrates in the oral cavity after ingestion by the patient without chewing. The rate of disintegration may vary, but it is faster than the rate of disintegration of traditional solid doses, or those that are chewed by the patient (tablets or capsules), or that are swallowed immediately after taking them. Oral disintegration (ODT) compositions according to the present invention contain pharmaceutically acceptable components, which are components that swell, dissolve, or otherwise serve to facilitate the processes of disintegration or dissolution of the ODT composition. These components include a disintegrant substance, sugar alcohol, saccharide, or a mixture of these components, with a water-soluble binder, and with a fusible solid (such as wax), which are substances that release lamotrigine when it enters the Stomach.

The term "about" used in this text refers to a numerical quantity that includes "exactly". For example, the term "about 60 seconds" includes exactly 60 seconds, along with other values close to 60 seconds (ie 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.). When the term "about" is used to refer to a certain range of values, this term here refers to both the minimum and maximum value falling within a certain range. For example, the term about 1 50 µm means from about 1 µm to about 50 µm.

In most embodiments, the ODT compositions of the present invention comprise a therapeutically effective amount of lamotrigine coated with a taste-blocking layer, i.e. in a tablet form that additionally contains granules comprising disintegrated materials.

When an ODT tablet of the present invention is administered into the oral cavity of the patient, the tablet quickly disintegrates into lamotrigine particles coated with a taste-blocking layer, while the sugar alcohol/saccharide-containing granules dissolve to form a soft suspension that can be easily swallowed.

Regarding the disintegration rate of ODT formulations according to the present invention within the oral cavity of the patient, it may reach about 60 seconds or less, 50 seconds or less, 40 seconds or less, 30 seconds or less, or 20 seconds. Or less, or 10 seconds or less.

Alternatively, the rate of disintegration of the ODT composition according to the present invention can be measured using various laboratory testing methods, such as a disintegration test USP <701>. When using this test, the rate of disintegration of ODT formulations is faster than in the case of traditional formulations other than ODT formulations, as this rate reaches, for example, about 60 seconds or less, or about 30 seconds or less, or about 20 seconds or less, or about 10 Seconds or less.

The dissolution rate of lamotrigine in ODT formulations can be evaluated according to the present invention, using the USP-2 device (rotation speed of 75 revolutions per minute in 900 ml of buffer solution containing 0.01 p HCl). When using the test with the aforementioned device 2, the dissolution rate of the drug (lamotrigine) is equal to it in the case of traditional formulations that do not contain ODT, that is, the rate here is about 70% or more, or about 75% or more, or about 80% or more, or About 85% or more, about 90% or more, about 95% or more, or about 100% of the total amount of lamotrigine released in 30 minutes.

“Highly disintegrates” means that the disintegration level is approximately at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% for the ODT formulation. The term “lamotrigine release profiles” refers to those aspects of the dissolution of a formulation containing lamotrigine (Figure 2), and/or aspects of the concentration of this compound in plasma over time (Figure 6), and/or the average Cmax or AUC value (0- 24) (Figures 7, 8). In the ODT compositions of the present invention, the release profiles of lamotrigine are substantially equivalent to those of non-ODT immediate-release oral lamotrigine compositions when administered at the same dose as lamotrigine (e.g., LamictalIR). Thus, an ODT composition of the present invention that features variables relating to dissolution aspects, plasma concentration over time, Cmax, AUC(0-24), or any combination of such variables is substantially similar to the variables characterizing the lamotrigine composition. The immediate-release and non-ODT formulations, in this case, have the same lamotrigine release profiles that are very similar to those of the lamotrigine immediate-release, non-ODT formulation.

The term “substantially similar” means that the release profile of lamotrigine in the ODT formulations of the present invention differs by 25% or less from the release profile of lamotrigine in the immediate-release, non-ODT formulations when given at the same dose as lamotrigine. Alternatively, the term “substantially similar” means that the release profiles of lamotrigine are not statistically different from the release profiles of immediate-release oral formulations of lamotrigine that do not contain ODT, when given at the same dose as lamotrigine.

The term “lamotrigine immediate-release, non-ODT formulation” refers to non-ODT formulations that contain lamotrigine without coatings that produce long-term or controlled release. For example, non-ODT immediate-release formulations include conventional tablets that are swallowed and dissolved in the gastrointestinal tract, chewable tablets for the purpose of breaking down the tablet structure, or variations of popular capsules.

As used in this text, the term “fine particle” refers to a particle or granule whose particle size does not exceed 400 micrometers, and more specifically, a particle size of no more than 300 micrometers. The terms "particle", "fine particle", "granule" and/or "fine granule" are used interchangeably to denote a particle size not exceeding 400 micrometers, regardless of whether the particle in question contains or does not contain on lamotrigine and/or on sugar alcohol. The term “lamotrigine microcaps” refers to particles containing lamotrigine coated with a taste-blocking layer. In these particles, the average particle size does not exceed 400 micrometers.

Fine particles can be classified as primary particles and secondary particles. Primary particles are not agglomerated, while secondary particles are elementary particles in agglomerated form, and therefore, primary particles are smaller in size than secondary particles. In elementary particles the average particle size ranges from about 1 µm to about 300 µm, including limits ranging from approximately 1 to 50, from about 1 to 100, and from about 1 to 150 µm.

Unless otherwise indicated in the text, all percentages and percentages are calculated by weight, on the basis of the total weight of the composition.

As discussed above, the primary therapeutic goal for epilepsy is to maintain adequate levels of anti-epileptic drug, and prevent subsequent epileptic seizures. In patients with bipolar disorders, the goal is to prevent relapse and stabilize mood. In both cases, patient compliance with the prescribed dosage regimen is essential to maintaining therapeutic levels of the drug in the blood. One method used to improve compliance is to administer lamotrigine as an orally disintegrating tablet (ODT) to form a soft, palatable suspension containing lamotrigine that can be swallowed easily (by patients with dysphagia). Likewise, ODT can also prevent fullness in the cheeks in case it disintegrates quickly and moves away from the mouth area. Therefore, an ODT formulation with a laboratory disintegration time of 30 seconds or less according to the disintegration test USP <701> would be an ideal formulation, given that it prevents the drug from being flushed out after the cheeks are full, specifically in older patients with bipolar disorders. .

However, even if a therapeutic ODT formulation has a reasonable disintegration time, the formulation must also be taste-acceptable, i.e. have acceptable taste and mouthfeel characteristics. For medications with a bitter taste, such as lamotrigine, the ODT formulation may include a polymeric substance to mask this taste and improve palatability, while also containing a disintegrant, a sugar alcohol, a saccharide, or a mixture of these substances, in order to provide rapid disintegration. Oral cavity and "creamy" mouthfeel. In addition, the therapeutic ODT formulation must also provide acceptable pharmacokinetics and a good degree of bioavailability for the desired therapeutic effect to be achieved. These desirable properties of an ODT formulation may be contradictory to each other, meaning that components in the formulation that provide bitterness-blocking properties could simultaneously inhibit or delay the release of lamotrigine, thus resulting in undesirable pharmacokinetics. Conversely, ingredients in the therapeutic formulation that enhance the release of lamotrigine may result in an unacceptable taste or mouthfeel. Accordingly, there must be a balance in the ODT therapeutic formula between these contradictory properties, in order to obtain an acceptable taste, rapid disintegration, and acceptable pharmacokinetics. The ODT compositions according to the present invention are characterized as therapeutic formulas containing lamotrigine, and they have good properties, related to the degree of disintegration and pharmacokinetics, which improves the level of compliance on the part of patients who need treatment with these compositions, or who suffer from difficulty swallowing traditional lamotrigine tablets, or who Patients with bipolar disorder, compared to formulations containing lamotrigine other than ODT.

Compositions of the present invention may include any combination comprising a therapeutically effective amount of lamotrigine with one or more pharmaceutically acceptable components that provide the ODT composition defined herein. For example, lamotrigine may be combined with a disintegrant, sugar alcohol, saccharide, and/or binder, wherein the sugar alcohol, disintegrant, and/or binder are swellable and/or It dissolves in the saliva of the patient's oral cavity, and then a soft, easy-to-swallow suspension containing lamotrigine is formed. In addition, there are synthetic sweeteners such as sucralose, cherry flavors and/or similar or different disintegrants added to the formulation for the purpose of promoting rapid disintegration, and to improve the sensory properties of the therapeutic ODT formulation containing lamotrigine.

In one embodiment, the ODT compositions of the present invention comprise granules (fine granules or fine particles) that are prepared by the following steps:

A granulation and/or encapsulation of axons pulposus containing lamotrigine;

b - Mixing granulated or encapsulated pulp axes containing lamotrigine with granules containing a disintegrant substance and/or sugar alcohol and/or saccharide (hereinafter referred to as “rapidly dispersing microgranules);

C - Compress the mixture into ODT tablets.

In another embodiment, the lamotrigine-containing granules of the present invention may be granules containing crystals of lamotrigine with a binder forming a thin film and prepared by a granulation method. Lamotrigine crystals may have an average particle weight ranging from about 1 µm to about 300 µm, i.e. from about 1 to about 50 µm, or from about 1 to 100 µm, or from about 1 to 150 µm, or from about 1 to 200 µm, , or about 1 to 250 µm, or about 50 to 100 µm, or about 50 to 150 µm, or about 50 to 200 µm, or about 50 to 250 µm, or about 50 to 300 micrometres, or about 100 to 150 micrometres, or about 100 to 200 µm, or about 150 to 200 µm, or about 150 to 250 µm, or about 150 to 300 µm, or about 200 to 250 µm, or about 200 to 300 µm, or about 250 to 300 µm.

The binder forming the film may include any suitable binder used in granulation operations. Non-specific examples of chip binders include binders dissolved in water, binders dissolved in alcohol, or binders dissolved in mixtures of water and acetone, such as polyvinylpyrrolidone (PVP), cornstarch, polyethylene oxide, or polyethylene glycol, hydroxypropyl methylcellulose (HPMC), methylcellulose, or hydroxypropylcellulose (HPC). The amount of binder forming the thin film in granules containing lamotrigine can range from about 0.5% to about 10%, for example from about 0.5% to 1%, or from about 0.5% to 2%, or from about 0.5% to 5%. , or from about 0.5% to 7%, or from about 1% to 2%, or from about 1% to 5%, or from about 1% to 7%, or from about 1% to 10%, or from about 2 % to 5%, or from about 2% to 7%, or from about 2% to 10%, or from about 5% to 7%, or from about 5% to 10%, or from about 7% to 10%.

The lamotrigine granules of the present invention may also include other pharmaceutically acceptable filler and diluent components, such as mannitol, lactose, microcrystalline cellulose, potassium sulfate, calcium phosphate, modified starch, and mixtures of such pharmaceutically acceptable components representing fillers or fillers. Diluents in granules containing lamotrigine. The proportion of these components ranges from about 5% to 80%, including proportions ranging from about 5% to 70%, or from about 5% to 60%, or from about 5% to 50%, or from about 5% to 40 %, or from about 5% to 30%, or from about 5% to 20%, or from about 5% to 15%, or from about 5% to 10%, or from about 10% to 70%, or from about 10% to 60%, or from about 10% to 50%, or from about 10% to 40%, or from about 10% to 30%, or from about 10% to 20%, or from about 10% to 15% , or from about 20% to 70%, or from about 20% to 60%, or from about 20% to 50%, or from about 20% to 40%, or from about 20% to 30%, or from about 20% to 25%, or from about 30% to 70%, or from about 30% to 60%, or From about 30% to 50%, or from about 30% to 40%, or from about 30% to 35%, or from about 40% to 70%, or from about 40% to 60%, or from about 40% to 50%, or from about 40% to 45%, or from about 50% to 70%, or from about 50% to 60%, or from about 50% to 55%, or from about 60% to 70%, or from about About 60% to 65%.

Lamotrigine granules can be prepared in accordance with this invention, by any of the appropriate methods. For example, such granules may be prepared by granulating lamotrigine crystals, with one or more disintegrants, and with one or more fillers (sugar alcohol, saccharide, and/or microcrystalline cellulose) in A granulation device that operates at a high shear speed, or in a granulation device equipped with a fluid bed in which a solution containing one or more polymeric binders is used, and then a drying process is carried out in a device equipped with a fluid bed or in trays. Placed inside an oven, resulting in granules containing lamotrigine.

The ODT compositions according to the present invention include rapidly dispersing granules, which comprise a disintegrant with a sugar alcohol and/or with a saccharide. Non-specific examples of suitable disintegrants used with granules include crospovidone (cross-linked PVP), sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, substituent hydroxypropylcellulose, and mixtures thereof. The amount of loose material in rapidly dispersing granules ranges from about 1% to 10%, or from about 5% to 10% of the total weight of the granules, and this includes all percentages within those limits.

Sugar alcohols are known as hydrogenated carbohydrates in which the carbonyl group (aldehyde or ketone) is reduced to a primary or secondary hydroxyl group. Non-specific examples of sugar alcohols suitable for use with rapidly dispersing granules in ODT compositions according to the present invention include: arabitol, isomalt, erythritol, glycerol, lactitol, mannitol, sorbitol, xylitol, maltitol, and mixtures of such alcohols. The term "saccharide" is considered synonymous with the term "sugars", and it includes monosaccharides such as glucose, fructose, the lactose, and ribose; And disaccharides such as sucrose, lactose, maltose, trehalose, and cellobiose. In one embodiment, non-exclusive examples of suitable saccharides that can be used in compositions of the present invention include: lactose, sucrose, maltose, and mixtures of such saccharides. In another embodiment, the rapidly dispersing granules comprise at least one disintegrant material coupled to a sugar alcohol. In another embodiment, the rapidly dispersing granules comprise at least one disintegrant associated with a saccharide. In yet another embodiment, the granules containing the disintegrant comprise at least one disintegrant conjugated to a sugar alcohol or saccharide. The amount of sugar alcohol and/or saccharide in rapidly dispersing granules ranges from about 99% to 90% or from about 95% to 90% of the total weight of the granules, including all other percentages within those limits. In one embodiment, the average particle size of the sugar alcohol and/or saccharide is 30 µm or less, i.e., from about 1 µm to 30 µm, or from about 5 µm to 30 µm, or from about 5 µm to 25 µm µm, or from about 5 µm to 20 µm, or from about 5 µm to 15 µm, or from about 5 µm to 10 µm, or from about 10 µm to 30 µm, or from about 10 µm to 25 µm, or from about About 10 µm to 20 µm, or from About 10 µm to 15 µm, or from about 15 µm to 30 µm, or from about 15 µm to 25 µm, or from about 15 µm to 20 µm, or from about 20 µm to 30 µm, or from about 20 µm to 25 µm µm, or from about 25 µm to 30 µm.

Rapid dispersing granules can be prepared according to the present invention by any suitable method. For example, such granules may be prepared by granulating one or more disintegrants with one or more sugar alcohols and/or with one or more saccharides, using a granulation device operating at a high shear speed, and then a drying process is carried out. In a device equipped with a fluidized bed or in trays inside a conventional oven to produce rapidly dispersing granules in the form of fine granules. These fine granules can also be prepared according to the method described in US Patent Application No. 10/827106 filed on April 19, 2004 and used here as a technical reference for this invention and all its purposes.

The compositions of the present invention comprise a quantity of rapidly dispersing granules and/or a mixture of disintegrant and sugar alcohol and/or saccharide, such quantity being sufficient to provide a suitable disintegration rate in the oral cavity of the patient, to form This is a soft suspension that has an acceptable taste and is easy to swallow and contains lamotrigine particles.

The amount of disintegrant in the rapidly dispersing granules and/or the amount of the disintegrant mixture with sugar alcohol and/or saccharide can be adjusted and modified relative to the lamotrigine present in the compositions of the present invention, in order to obtain an appropriate disintegration rate, and also to form a loose suspension with It has an acceptable taste, is easy to swallow, and contains lamotrigine particles. For example, the compositions of the present invention contain an amount of the mixture of disintegrant and sugar alcohol/saccharide relative to lamotrigine, which is sufficient to provide a disintegration time (in vitro) of 30 seconds or less according to the disintegration test USP <701>.

The amount of rapidly dispersing granules or the amount of mixture containing the disintegrant and sugar alcohol/saccharide may vary relative to lamotrigine, depending on the desired rate of dispersal and on the desired sensory properties, including off-taste blocking properties, mouthfeel, and feel. Post tasting. The amount of the mixture containing the disintegrant and sugar alcohol/saccharide in the compositions of the present invention may range from about 40% to about 95%, and this range includes percentages of about 40%, about 45%, about 50%, and about 55%. %, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, including the values and boundaries between them. In one embodiment, the amount of the mixture containing the disintegrant with sugar alcohol/saccharide ranges from about 60% to 70%, based on the total weight of the composition. In another embodiment, this percentage reaches about 65% by weight.

Likewise, the compositions of the present invention shall contain a sufficient quantity of lamotrigine granules, or pulp axes consisting primarily of lamotrigine with a coating to mask the unpleasant taste, such that such quantity will provide the desired therapeutic effect for the lamotrigine dose. This quantity can be adjusted and adjusted to obtain a therapeutically effective dose of lamotrigine.

The amount of lamotrigine in ODT compositions according to the present invention may range from about 5% to about 50%, and this range includes proportions of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, and about 35%, about 40%, about 45%, about 50%, with all other values and limits within the stated range. In one embodiment, the amount of lamotrigine-containing granules in the ODT compositions of the present invention is approximately 30% on a weight basis of the ODT composition.

In another embodiment, the lamotrigine-containing granules of the present invention can be in the form of beads with layers of lamotrigine.

These beads include a core core, i.e., for example, a pharmaceutically acceptable sugar bead coated with a layer of lamotrigine. These may be prepared, for example, by dissolving or suspending lamotrigine in a solution of a polymeric binder, which is then sprayed or coated in inert particles (i.e., sugar or cellulose beads). sugar spheres or cellulose spheres such as Celphere). Suitable polymeric materials include any of those materials disclosed in this text, such as starch, modified celluloses (hydroxypropylcellulose, carboxymethylcellulose sodium), alginic acid, polyvinylpyrrolidone (PVP), and mixtures thereof. The amount of lamotrigine, as well as the thickness of the lamotrigine layer, can be adjusted and modified to obtain a therapeutically effective dose of lamotrigine. This layer includes a percentage of lamotrigine ranging from about 90% to about 99%, with a percentage of binder ranging from about 1% to about 10%.

In another embodiment, the compositions of the present invention may comprise lamotrigine particles (crystals) coated with a coating that blocks the unpleasant taste, and this coating is applied to the lamotrigine particles by any of a suitable method, such as a fluidized bed encapsulation method.

Compositions of the present invention may comprise a mixture of lamotrigine-containing granules or lamotrigine-containing particles with an off-taste coating (such as lamotrigine-coated granules, lamotrigine crystals, or beads containing lamotrigine coatings described herein). demand), with rapidly dispersing granules. The compositions of the present invention may also include one or more medicinally acceptable flavourings, which include, but are not limited to, cherry, mint or orange flavours, or any other acceptable fruit, or mixtures of cherry, mint, orange and any other acceptable fruit, in proportion It amounts to about 3% based on the total weight of the tablet. In addition, the compositions of the present invention may also comprise one or more sweeteners such as aspartame, sucralose, or any other pharmaceutically acceptable sweetener, or a mixture thereof, up to about 2% on a basis. Total disc weight. The compositions of the present invention may also include one or more colorants (FD&C), up to about 0.5% based on the total weight of the tablet.

In addition, the compositions of the present invention may include an additional disintegrant that is associated with the disintegrant in the granules (lamotrigine-containing granules or rapidly dispersing granules). The additional loose material may be the same material used in the granules containing the loose material, or it may be a different material. Additional disintegrant may be used in the compositions of the present invention at a rate of up to 10% based on the total tablet weight.

Compositions of the present invention may also comprise a pharmaceutically acceptable microcrystalline cellulose, such as Avicel PH101, Avicel PH102, Ceolus KG-802, Prosolv SMCC 50, SMCC90, or any other grade of microcrystalline cellulose. Cellulose, which is pharmaceutically acceptable, as well as mixtures of these materials.

Lamotrigine-containing particles (crystals, granules, or beads containing layers of the drug) can be coated in compositions of the present invention, using a coating to mask the unpleasant taste and improve the palatability of the composition. Here, lamotrigine particles are coated with a taste-blocking layer, using a water-soluble polymer, such as ethylcellulose, or:

polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate (CAB), methacrylate copolymers

Such as those commercially available as EUDRAGIT (types RL, RS, NE30D), or a combination of these polymers.

In one embodiment, the water-soluble polymer is ethylcellulose having a viscosity of about 90 to about 110 centipoise when tested in a viscometer such as an Ubbelohde using a 5 wt% toluene/ethanol (80:20) solution and under a temperature of 25°C .

In one embodiment, the ODT compositions of the present invention comprise about 25% to 35% of lamotrigine crystals contained in microcapsules with an odor-blocking coating consisting of a water-soluble polymer such as ethylcellulose; About 60% to 70% are rapidly dispersing granules (such as those containing crospovidone and mannitol); about 5% of an additional disintegrant (eg crospovidone); About 1% of one or more flavoring substances; With a percentage of materials The sweetener (sucralose) ranges from about 0.5% to about 1%.

Since encapsulation of lamotrigine particles (crystals, granules, or beads containing layers of drug) with a water-soluble polymer may reduce the rate of lamotrigine release, the encapsulation material in this case may also include a pore-forming material, which is Soluble in water or stomach fluids. As for the substances that form pores and are soluble in stomach fluids, they are substances that are not dissolved in water or saliva, but they dissolve quickly in acidic environments, such as those found in the stomach. Non-exclusive examples of water-soluble pore-forming substances include sodium chloride, sucrose, povidone, and mixtures of these substances. Non-exclusive examples of pore-forming substances that are soluble in stomach fluids include: calcium carbonate, magnesium citrate, magnesium hydroxide, and mixtures of these substances. The ratio between the water-insoluble polymer and the pore-forming material that is water-soluble or in stomach fluids may range from about 95/5 to about 50/50, thus obtaining granules containing lamotrigine and coated with a layer that blocks Unacceptable taste. Regarding the amount of coating material relative to the total weight of the coated granule containing lamotrigine, it ranges from about 5% to about 30% by weight, or from about 5% to 25%, or from about 5% to 20%, or from about 5%. to 15%, or from about 5% to 10%, or from about 10% to 30%, or from about 10% to 25%, or from about 10% to 20%, or from about 10% to 15%, or From about 15% to 30%, or from about 50% to 25%, or from about 15% to 20%, or from about 20% to 30%, or from about 20% to 25%, or from about 25% to 30%.

In one embodiment, the present invention provides a method for producing lamotrigine-containing ODT compositions that have an acceptable taste and have lamotrigine particles ranging in average size from 100 micrometers to 400 micrometers. This method includes the following steps:

1 - Preparation of drug-containing pulp axons containing lamotrigine crystals of appropriate average particle size, such as microbeads, lamotrigine crystals, or beads with layers of the drug;

2 - Preparation of granules containing disintegrant and/or sugar alcohol and/or saccharide;

3 - Compress a mixture containing lamotrigine microparticles and granules of the disintegrant, and optionally containing a pharmaceutically acceptable flavoring agent(s), a sweetener(s), another disintegrant(s), and/or Colored material(s), and/or material(s) that aid in compression, such as microcrystalline cellulose, in a quantity sufficient to use an ODT tablet compression device, such as a rotary compression device equipped with an external lubrication system before compression. ODT tablets disintegrate quickly when exposed to saliva in the mouth, transforming into a soft suspension that is easy to swallow without leaving stones after tasting them.

In another embodiment, the present invention provides a method for preparing therapeutic formulations of ODT tablets comprising lamotrigine microparticles with an average particle size ranging from 100 µm to 400 µm. This method also includes a process for coating lamotrigine particles with odor-blocking coatings (lamotrigine crystals, lamotrigine-containing granules, or drug-layered beads), by agglomeration or fluidized coating prior to mixing and compressing the ODT tablets. For example, crystalline lamotrigine, whose average particle size ranges from 1 µm to 200 µm, and specifically from 50 µm to 150 µm, can be coated here with a layer that blocks the unpleasant taste, either by fluidized bed coating, or by agglomeration with... A solvent according to other aspects of this invention. Crystalline lamotrigine, whose average particle size ranges from 5 µm to 50 µm, can also be coated with an odor-blocking layer by agglomeration in a solvent, which is the method described in this text.

The method of producing beads containing layers of the drug in one embodiment of the present invention includes dissolving or suspending lamotrigine in a solution of a polymeric binder, then layering them into inert particles (with a mesh width of 50 to 100 mesh, or a diameter of 150 to 300 µm), such as sugar spheres or cellulose spheres (CelphereCP-203) using a fluidized bed coating device equipped with a Wurster primer for basic spraying. These beads containing lamotrigine can then be coated with a layer that blocks the unpleasant taste, using the fluidized bed coating or agglomeration methods described previously.

In another embodiment, the method for preparing the compositions of the present invention includes a step to mask the unacceptable taste. This process can be carried out in different ways, including agglomeration in a solvent, and in this method a water-soluble polymeric material such as ethylcellulose is used. The water-dissolved polymer (ethylcellulose), the phase catalyst (polyethylene), and lamotrigine are loaded into an agglomeration tank containing cyclohexane. The mixture is then heated inside the tank to a temperature of approximately 80°C to dissolve the ethylcellulose, the mixture is then cooled slowly under controlled conditions, and the phase-induced lamotrigine particles are microencapsulated using the ethylcellulose. Microencapsulation or agglomeration refers to a process in which a membrane is applied by separating the phases, to impart taste-blocking or slow-release properties. When the suspension reaches normal ambient temperature, the lamotrigine particles preserved in microcapsules are filtered, then these particles are washed with a new amount of cyclohexane, and then dried in order to reduce the solvent residue within acceptable limits (i.e. in an amount less than 4,000 ppm, or less than Another embodiment of 1,000 ppm). The weight of the coating material in microencapsulated lamotrigine particles can range from about 5% to about 30%, and these limits include percentages of about 10%, 15%, 20%, 25%, and all other values within the stated range. There are examples of the agglomeration process, and this was described in US Patents No. 5,252,337, 5,639,475, 6,139,865, and 6,495,160, which are the patents that were used here as technical references for this invention.

Alternatively, the clumping solution may include a mixture of a water-insoluble polymeric substance (such as ethylcellulose) and another pore-forming substance that is water-insoluble but soluble in stomach fluids (such as calcium carbonate). The ratio between the water-insoluble polymeric material and the pore-forming material ranges from about 50/50 to 95/5, and these limits include ratios of about 55/45, about 60/40, about 65/35, and about 70 /30, about 75/25, about 80/20, about 85/15, about 90/10, with all other values within the range mentioned. The shell weight of lamotrigine particles contained in microcapsules ranges from about 5% to about 30%, and these limits include percentages of about 10%, 15%, 20%, and 25%, with all other percentages falling within the stated range. In another embodiment, the agglomeration step comprises suspending the drug particles in a solution containing water-soluble ethylcellulose at a temperature of 80°C in an agglomeration tank. During the cooling cycle, the material forming the micron-sized particles is introduced into the tank at a temperature of approximately 58°C, with the suspension continuously stirred to homogenize the distribution of the material forming the pores in the microcapsule membrane within the forming/hardening phase. There are examples of the agglomeration process, and this was disclosed in US Patent Application No. 11/213266, which is used here as a technical reference for this invention for all its purposes.

In another embodiment, the compositions of the present invention may be in the form of tablets that disintegrate in the mouth and are prepared by mixing fine granules containing lamotrigine or fine particles of lamotrigine coated with taste-blocking coatings, with one or more flavoring materials, sweeteners, or Rapidly dispersing microgranules, or microcrystalline cellulose, or with an additional disintegrant material. This mixture is then compressed into tablets that disintegrate in the mouth upon contact with saliva inside. Oral cavity. These tablets have an acceptable taste (good creamy taste), and the dose is released quickly and completely in the stomach.

In still another embodiment, the composition of the present invention is a tablet that disintegrates in the mouth, and this tablet is formed by compressing a composition containing lamotrigine particles, rapidly dispersing granules, and optionally flavoring materials and other sweetening materials, with pharmaceutically acceptable justifications. This process is carried out in a pressing device equipped with an external lubrication system, and thus grease-free formulations of therapeutic tablets can be obtained.

The oral disintegrating tablets produced by this method are sufficiently hard, with a low degree of fragility, to make them suitable for packaging in HDPE bottles and to withstand storage, transportation and commercial distribution.

In the medicinal composition according to the present invention (ODT formulations containing lamotrigine microbeads or microparticles coated with taste-blocking layers), there is an acceptable degree of taste-blocking in the mouth when the composition is placed in it until it is swallowed (which means that there is a percentage of 10 % or more of the lamotrigine dose, and these are released in about 3 minutes when tested in a simulated oral saliva substance with a pH of about 7). ODT tablets disintegrate within approximately 30 seconds when evaluated using the disintegration test USP <701>. Typically, disintegration occurs when ODT tablets come into contact with saliva in the oral cavity after approximately 60 seconds, resulting in a loose, easy-to-swallow emulsion containing fine particles coated with a taste-blocking substance.

These fine particles are completely released when they enter the stomach (i.e. a release rate of no less than 60%, or specifically a release rate of no less than 70% of the dose after approximately 30 minutes when tested in a liquid simulating gastric fluid or in HCl 0.1 p).

In another embodiment, the present invention provides a method for manufacturing tablets that disintegrate in the mouth. This method includes the following steps:

A) Preparing fine particles containing lamotrigine, by forming crystalline granules of lamotrigine with an average particle size ranging from about 5 micrometers to 50 micrometers, with one or more diluents/fillers such as lactose, mannitol, and microcrystalline cellulose. , and mixtures of these materials, and with a polymeric binder, and a granulation device operating with high shear force is used, or a fluidized bed packaging device;

b) Formation of granules from one or more sugar alcohols and/or saccharides, such that the average particle diameter in each of these substances does not exceed about 30 micrometers, with a disintegrant substance such as crospovidone, and water or a mixture of water and alcohol is used in a device. Traditionally, to form granules, then a process is carried out to dry the granulation products in a fluidized bed device or in a conventional oven to produce fine, rapidly dispersed granules with an average particle size of no more than about 400 micrometers, as described in the filed US Patent Application No. 10/827106. in 19 April 2004;

c) Mixing the lamotrigine microbeads obtained in step (a) with one or more flavoring agents, one or more sweeteners, one or more microcrystalline cellulose, and an additional disintegrant, along with rapidly dispersing microbeads. microgranules resulting in step (b);

d) Compress the resulting mixture in step (c) and form it into tablets using a traditional rotary compressor equipped with an external lubrication system for the molds.

In another embodiment, the present invention provides a method for manufacturing tablets that disintegrate in the mouth, which method includes the following:

a) Preparing a particle of a pulp containing the drug (lamotrigine crystals, beads with layers of the drug, or microbeads containing lamotrigine), by forming a pellet of the drug, optionally with one or more diluents/fillers such as lactose, And mannitol, and microcrystalline cellulose, and mixtures of these materials, and with a polymeric binder, and a granulation device that operates at a high shear speed is used, or a packaging device equipped with a fluidized bed, or layers of the drug are made on an inert particle (sugar globules). Or a cellulose sphere (sugar sphere or cellulose sphere, such as Celphere CP-203 with a perforation capacity ranging from 60 to 100 mesh) using a solution/suspension containing a polymeric binder or medicine. A fluidized bed packaging device is used, and optionally a non-stick coating is placed here. port (e.g. Opadry Clear covers);

b) Applying taste-blocking layers to the pulp particles through microencapsulation, using a process of agglomeration in a solvent, or a process of coating in a fluidized layer using a water-insoluble polymeric material such as ethylcellulose, or with a mixture of water and a non-water-insoluble polymer. Water-soluble, a pore-forming substance that is soluble in water or in stomach fluids, such as: ethylcellulose, sodium chloride, or calcium carbonate, in a ratio of 50/50 to 95/5, to produce fine particles of acceptable taste with a desirable particle size distribution (average particle size of not more than about 400 µm or not more than about 300 µm);

c) Forming granules from one or more sugar alcohols and/or saccharides, such that the average particle diameter in each of these substances does not exceed about 30 micrometers, with a disintegrant substance such as crospovidone, and water or a mixture of water and alcohol is used in a device. Conventional granule formation, and then a process of drying the granulation products in a fluidized bed apparatus or in a conventional oven to produce rapidly dispersing fine granules with an average particle size not exceeding about 400 micrometers;

d) Mixing the lamotrigine microbeads obtained in step (a) with one or more flavoring agents, one or more sweeteners, one or more microcrystalline cellulose, and an additional disintegrant, in addition to the rapidly dispersing microbeads. microgranules resulting in step (b);

e) Compressing the resulting mixture in step (c) and forming it into tablets using a traditional rotary compressor equipped with an external lubrication system for the molds.

Disintegration period and dissolution test (laboratory):

Disintegration times were measured using disintegration test USP <701> procedures. The taste-blocking property of fine particles, and the extent of disintegration of tablets in the mouth, can be evaluated by determining the percentage of drug release when testing its dissolution by USP-2 (rotation speed of 75 rpm) in 900 ml of a liquid that simulates saliva, and at a pH ( pH) of 6.8 - 7 (a release rate of no more than about 10% of the dose over a period of about 3 minutes is acceptable). In addition, the rapid release property in the stomach can be evaluated for fine particles coated with a taste-blocking layer, and also for tablets that disintegrate in the mouth, by determining the percentage of drug release when tested with a USP-2 device (rotation speed of 75 rpm) at 900 ml of HCl (0.01 p) at a temperature of 37°C (0.5°C) (a release rate of at least about 70% of the dose over a period of about 30 minutes is acceptable). The strength of the tablets and the percentage of drug dissolved were determined at different time points, using an HPLC chromatograph equipped with a stainless column (150 4.6 mm) packed with Phenomenex Luna C18 (3 μM), or using a suitable alternative method.

The following are the characteristics of compositions of the present invention (ODT compositions) containing lamotrigine microbeads:

1 - An acceptable degree of hardness and a low degree of breakage, so that the composition can be filled in bottles, and so that it can withstand packaging, storage, transportation and commercial distribution;

2 - The composition disintegrates upon contact with saliva in the oral cavity after approximately 60 seconds, forming a soft, easy-to-swallow emulsion with an acceptable taste, which also meets the requirements for disintegration after 30 seconds according to the disintegration test USP <701>;

3 - The dose is released quickly and completely from the lamotrigine microbeads after entering the stomach, and this is supported by meeting the dissolution specifications at a rate not exceeding about 10% of the dose in about 3 minutes in a buffer solution containing a saliva-mimicking liquid with a pH of 6.8. At least about 75% of the dose in about 30 minutes in 900 mL of buffer solution containing HCl (0.01 p), when testing the degree of dissolution using a USP-2 device (rotation at 75 rpm).

In another embodiment, the present invention presents the properties of an ODT tablet composition comprising a crystalline substance of lamotrigine coated with a taste-blocking layer by agglomeration in a solvent with ethylcellulose, as follows:

1 - An acceptable degree of hardness and a low degree of breakage, so that the composition can be filled in bottles, and so that it can withstand packaging, storage, transportation and commercial distribution;

2 - The composition disintegrates upon contact with saliva in the oral cavity after approximately 60 seconds, forming a soft, easy-to-swallow emulsion with an acceptable taste, which also meets the requirements for disintegration after 30 seconds according to the disintegration test USP <701>;

3 - The dose is released quickly and completely from the lamotrigine microbeads after entering the stomach, and this is supported by meeting the dissolution specifications at a rate not exceeding about 10% of the dose in about 3 minutes in a buffer solution containing a saliva-mimicking liquid with a pH of 6.8. At least about 75% of the dose in about 30 minutes in 900 mL of buffer solution containing HCl (0.01 p), when testing the degree of dissolution using a USP-2 device (rotation at 75 rpm).

The compositions of the present invention are used to treat cases of epilepsy and/or bipolar disorder, and they contain a therapeutically effective amount of lamotrigine. The compositions of the invention may contain an amount of lamotrigine ranging from about 1 mg to about 250 mg, and this range includes amounts of lamotrigine of 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg. The compositions of the present invention can be administered to the patient according to any appropriate dosage schedule determined by the specialist physician. For example, these formulations may be given in a single daily dose or in several daily doses, and this depends on the severity of the disease and the physical condition of the patient.

The following non-exclusive examples illustrate compositions of this invention comprising lamotrigine microgranules, taste-blocking coated microgranules, or tablets that disintegrate in the mouth.

These formulations have been prepared using the methods described in this application, and they are characterized by acceptable sensory characteristics when placed in the mouth, and the active ingredient is released quickly and completely when it reaches the stomach.

Example 1:

Lamotrigine fine granules (A):

Mannitol 25 (69.4 wt%) and crospovidone XL-10 (3.7 wt%) were co-milled 95/5 by passing them through a Comil grinder equipped with 0.225-inch spacers and operating at approximately 1,400 to 1,500 rpm. . Mannitol, crospovidone and crystalline lamotrigine from Teva (26.9% by weight) were mixed for 3-5 minutes in order to homogenize and mix the ingredients. A Glatt-GPCG-3 fluidized bed machine, equipped with an overhead granulation chamber and a granulation vessel, was also charged using a pre-prepared mixture containing mannitol, crospovidone, and lamotrigine (batch size = 1,500 g), and the mixture was then granulated by spraying with purified water. From a 1.2 mm nozzle, under a spray pressure of about 1.25 bar, at a spray rate of 30 to 50 ml/min, and at a temperature at the exit hole of more than 70°C and less than 33°C in the product. The wet mass was then dried until the moisture level reached less than 1%.

Lamotrigine fine granules (B):

Mannitol 25 (59.8 wt%) and crospovidone XL-10 (3.1 wt%) were co-grinded to a 95/5 ratio, passing the mixture through a Comil grinder equipped with 0.5715 cm (0.225 in) spacing and operating at a speed of approx. 1400 to 1500 rpm. Mannitol, crospovidone, and calcium carbonate (10% by weight) were mixed with crystalline lamotrigine from Glaxo SmithKline (26.9% by weight), for a period ranging from about 3 to about 5 minutes in order to homogenize and mix the components with each other, and then the The granulation process is done by spraying an aqueous solution containing hydroxypropylcellulose (Klucel LF at 0.2 wt%) using the Glatt apparatus described above.

Lamotrigine fine granules (C):

Lactose monohydrate (35% by weight) was mixed with Glaxo SmithKline crystalline lamotrigine (26.9% by weight) for 3-5 minutes to homogenize and mix the ingredients together. Hydroxypropylcellulose (Klucel LF, 5 wt%) was slowly added to water in a stainless steel container, dissolving and stirring to obtain a vortex. The mixture of lactose and lamotrigine was then granulated in a Glatt-3 device by spraying with an aqueous solution containing a binder at a rate of 25-50 ml/min as described above.

Lamotrigine fine granules (D):

Mannitol 25 (58.5 wt%) and crospovidone XL-10 (3.1 wt%) were co-grinded 95/5 by passing the mixture through a Comil grinder. Mannitol, crospovidone, microcrystalline cellulose (Avicel PH-101, 10% by weight) and crystalline lamotrigine from Glaxo SmithKline (26.9% by weight) were mixed for about 3-5 minutes to homogenize and mix the ingredients together. Hydroxypropylcellulose (Klucel LF 1.5 wt%) was then slowly added to the water inside a stainless steel bowl, dissolved and vortexed vigorously. The above mixture was also granulated using a Glatt-3 device by spraying a binder at a rate of 25-50 ml/min as described above. The granules were also prepared by reducing the binder content to 0.2 wt%.

Tablet formation:

A Hata tablet compactor, equipped with a vacuum conversion system, dust disposal, metal detector and Matsui Ex-lube system, has been calibrated according to standard operating procedures. Magnesium stearate was used to aid in the curing process, that is, to lubricate the surfaces of the mold externally, so this substance was used in small quantities on the tablets. The weight range was 5% relative to the target weight of the disc.

The Ex-lube system has been started to ensure that the lubricant is properly sprayed during operation of the tablet press. Below are the data for tablet variables, such as filler depth (mm), pre-compression position (mm or kN), and main compression position (mm or kN), which are adjusted on the press in order to produce 25 mg tablets that meet standard specifications:

Disk-specific variables

Target value

Term

Weight of one tablet (mg)

100

95 105 ( 5٪)

Thickness (mm)

2.40

2.00 2.80

Hardness (Newton)

28

8 - 48

Breakability (%)

0.6

1.0

Weight/10 tablets (g)

1.00

0.96 1.04 ( 4٪)

After the calibration process was completed successfully, the compressor was set to “automatic operation” mode until the tableting process was completed. During operation, samples of the discs were periodically checked to ensure compliance with the above specifications.

Example 2:

Microcapsules containing lamotrigine with a 10% shell substance:

A 5-gallon agglomeration tank equipped with a high-cutting speed (4 6-inch) stirrer blade and a 3-blade attachment was shipped using 10 kg of cyclohexane, 1,350 grams of crystalline lamotrigine, and 150 grams of ethylcellulose. (Ethocel standard 100), and 100 grams of polyethylene (Epoline C-10). The tank was then heated to a temperature of about 80°C, stirring at a speed of about 200 rpm to dissolve the ethylcellulose. The tank was also subjected to a controlled cooling process, in order to induce the separation of the phases from each other. After cooling to normal ambient temperature, the microcapsules were filtered, then those capsules were rinsed with a new amount of cyclohexane, and then the filtrate was transferred to a fume hood to allow the remaining cyclohexane to evaporate, and then it was possible to obtain microcapsules containing an amount of cyclohexane. Taste-blocking coating of 10% by weight.

Microcapsules containing lamotrigine with an encapsulation content of 15% or 20%:

Microcapsules containing lamotrigine were prepared with 15% or 20% ethylcellulose shells, in a manner similar to that described above.

Microcapsules containing lamotrigine with 10% encapsulating substance (ethylcellulose + pore-forming substance):

These capsules were also prepared by charging a 5-gallon tank with 1,080 grams of lamotrigine, 270 grams of micronized calcium carbonate, 150 grams of polyethylene, and 150 grams of Epoline. C-10 of 100 grams, using a method similar to that described above.

Rapidly dispersing microgranules:

Rapidly dispersing microgranules may contain a sugar alcohol such as mannitol, and/or a saccharide such as lactose, with a superdisintegrant such as crospovidone XL-10.

Typically, the ratio between sugar alcohol and/or saccharide and the disintegrant in rapidly dispersing microgranules ranges from about 99/1 to about 90/10 (sugar alcohol and/or saccharide: disintegrant).

For example, D-mannitol, a sugar alcohol with an average particle size of about 15 micrometers, may be used here with crospovidone XL-10, an ultradisintegrant, in a ratio of about 95/5 in a granulator It works at a high cutting speed and uses pure water as a fluid to form the granules. The drying process is then carried out by spreading the granulated mixture on trays inside a heated convection oven.

Lamotrigine ODT Tablets, 25 mg, 200 mg:

Sucralose was mixed with cherry or mint flavor, crospovidone XL-10, and microcrystalline cellulose, then a second mixing was performed with rapidly dispersing microbeads and with lamotrigine microcapsules containing a 10%, 15%, 20%, or 20% encapsulation layer. 10% (ethylcellulose + pore-forming material), then the mixture was compressed under different pressure forces to obtain oral disintegrating tablets weighing 200 mg (ODT) and 14 mm or 15 mm in diameter with a weight ranging from 800 mg to 1000 mg, in order to improve the following variables. of the formation process Discs:

- Weight (target weight = 800 mg),

- hardness,

- Breakability (target value less than 0.6%),

- Disintegration period (target period less than 30 seconds),

- dissolution,

- taste,

- mouthfeel,

- Formation of stones in the mouth aftertaste (grittiness),

- Content of flavor or sweetener substances.

Example 3:

Lamotrigine fine granules:

Mannitol 25 (58.5 wt%) and crospovidone XL-10 (3.1 wt%) were co-grinded 95/5 by passing the mixture through a Comil grinder. Mannitol, crospovidone, microcrystalline cellulose (Avicel PH-101, 10% by weight) and crystalline lamotrigine from Glaxo SmithKline (26.9% by weight) were mixed for about 3-5 minutes to homogenize and mix the ingredients together. Hydroxypropylcellulose (Klucel LF 1.5 wt%) was then slowly added to the water inside a stainless steel bowl, dissolved and vortexed vigorously. The above mixture was also granulated using a Glatt-3 device by spraying a binder at a rate of 25-50 ml/min as described above. The granules were also prepared by reducing the binder content to 0.2 wt%.

Archetypes 1 3 for sensory testing:

Table 1 below indicates details of the original sample formulations 1 3. A starting mixture containing sucralose, cherry or mint flavors, and crospovidone XL-10 was first prepared using a 0.25 cubic foot V-mixer. The lamotrigine microbeads were then incorporated into the above mixture, and the resulting formulation was compressed and made into orally disintegrating (100 mg) tablets, 11 mm diameter tablets with a weight of 400 mg (Original Form 1; 1220-NHV-056), or to Tablets (200 mg) disintegrate in the mouth, are 14 mm diameter tablets weighing 800 mg (Original Form 2:1220-NHV-088, Original Form 3:1220-NHV-072).

Table 1: Original form formulations containing lamotrigine

the components (%)

Original form - 1

(100 mg cherry)

Original form - 2

(200 mg mint)

Original form - 3

(200 mg cherry)

lamotrigine granules

90.91

92.94

93.61

Crospovidone XL-10

7.09

5.16

4.39

Sucralose

0.50

0.4

0.50

Kriz 376120

1.50

-

1.50

Mint 376120

-

1.50

-

the total

100.0

100.0

100.0

Lamotrigine Microcapsules containing 15% encapsulation material:

A 5-gallon tank equipped with a high shear speed (6 4-inch) agitator blade and a 3-blade wedge was charged with 10 kg of cyclohexane, 850 grams of crystalline lamotrigine, and 150 grams of ethylcellulose (ethocyl standard 100). , and 100 grams of polyethylene (Epoline C-10). The tank was then heated to a temperature of about 80°C with stirring at a speed of about 200 rpm to dissolve the ethylcellulose. The tank was then subjected to a controlled cooling process to induce separation of the phases from each other. After cooling to normal ambient temperature, the microcapsules were filtered, rinsed with cyclohexane, and the leachate was transferred to a fume hood, allowing the remaining cyclohexane to evaporate and thus obtaining Microcaps with 15 wt% coating material. Additional microcapsules were prepared using similar procedures.

Archetypes 4 and 5 for sensory testing:

A starting mixture containing 0.4% sucralose, 1% Cres (364450), and 5% crospovidone XL-10 was first prepared by mixing these ingredients together in a 0.25 cubic foot V-mixer. Rapidly dispersing microcapsules (64.19 wt%) were then added to this mixture along with microcapsules containing lamotrigine (29.41 wt%), which are the resulting capsules in Example 2. The resulting formulation is compressed into 100 mg, 11 mm diameter, 400 mg tablets (original form 4:1220-NHV-104), or into 200 mg, 400 mg tablets. Its diameter is 14 mm and its weight is 800 mg (original form 5: 1220-NHV-120).

The solvation aspects of the original models 1 3 and 4 5 are shown in Figure 1 and Figure 2, respectively. Sensory evaluation of the original models of ODT tablets (original models 1 and 3 based on the granulation method and original models 4 and 5 based on the Microcap method) was used here, according to a blinded randomized design in 9 healthy male volunteers aged 18 to 55 years. For the purpose of evaluating the in vivo disintegration time (the actual time during which the tablet disintegrates inside the mouth, estimated in seconds); With post-dose evaluation of oral sensation and taste (bitterness scale: 1 = very bitter, 5 = more buffering agents needed, 10 = good taste); And also evaluate the flavoring or sweetening substance (balance scale: 1 = there is a need to increase the substance, 8 = an optimal level of the substance, 10 = the substance is present in excess and the amount needs to be reduced). These results are represented in Figures 3 and 5, and also summarized as follows:

Sensory test results:

- Statistical analysis demonstrated that there are fundamental differences between Microcap formulas and granular formulas, and that Microcap formulas were superior in terms of dissolution period and flavor and taste characteristics after taking a dose compared to granular formulas.

Microcap formulas were characterized by a clear improvement in disintegration time compared to granular formulas.

Microcaps formulas had significantly higher post-dose scores for taste and aftertaste compared to granule formulas.

- There were no significant differences between Microcaps and granular formulas in terms of oral sensation, and the values were acceptable in both cases.

- There were no significant differences between the Microcaps formulas when comparing two different strength values, and these values were acceptable in both cases.

Example 4:

Lamotrigine fine granules:

The Glatt GPCG-120 device was shipped with 48.8 kg of lamotrigine, 103.7 kg of mannitol USP (mannitol 25 conjugate), and 5.5 kg of crospovidone NF XL-10 (conjugated). The powder mixture was granulated by spraying it with an aqueous solution of hydroxypropylcellulose (Klucel LF; 1.25 wt%) under a pressure of 4 bar and at a spray rate ranging from 900 to 1,200 g/min. The mixture was then dried until the moisture content reached a level of less than 1. %.

Lamotrigine Microcaps:

A mixture containing lamotrigine fine granules prepared according to the method above in Example 2 (78.3 kg), Ethosil with a viscosity of 100 cP (13.8 kg), and Epolene (9.2 kg) was transferred to a hopper in a 500-gallon agglomeration tank containing 312.5 gallons Cyclohexane, stirring at 40 rpm. The encapsulation process was carried out in an automatic mode, and the stirring device was set at static at a speed ranging from 66 to 70 revolutions per minute, while the temperature in the tank was set at 81 C (78 C - 85 C). When the mixture reaches normal ambient temperature after being cooled to a controlled degree, the composition is filtered under vacuum using a new amount of cyclohexane, then the resulting encapsulated material is dried in a fluidized bed dryer at a temperature ranging from 25°C to 99°C and with an air flow of 2,500 cubic feet per minute, for a period ranging from 3 to 5 hours. The dried Microcaps were filtered using a Kason strainer, then placed in a clean 30-gallon fiber drum lined with two polyethylene bags (4 ml). These same procedures were used in a system containing a 200-gallon agglomeration tank and a fluidized bed dryer.

Lamotrigine ODT Tablets (25 mg, 200 mg):

Sucralose 0.40 wt% and crospovidone (5 wt%) were initially mixed by passing the mixture through a Comil blender to homogenize and mix the ingredients together. Likewise, cherry flavor (1% by weight) was initially mixed with a small amount of rapidly dispersing microgranules (64.19% by weight), and then a process of combining the two mixtures was carried out to the point of homogeneity. Microparticles coated with taste-blocking layers were also prepared according to the method described above (29.41% by weight), with the remaining part of the rapidly dispersing microgranules mixed with the above mixture containing crospovidone, the flavoring agent, and the sweetener, in order to manufacture Batch of product weighing from 501 to 626 kg.

Example 5:

Pilot study to test pharmacokinetics (PK) in humans:

A randomized, four-way pharmacokinetic (PK) pilot study was conducted in 16 healthy adult subjects, to compare lamotrigine formulations of the present invention with conventional lamotrigine formulations in which the active ingredient is immediate-release (IR), such as Lamictal. The Lamictal formulation is known as an immediate release (IR) formulation and is almost completely absorbed after being administered orally to the patient (absolute bioavailability = 98%). Its concentrations in blood serum reach their maximum within a period ranging from 1.3 to 4.7 hours. The half-life after a single dose of this formulation is approximately 33 hours. This therapeutic formula disappears from the mouth within an approximately double period, and its t1/2 value decreases to about 15 hours in the case of an enzyme-inducing and anti-epileptic drug such as carbamazepine.

Four dosage forms were compared:

- A: 25 mg of lamotrigine tablets, which have an immediate release (IR) active ingredient.

- B: 25 mg lamotrigine tablets (ODT),

- C: 200 mg lamotrigine immediate-release (IR) tablets,

- D: 200 mg lamotrigine tablets (ODT).

The ODT doses were prepared according to the methods of the present invention (Example 4 using lamotrigine Microcaps produced in the 200-gallon system). Blood samples were also drawn from the study participants after 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 24 hours, with Determination of drug levels in plasma through bioanalytical methods. Plasma concentrations of the drug are shown in Figures 6 to 8, while Tables 2 and 3 below show pharmacokinetic (PK) variables. Patient-administered ODT formulations have been evaluated as being equivalent to corresponding lamotrigine immediate-release (IR) tablets (Lamictal).

Table 2: Pharmacokinetic (PK) variables in lamotrigine tablets (ODT) versus reference tablets:

Pharmacokinetic (PK) variables

Tag (hour)

Tmax(hour)

Cmax (ng/ml)

AUC (ng h/ml)

25 mg ODT

25 mg IR

25 mg ODT

25 mg IR

25 mg ODT

25 mg IR

25 mg ODT

25 mg IR

SMA

-

-

-

-

0.368

0.382

5.98

5.89

Mediator

0.00

000

2.00

1.60

0.383

0.365

6.07

5.77

Geometric mean

-

-

-

-

0.364

0.368

5.92

5.76

minimum

0.00

0.00

0.50

0.25

0.276

0.228

4.87

3.89

maximum

0.50

0.00

4.00

3.00

0.482

0.689

8.17

8.08

Correlation coefficient (%)

-

-

-

-

16.1

30.1

14.6

21.6

200 mg ODT

200 mg IR

200 mg ODT

200 mg IR

200 mg ODT

200 mg IR

200 mg ODT

200 mg

IR

SMA

-

-

-

-

2.89

3.25

49.0

51.8

Mediator

0.00

0.00

2.25

1.00

2.75

3.03

47.5

49.6

Geometric mean

-

-

-

-

2.85

3.18

48.4

50.8

minimum

0.00

0.00

0.75

0.5

2.21

2.35

36.0

40.4

maximum

0.25

0.00

8.00

4.0

3.95

5.08

63.6

81.2

Correlation coefficient (%)

-

-

-

-

17.9

22.3

16.1

23.1

Table 3: Experimental pharmacokinetic data for lamotrigine-containing ODT tablets versus IR tablets

Pharmacokinetic (PK) variables

Comparison

The value of the geometric mean of least squares in the test subject

The value of the geometric mean of least squares in the reference material

Ratio between test substance and reference substance (CI = 90%)

AUC0-24hrs

(ng*h/ml)

25 mg ODT

25 mg IR

5.922

5.760

1.028

(0.934-1.131)

200 mg ODT

200 mg IR

48.409

47.522

1.019

(0.922-1.125)

Cmax

(ng/ml)

25 mg ODT

25 mg IR

0.364

0.368

0.988

(0.880-1.110)

200 mg ODT

200 mg IR

2.850

2.994

0.952

(0.844-1.073)

Lamotrigine beads (IR):

Hydroxypropylcellulose (Klucel LF; 20 g) was slowly added to a 95/5 mixture of acetone and water for dissolution, with constant stirring. Lamotrigine (180 g) was then added to the binder solution until dissolved. The Glatt GPCG, equipped with a Wurster bottom spray plug, is shipped with 900 grams (60-80 mesh) of sugar pellets. The solution for layering the drug was sprayed under a spray pressure of 1.5 bar and at a spray rate ranging from 10 to 30 mg/min, while maintaining the product temperature at a level ranging approximately from 30 C to 33 C. These beads were provided with Opadry Clear (2%) sealing coatings, to produce IR beads with a drug loading strength of approximately 20% by weight.

Lamotrigine beads containing taste-blocking coatings:

IR beads were coated with a film using a spray solution containing micron-sized ethylcellulose with calcium carbonate, soluble in stomach fluids, in a 70/30 ratio, yielding a bead weight increase of approximately 10% based on the total weight of the coated bead.

Lamotrigine ODT Tablets (25 mg, 50 mg):

Sucralose (0.5%), cherry flavor (1%), FD&C Blue-2 (0.2%), and crospovidone (5%) were initially mixed in a 0.25 cubic foot V-mixer, and then a second mixing was performed with layer-coated lamotrigine beads. Flavor-blocking prepared according to the above method (43%), and with rapidly dispersing microgranules (50.3%) prepared by the method mentioned in Example 2. The mixture was then compressed into ODT tablets (25 mg, 50 mg) weighing approximately 400 mg. and 800 mg, respectively, using the methods described in this text.

We must realize that although this invention is described with reference to specific specific embodiments, the above-mentioned description and the examples that follow are here for clarification and are not intended to limit or restrict the scope of the invention. There are modifications that fall within the framework of this invention, and those experienced in this field are aware of these.

All documents have been used here as technical references for the invention, provided that the reference to any of these documents should not be interpreted as evidence that the document represents prior technology relative to the current invention.