KR20180035723A - Controlled release formulation for administration of Lacosamide - Google Patents

Abstract

The present invention relates to a sustained release formulation of lacosamide, and more particularly, to a sustained release formulation of lacosamide which exhibits an effect of maintaining a constant drug release rate in various pH ranges of a gastrointestinal tract by comprising a sustained matrix of a mucoadhesive polymer and a water-soluble diluent. The sustained release formulation of lacosamide according to the present invention can effectively control the release of active substances through adjusting the ratio and particle size of the mucoadhesive polymer so that a concentration of the drug in blood can be easily controlled, and can be usefully used as an oral effect-sustaining drug delivery system since the mucoadhesive polymer is attached to the gastrointestinal mucosa.

Description

≪ Desc / Clms Page number 2 > Controlled release formulation for administration of Lacosamide &

The present invention relates to a sustained-release preparation of lacosamide, and more particularly to a sustained release formulation of lacosamide, which comprises a sustained-release matrix of a mucoadhesive polymer and a water-soluble diluent, and which exhibits an effect of maintaining a constant drug release rate in various pH ranges of the gastrointestinal tract It is about sexual preparation.

Racosamid is a white or whitish crystalline powder. Its chemical name is (2R) -2- (acetylamino) -3-methoxy-N- (phenylmethyl) propanamide and has a molecular weight of 250.29. Racosamid has a solubility of at least 20 mg / ml in a physiologically relevant pH range, especially in a pH 1.2 to pH 6.8 solution and is 100% in vivo. Within 15 minutes in an eluate of pH 1.2 to pH 6.8, 85% Is a Class I drug according to the BCS (Biopharmaceutics Classification System). Racosamid is used as an adjunct to partial seizure therapy with or without secondary systemic seizures in epileptic patients over 16 years of age.

 Racosamid is rapidly and completely absorbed after oral administration and the effect of liver transfusion is negligible. In vivo absorption and absorption rate of racosamide by food are not affected. Racosamid binds to less than 15% of plasma proteins and has a half-life in vivo of approximately 13 hours. The plasma concentration of racosamide is known to increase linearly and proportionally up to a dose of 800 mg and exhibit less variation between subjects and subjects. It also exhibits a maximum blood concentration between 1 and 4 hours after oral administration.

Racosamid has two new anticonvulsive mechanisms, the slow activation of the sodium channel and the binding of the collap-sin-response mediator protein 2 (CRMP-2) to the sodium channel It does not act on fast inactivation but acts on slow inactivation to normalize the threshold of activation, thereby reducing pathophysiological overaction. CRMP-2 is known to be involved in neurodevelopment and can contribute to neural differentiation, polarization, and axonal proliferation induced by neurotrophic factors, so that sprouting of neuronal connections involving pathophysiology of epilepsy and ideal It can affect re-heat. Major clinical side effects include dizziness, headache, nausea and diplopia. Other side effects except headache have been reported to be related to dose.

In general, antiepileptic drugs are not treatments that solve the cause of the disease, but they act to alleviate and suppress the symptoms of brain metastasis. Racosamide also has the same effect. Because of the nature of epilepsy, the daily routine time is suddenly symptomatic. It is directly related to the life of the patient. Therefore, the antiepithelium drug has a continuous effect during the daytime to continuously suppress the symptoms of the disease. It should be designed so that the medicinal compliance can be improved and the action of the medicinal effect can be stably displayed. However, unlike other antiepithelial drugs, lacosamid should be taken 2 times a day at a certain interval, which is not preferable to other drugs in terms of ease of taking the patient. If the dose is exceeded, Because it is short in time, it is difficult to show the desired drug effect, and it is difficult to suppress sudden seizure symptoms properly.

A sustained-release preparation for oral administration is proposed as a drug-taking formulation which is easy to take, easy to take, easy to take, and easy to manufacture, and which can be easily and simply taken by a patient. .

The oral sustained-release preparation is a formulation designed to maintain the optimal blood concentration in vivo by controlling the release of pharmacologically active substances to a predetermined degree. The purpose of such oral sustained release preparations is to make the blood concentration of the pharmacologically active substance effective By continuously maintaining the concentration within the blood concentration range, it is possible to reduce the administration frequency of the pharmacologically active substance, increase the compliance of the patient with the medication, and prevent side effects such as toxicity of the pharmacologically active substance.

Various attempts have been made to produce an oral sustained release preparation in which the release pattern of pharmacologically active substances is controlled. However, there are five types of useful systems.

A drug release control agent containing a microsphere / microparticle (Elan's SODAS system), a drug release control agent containing a liquid, a hydrogel or a mucoadhesive drug release control agent , A pulsatile drug delivery system, and finally the most common polymer matrix / coating drug release control formulation (Skyepharma's Geomatrix).

However, in the case of Alza's OROS system, due to the nature of the technology, toxic organic solvents must be used indispensably and special equipment is required, which is disadvantageous in that the manufacturing cost is expensive. In the case of Elan's SODAS system, It is very difficult to control the drug release while securing a constant absorption pattern of the drug. Therefore, it requires complicated manufacturing and requires expensive manufacturing cost because it requires more than 100 multipaticular (multi-particle) The pulsatile drug delivery system, which is actively studied for application, has a disadvantage in that the size of the device is too large and the number of times of administration is limited, and a liquid drug release control technique using mainly a microemulsion type is used to manufacture an emulsion A toxic organic solvent must be contained, and a liquid agent Due to the nature of the mold, the patient is likely to break during carriage and there may be a disadvantage that the liquid phase will leak from the formulation.

In the case of mucoadhesive drug controlled release systems, various mucoadhesive materials are used to maximize the retention of the drug in a specific site. However, in order to improve adhesion with the mucosa, it is necessary to use a polymer having polarity. However, if it is possible to show a pH-independent dissolution profile by a proper combination with the most commonly used polymer matrix preparation, it is possible to obtain a uniform rate of dissolution on the matrix If the adherence is maintained in the mucosa of the gastrointestinal tract while maintaining the release, it can be implemented as a technique capable of sustaining pharmacological action by more stable and continuous drug release.

In general, the mechanism of the mucosal adhesion drug delivery system is that the polymer is bound to mucin, which is the main component of the mucosa, while the polymer is in contact with the mucous membrane, and a weak chemical bond such as hydrogen bonding is temporarily formed between the chains. Therefore, in order for the polymer to have an effective mucosal adhesion to the mucosa, it has a hydrophilic functional group such as a hydroxyl group or a carboxyl group or an amine group so that a hydrogen bond can be formed in the molecular molecular structure.

In the gastrointestinal tract where the mucosa is distributed over the widest part of the body, it is a relatively non-keratinized structure due to relatively frequent movement as a main route for dietary absorption and excretion, and absorption of the drug is comparatively low It is easy. However, since the mucoadhesive polymer has a hydrophilic functional group such as a hydroxyl group or a carboxyl group or an amine group, it exhibits a pH-dependent solubility. Since the gastrointestinal tract, which is a digestive organs, exhibits a wide pH range within a pH range of 7, It is very difficult to show the continuous absorption of pharmacologically active substances by a certain release throughout the gastrointestinal tract through the oral sustained-release preparation used.

Accordingly, the present inventors have made efforts to develop stable and sustained release formulations throughout the gastrointestinal tract by using a mucoadhesive adhesive polymer for the purpose of enhancing the ease of taking a patient and maintaining the drug efficacy of racosamide constantly. As a result, it was found that a formulation containing a mucosa-adherent water-soluble polymer including racosamide can maintain a constant drug release rate even in various pH ranges of the gastrointestinal tract, thereby completing the present invention.

Accordingly, an object of the present invention is a sustained release preparation comprising racosamide or a pharmaceutically acceptable salt thereof, a water-soluble diluent and a mucoadhesive polymer, wherein the mucoadhesive polymer has a particle diameter (d10) corresponding to 10% And a particle diameter (d90) corresponding to 90% is 100 占 퐉 to 400 占 퐉.

Another object of the present invention is a sustained release preparation comprising racosamide or a pharmaceutically acceptable salt thereof, a water-soluble diluent and a mucoadhesive adhesive polymer, wherein the mucoadhesive adhesive polymer is present in an amount of 4 to 30 wt% And a sustained-release preparation containing the sustained-release preparation.

In order to accomplish the above object of the present invention, the present invention provides a sustained-release preparation comprising racosamide or a pharmaceutically acceptable salt thereof, a water-soluble diluent and a mucoadhesive adhesive polymer, wherein the mucoadhesive adhesive polymer corresponds to 10% (D10) of 1 to 5 占 퐉 and a particle diameter (d90) corresponding to 90% of 100 占 퐉 to 400 占 퐉.

Another object of the present invention is to provide a sustained-release preparation comprising racosamide or a pharmaceutically acceptable salt thereof, a water-soluble diluent and a mucoadhesive adhesive polymer, wherein the mucoadhesive polymer has a total weight of By weight based on the total weight of the composition.

Hereinafter, the present invention will be described in detail.

The present invention relates to a sustained release preparation comprising racosamide or a pharmaceutically acceptable salt thereof, a water-soluble diluent and a mucoadhesive adhesive polymer, wherein the mucoadhesive adhesive polymer is contained in an amount of 4 to 30% by weight based on the total weight of the preparation And a sustained-release preparation.

Expression "sustained release" throughout this specification means that the active principle, racosamide, is released by 15% to 70% at 2 hours after administration and by 70% or more at 8 hours.

In the present invention, the above-mentioned lacosimide is R-2-acetamido-N-benzyl-3-methoxyprypionamide having the structural formula (1): N-methyl-D-aspartate Is a functionalized amino acid identified as a promising anti-epileptic among the 24,000 molecules in the US National Institutes of Health's (NIH's) extensive exploration program. It is also an anticonvulsant that is being developed simultaneously as a treatment for epilepsy and a pain reliever.

In the present invention, it can be used in the form of racosamide itself or a pharmaceutically acceptable salt thereof. The term " pharmaceutically acceptable " as used herein means physiologically acceptable and does not normally cause an allergic reaction or a similar reaction when administered to humans, and includes a free base of lacosamide, various pharmaceutically acceptable acids May be in the form of an addition salt. Non-limiting examples thereof include forms of hydrochloride, succinate, fumarate, malate, glutarate, adipate, pimelate, maleate, malate, tartrate, acetate, nicotinate or addition salts thereof .

In the present invention, the content of racosamide can be defined as the unit dosage form of the preparation to be administered at once, for example, the content of racoside contained in one tablet. At this time, even when the formulation or the unit dosage form contains racosamide in the form of a pharmaceutically acceptable salt such as an acid addition salt, the content of racosamide is higher than that of the acid component added to lacosamide Can be defined as the content of lacosamide except for the weight of lacosamide. Preferably, in the present invention, the racosamide or a pharmaceutically acceptable salt thereof is contained in an amount of 40 to 70% by weight based on the total weight of the preparation. More preferably 40 to 65 wt%, 40 to 64 wt%, 40 to 63 wt%, 40 to 62 wt%, 40 to 61 wt%, 40 to 60 wt%, and 45 to 60 wt% have.

Racosamid has a half-life of about 13 hours, which is more than 85% released within 15 minutes under the condition of pH 1.2 to 6.8. Therefore, unlike other anti-epileptic drugs, There is. In contrast, the sustained-release preparation of the present invention can exhibit a constant drug release rate even under various pH ranges of the gastrointestinal tract by the combination of the mucoadhesive polymer and the water-soluble diluent, and the mucoadhesive polymer adheres to the gastrointestinal mucosa, It is easy to control the concentration.

That is, in one embodiment of the present invention, the present inventors confirmed that the desired sustained-release effect can be achieved through the combination of the mucoadhesive polymer and the water-soluble diluent, the ratio of the mucoadhesive polymer and the particle size.

In general, a mucoadhesive polymer has a hydrophilic group such as a hydroxyl group or a carboxyl group or an amine group so that a hydrogen bond can be formed in the molecular structure of the polymer in order to have an effective mucoadhesive property. Therefore, when a drug is formulated only with a mucoadhesive polymer, it exhibits a pH-dependent solubility, and thus it is difficult to achieve the purpose of constant drug release under a condition showing a wide pH range such as gastrointestinal tract.

In one embodiment of the present invention, the present inventors have solved the problems of the above-described mucoadhesive polymer by a combination with a water-soluble diluent. Since the pH-dependent mucoadhesive polymer does not swell sufficiently at a low pH, it does not swell sufficiently, and since the solvent quickly and quickly penetrates into the center of the tablet, the elution quickly occurs. Therefore, by adding a relatively water-soluble diluent, By controlling the water penetration into the core, the dissolution of the drug was delayed, minimizing the change in the dissolution rate of the formulation according to pH.

In the present invention, the water-soluble diluent is preferably contained in a proportion of 10 to 35% by weight based on the total weight of the tablets. More preferably 15 to 20 wt%, 15 to 25 wt%, 15 to 26 wt%, 15 to 27 wt%, 15 to 28 wt%, 15 to 29 wt%, 15 to 30 wt%, 16 to 20 wt% 16 to 25 percent by weight, 16 to 26 percent by weight, 16 to 27 percent by weight, 16 to 28 percent by weight, 16 to 29 percent by weight, 16 to 30 percent by weight, 17 to 20 percent by weight, 17 to 25 percent by weight, 17 to 26 wt%, 17 to 27 wt%, 17 to 28 wt%, 17 to 29 wt%, 17 to 30 wt%, 18 to 20 wt%, 18 to 25 wt%, 18 to 26 wt% 27 to 18 wt%, 18 to 28 wt%, 18 to 29 wt%, and 18 to 30 wt%.

When the content of the water-soluble diluent is less than 10% by weight, it is difficult to control the physical properties and solubility of the raczamide contained therein in a high content, so that it is difficult to secure uniformity of mixing and it may be difficult to obtain tablets of appropriate quality, If it exceeds 35% by weight, the size of tablets becomes unnecessarily large, which reduces the ease of taking in patients suffering from pediatric and / or swallowing difficulties, and ultimately decreases the compliance with the medicinal drug, which makes it impossible to exhibit desired drug efficacy.

Preferably, the aqueous diluent is selected from the group consisting of dextrin, lactose, sodium alginate, methylcellulose, saccharose, carboxymethylcellulose sodium, glucose, fructose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxyethylcellulose, calcium monohydrogen phosphate , Propylene glycol, sodium chloride, casein, dicalcium phosphate and sodium hydrogencarbonate, most preferably, but not exclusively.

In the present invention, the mucoadhesive polymer may be selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, polyvinylpyrrolidone / vinyl acetate copolymer, carboxymethylcellulose sodium, It is preferably selected from the group consisting of cellulose calcium, polycarboxy methylene, polymethacrylate, povidone, alginic acid, sodium alginate, xanthan gum, gum arabic, chitosan, starch, dextrin, propylene glycol and glycol derivatives, May be polycarboxy methylene, but are not limited thereto.

Such a mucoadhesive polymer may be mixed with the water-soluble diluent to overcome the disadvantages caused by the rapid release of the drug and the initial burst effect in the pH range in the gastrointestinal tract, which may be a problem in the conventional formulation, And ease of taking along with the extension.

In the sustained-release preparation of the present invention, the mucoadhesive polymer is contained in a proportion of 4 to 30% by weight, preferably 4 to 25% by weight, 4 to 26% by weight, 4 to 27% by weight, From 5 to 29% by weight, from 4 to 29% by weight, from 4 to 30% by weight, from 5 to 25% by weight, from 5 to 26% by weight, from 5 to 27% 6 to 30% by weight, 6 to 25% by weight, 6 to 26% by weight, 6 to 27% by weight, 6 to 28% by weight, 6 to 29% by weight and 6 to 30% by weight.

When the content of the mucoadhesive polymer is less than 4% by weight, sufficient swelling is not exhibited at a low pH as well as at a high pH, so that it is difficult to exhibit a desired sustained release effect. When the content exceeds 30% by weight, Which is not preferable because it causes the patient to feel a foreign body feeling, and further, there is a problem that side effects such as abdominal pain can be caused.

The present invention also relates to a sustained release preparation comprising racosamide or a pharmaceutically acceptable salt thereof, a water-soluble diluent and a mucoadhesive adhesive polymer, wherein the mucoadhesive adhesive polymer has a particle diameter (d10) of 10% To 5 탆, and a particle diameter (d90) corresponding to 90% is 100 탆 to 400 탆.

In the case of polycarboxy methylene used as a mucoadhesive polymer in the embodiment of the present invention, powdered Carbopol 971P NF polymers (Lubrizol), Carbopol 971P NF polymers (Lubrizol) and granules Type Carbopol 71G (Carbopol 71G NF Polymer, Lubrizol). Carbopols 974P and 971P in powder form are known to have a particle size of more than 70% passing through 100 mesh. Carbopol 71G in granular form is known to have particles of 40 to 100mesh in most particles, specifically 40mesh (425um) And the rate of passing 100mesh (150um) is at most 10% or less.

Since the surface area of the mucoadhesive polymer having a small particle diameter is larger than that of the mucoadhesive polymer, the characteristics of the swelling polymer are apparent, but the fluidity is poor and the mixing uniformity is low and formulation is difficult. On the other hand, since the surface area of the granule having a relatively large particle diameter is small, the swelling polymer is reduced in its properties, but the granulation fluidity is excellent in the formulation and the uniformity of mixing is excellent.

In one embodiment of the present invention, the correlation between the particle size of the mucoadhesive polymer and the sustained release effect of the preparation was evaluated. As a result, it was found that the particle diameter (d10) corresponding to 10% (D90) of not more than 400 mu m, it was confirmed that a good sustained release effect was exhibited irrespective of the content of the mucoadhesive polymer contained in the tablet. Thus, the preparation of the present invention preferably comprises a mucoadhesive polymer having a particle diameter (d10) corresponding to 10% of not less than 1 mu m and a particle diameter (d90) corresponding to 90% of not more than 400 mu m In terms of the aspect of the sustained-release effect and formulation.

The formulations of the present invention may contain a number of inert materials known as excipients in addition to racosamide, water-soluble diluents and mucoadhesive polymers. They can be classified according to the role they play in the final formulation. The main compositions include fillers, binders or diluents, lubricants, disintegrants, and lubricants. Other excipients that impart physical properties to the finished tablets include colorants, and flavors in the case of chewable tablets. Typically, excipients are added to the formulation to impart excellent fluidity and compressibility to the material being compressed. Most drugs and pharmaceutical ingredients can not be directly compressed into tablets without excipients. This is mainly due to poor fluidity and tackiness of most drugs. Typically, excipients are added to the formulation to impart excellent fluidity and compressibility to the material being compressed. These properties are imparted through a pretreatment step, such as wet granulation, slugging, spray drying, sphering or crystallization.

Examples of pharmaceutically acceptable binders include starch; Cellulose and derivatives thereof such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose and hydroxylpropyl methylcellulose; Sucrose; Dextrose; Corn syrup; Polysaccharides; And gelatin.

Optionally, one, two, three or more diluents may be added to the formulation of the present invention. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include confectionery sugars, compressible sugars, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc But are not limited thereto.

Optionally, one, two, three or more disintegrants may be added to the formulation of the present invention. Examples of pharmaceutically acceptable disintegrants include starches; clay; Cellulose; Alginate; sword; Crosslinked polymers such as crosslinked polyvinylpyrrolidone, crosslinked calcium carboxymethylcellulose and crosslinked sodium carboxymethylcellulose; Soy polysaccharides; And guar gum. The disintegrant is also an optional component of the tablet formulation, but a useful ingredient. Disintegration is included to ensure that the tablet has an acceptable disintegration rate. Typical disintegrants include salts of carboxymethylcellulose and starch derivatives.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable lubricants include colloidal silica, magnesium trisilicate, starch, talc, calcium tertiary phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, But are not limited to, magnesium, polyethylene glycol, powdered cellulose and microcrystalline cellulose.

Additional examples of useful excipients that may optionally be added to the compositions of the present invention are described in Handbook of pharmaceutical excipients, 3rd edition, Edited by AH Kibbe, American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X , Or [Handbook of Pharmaceutical Excipients (4th edition), edited by Raymond C. Rowe-Publisher: Science and Practice], which is hereby incorporated by reference.

The administration route of the sustained-release preparation of the present invention is not particularly limited, but is preferably for oral administration.

The formulation of the present invention is preferably a matrix type sustained release preparation. The matrix type sustained-release preparation has a structure in which the drug and the sustained-release base are uniformly present in the preparation, does not require strict production control as compared with the sustained-release coating, and is produced by the same manufacturing operation as a conventional rapid- It is possible. Therefore, high productivity is expected. In addition, even when a high-dose preparation of a drug is produced, the preparation of the preparation is easy and its size can be advantageously avoided. Therefore, the sustained-release formulation of the matrix type is more useful than the formulation of the sustained-release coating type in view of high productivity and downsizing of the preparation.

The sustained-release preparation of lacosamide according to the present invention can control the release of the active substance effectively by adjusting the ratio and the particle size of the mucoadhesive polymer so that the concentration of the drug in the blood can be easily controlled and the mucoadhesive polymer can be administered to the gastric mucosa And can be usefully used as an oral drug-sustaining drug delivery system.

Fig. 1 is a view showing a dissolution test result of the sustained-release preparation according to Example 1. Fig.
Fig. 2 is a view showing a dissolution test result of the sustained-release preparation according to Example 2. Fig.
3 is a view showing a dissolution test result of the sustained-release preparation according to Comparative Example 1. Fig.
Fig. 4 is a diagram showing the dissolution test results of the sustained-release preparation according to Examples 3 and 4. Fig.
Fig. 5 is a graph showing the dissolution test results of sustained-release preparations according to Comparative Examples 2 and 5 and 6. Fig.
Fig. 6 is a graph showing the dissolution test results of the sustained-release preparation according to Comparative Example 3, Examples 7 and 8. Fig.
Fig. 7 is a diagram showing the dissolution test results of the sustained-release preparation according to Comparative Examples 4 and 9 to 11. Fig.

Hereinafter, the present invention will be described in detail.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

≪ Examples 1 to 2 >

Matrix-type sustained-release tablet containing mucoadhesive polymer containing racosamide

Tablets in the form of a mucosal adhesive sustained release matrix containing lacosamide were prepared according to the compositional table given in Table 1 below.

The granules were prepared by adding lacosamide and a binding solution in which povidone was dissolved in an appropriate amount of water to a mixture of dicalcium phosphate, microcrystalline cellulose (type 101) or lactose as an excipient. After drying, the granules were mixed with microcrystalline cellulose (type 102), light silicic anhydride, polycarboxy methylene (Carbopol 71G) sieved with 40 mesh, and then magnesium stearate was added to the mixture to form a sustained-release tablet .

ingredient Example 1 Example 2 Comparative Example 1 Content (mg) Content (mg) Content (mg) Lacosamid 100 100 100 Dicalcium phosphate 50 - - Microcrystalline cellulose (type 101) - - 50 Lactose - 50 - Povidone 5 5 5 Polycarboxy methylene 30 30 30 Microcrystalline cellulose (type 102) 51.5 51.5 51.5 Light anhydrous silicic acid 1.1 1.1 1.1 Magnesium stearate 2.4 2.4 2.4 Tablet weight 240.0 240.0 240.0

≪ Examples 3 to 4 &

Preparation of a sustained-release formulation of lacosamide containing various ratios of mucoadhesive macromolecules

Tablets in the form of sustained release matrix containing racosamide were prepared according to the compositional table given in Table 2 below.

To the mixture of racosamide and lactose, a binding solution in which povidone was dissolved in an appropriate amount of water was added to prepare granules. The dried granules were mixed with microcrystalline cellulose (type 102), light anhydrous silicic acid, and 40 mesh mesylated polycarboxy methylene, followed by addition of magnesium stearate to prepare sustained release tablets. Tablets were prepared so as to contain 20% or 25% of polycarboxy methylene as a mucoadhesive polymer relative to the total weight of tablets.

ingredient
Example 3
Example 4 Content (mg) Content (mg) Lacosamid 100 100 Lactose 45 45 Povidone 10 10 Polycarboxy methylene 48 60 Microcrystalline cellulose (type 102) 27.5 21.5 Light anhydrous silicic acid 1.1 1.1 Magnesium stearate 2.4 2.4 Tablet weight 240.0 240.0

≪ Examples 5 to 8 >

Production of a sustained-release formulation of lacosamide according to the particle size of mucoadhesive macromolecule

For Examples 5 to 8 and Comparative Example 2 or 3, tablets in the form of sustained release matrix containing racosamide were prepared according to the compositional table shown in Table 3 below.

To the mixture of racosamide and lactose, a binding solution in which povidone was dissolved in an appropriate amount of water was added to prepare granules. After drying, the granules were mixed with microcrystalline cellulose (type 102), light silicic anhydride, polycarboxy methylene copolymerized with No. 30 or polycarboxy methylene copolymerized with No. 40, and then further mixed with magnesium stearate A sustained release tablet was prepared.

ingredient
Comparative Example 2
Example 5
Example 6
Comparative Example 3
Example 7
Example 8 Content (mg) Content (mg) Content (mg) Content (mg) Content (mg) Content (mg) Lacosamid 100 100 100 100 100 100 Lactose 45 45 45 45 45 45 Povidone 10 10 10 10 10 10 Polycarboxy methylene (30 mesh) 30 - - 54 - - Polycarboxy methylene (40 mesh) - 30 - - 54 - Polycarboxy methylene (60 mesh) - - 30 - - 54 Microcrystalline cellulose (type 102) 51.5 51.5 51.5 27.5 27.5 27.5 Light anhydrous silicic acid 1.1 1.1 1.1 1.1 1.1 1.1 Magnesium stearate 2.4 2.4 2.4 2.4 2.4 2.4 Tablet weight 240.0 240.0 240.0 240.0 240.0 240.0

≪ Examples 9 to 11 &

Production of a sustained-release formulation of racoside according to the amount of mucoadhesive polymer used

Tablets in the form of a sustained-release matrix containing racosamide were prepared according to the compositional table shown in Table 4 for Examples 9 to 11 and Comparative Example 4.

To the mixture of racosamide and lactose, a binding solution in which povidone was dissolved in an appropriate amount of water was added to prepare granules. After drying, microcrystalline cellulose (type 102), light silicic anhydride, polycarboxy methylene (40%), polycarboxy methylene (2%, 4%, 6%, and 15%) were mixed with the granules, and magnesium stearate was further mixed The mixture was triturated to produce a sustained-release tablet.

ingredient Comparative Example 4 Example 9 Example 10 Example 11 Content (mg) Content (mg) Content (mg) Content (mg) Lacosamid 200 200 200 200 Lactose 100 100 100 100 Povidone 10 10 10 10 Polycarboxy methylene 8 16 24 55 Microcrystalline cellulose 52 44 36 5 Light anhydrous silicic acid 2 2 2 2 Magnesium stearate 4 4 4 4 Tablet weight 376 376 376 376

≪ Test Example 1 >

Pretreatment and particle size evaluation of polycarboxy methylene

Polycarboxy methylene (Carbopol 71G), commercially available as a pharmaceutical additive, was sieved with 30 mesh, 40 mesh, and 60 mesh, and then subjected to particle size evaluation according to the following method.

≪ Particle size measurement method &

Analysis method: laser diffraction method which converts scattering distribution into particle size distribution

Analytical Instruments: Mastersizer 2000 (Malvern)

Analytical method: dry, 0.5 bar (10 g, 3 times analysis average)

d10 (um) d90 (um) Polycarboxy methylene (30 mesh) Lot.0000032532: 5.6um
LOt.0000025211: 2.079um
Lot.0000038517: 1.9um Lot.0000032532: 452.4um
LOt.0000025211: 404.1um
Lot.0000038517: 433.315um Polycarboxy methylene (40 mesh) Lot.0000032532: 1.4um Lot.0000032532: 328.6um Polycarboxy methylene (60 mesh) Lot.0000032532: 1.3um Lot.0000032532: 259.7um

≪ Test Example 2 &

Elution of lacosamide sustained-release preparation according to the water solubility of the diluent contained in the tablet

The following experiment was carried out in order to confirm the dissolution properties of the slow release formulation according to the water solubility of the diluent in the slow release formulation containing racosamide, diluent and mucoadhesive polymer. Concretely, through the combination of microcrystalline cellulose, lactose, dicalcium phosphate and mucoadhesive adhesive polymer, which are diluents, in order to achieve stable sustained release regardless of pH through Examples 1 and 2 and Comparative Example 1, To find a combination that receives less.

The dissolution test of Examples 1 to 2 and Comparative Example 1 was conducted according to Table 1 above using the paddle method of the second company of Kagaku Kogyo Co., The elution was carried out by using 900 ml of 0.1 N HCl and 900 ml of pH 6.9 to rotate the paddles at 37 ° C and 50 rpm and examine the elution pattern of each tablet. (Unit:% by mass).

The results are shown in FIG. 1 to FIG.

As shown in FIGS. 1 to 3, the compositions having the compositions of Examples 1 and 2 according to the present invention exhibited constant elution at various pH conditions. As the pH-dependent polymer, mucoadhesive polymer (polycarboxy methylene) does not swell sufficiently at a low pH and at a high pH, the solvent easily and rapidly penetrates into the refining core, leading to rapid dissolution. Relatively soluble in DW and sprangly soluble in DW slow the dissolution of the drug while retaining the moisture penetrated into the refining core as compared to insoluble insoluble water, It is believed that the swelling time of the polymer is increased and the effect of pH is reduced by helping to form a sustained release formulation.

≪ Test Example 3 >

Elution of sustained-release preparation according to the content of mucoadhesive polymer contained in the preparation

Tablets were prepared according to the composition shown in Table 2, and the elution properties were evaluated according to the contents of the mucoadhesive macromolecules contained in the tablets. The content of the mucoadhesive polymer contained in Examples 3 to 4 in the composition of Table 2 was 20% and 25%, respectively.

The elution test was conducted on the above Examples 3 to 4 using the paddle method of the second company of Kagaku Kogyo Co., The eluate was spun at 37 ° C and 50 rpm using 900 ml of 0.1 N HCl and the dissolution profile of each tablet was tested. (Unit:%)

The results are shown in Fig.

As shown in FIG. 4, it was found that the effect of sustained release over time was also increased when increasing from 20% to 25%.

<Test Example 4>

Elution of sustained-release formulation according to particle size of mucoadhesive polymer contained in the preparation

Tablets were prepared according to the composition shown in Table 3, and the elution properties of the mucoadhesive polymers contained in the tablets were evaluated according to their particle sizes.

The elution test was carried out on the above Examples 5 to 8 and Comparative Example 2 or 3 using the paddle method of the second company of Kagaku Kogyo Co., The elution was carried out by rotating the paddle at 50 rpm at 37 DEG C with 900 mL of 0.1 N HCl, and the elution pattern of each tablet was tested (unit:% by mass).

The results are shown in Fig. 5 and Fig.

As can be seen from FIGS. 5 and 6, when the mucoadhesive adhesive polymer contained in the preparation had a particle size of about 40 mesh or 60 mesh, the content of the mucoadhesive polymer contained in the preparation It was confirmed that it exhibited a good sustained-release effect.

On the other hand, in the case of Comparative Example 3, the content of the mucoadhesive polymer contained in the preparation was 22.5%, but it was judged that the desired sustained-release effect was not achieved due to the large particle size of the mucoadhesive polymer contained therein.

&Lt; Test Example 5 >

Elution of sustained-release preparation according to the content of mucoadhesive polymer contained in the preparation

Tablets were prepared according to the composition shown in Table 4, and the elution properties were evaluated according to the contents of the mucoadhesive macromolecules contained in the tablets.

The elution test was carried out for each of Examples 9 to 11 and Comparative Example 4 using the paddle method of the second company of Kagaku Kogyo Co., The elution was carried out by rotating the paddle at 50 rpm at 37 DEG C with 900 mL of 0.1 N HCl, and the elution pattern of each tablet was tested (unit:% by mass).

The results are shown in Fig.

As can be seen from FIG. 7, it was confirmed that the elution pattern varies depending on the content of the mucoadhesive polymer contained in the preparation. When the content of the mucoadhesive polymer contained in the preparation is 4% or more, sufficient sustained release effect Respectively.

On the other hand, in the case of Comparative Example 4 in which the content of the mucoadhesive polymer was 4% or less in the preparation, it was judged that the desired sustained-release effect was not achieved.

As described above, the present inventors have developed a preparation capable of achieving a good sustained-release effect even under a wide pH range of the gastrointestinal tract by mixing racosamide, a water-soluble diluent, and a mucoadhesive adhesive polymer. In particular, It was confirmed that it is possible to produce a preparation which achieves the most preferable sustained-release effect by controlling the content of the polymer or the size of the particles. Such racoceride sustained release preparation is disclosed for the first time through the present invention.

 The sustained-release preparation of lacosamide according to the present invention can control the release of the active substance effectively by adjusting the ratio and the particle size of the mucoadhesive polymer so that the concentration of the drug in the blood can be easily controlled and the mucoadhesive polymer can be administered to the gastric mucosa And can be usefully used as a drug-sustaining drug delivery system for oral use, and thus is highly industrially applicable.

Claims (11)

Wherein the mucoadhesive polymer has a particle diameter (d10) corresponding to 10% of 1 mu m to 5 mu m and an average particle diameter of 10 mu m to 10 mu m, , And the particle diameter (d90) corresponding to 90% is 100 占 퐉 to 400 占 퐉.
The sustained-release preparation according to claim 1, wherein the mucoadhesive polymer is contained in an amount of 4 to 30% by weight based on the total weight of the preparation.
The formulation according to claim 1, wherein the formulation comprises 40-70% by weight of racosamide or a pharmaceutically acceptable salt thereof, 10-35% by weight of a water-soluble diluent and 4 - 30% by weight of a mucoadhesive adhesive polymer, &Lt; / RTI &gt; by weight.
Wherein the mucoadhesive polymer is contained in an amount of 4 to 30% by weight based on the total weight of the preparation, characterized in that the mucoadhesive polymer is contained in an amount of 4 to 30% by weight based on the total weight of the preparation .
[5] The composition according to claim 4, wherein the mucoadhesive polymer has a particle diameter (d10) corresponding to 10% of 1 m to 5 m and a particle diameter (d90) corresponding to 90% of 100 m to 400 m Slow release formulation.
The composition according to claim 4, wherein the preparation comprises 40 to 70% by weight of racosamide or a pharmaceutically acceptable salt thereof and 15 to 30% by weight of a water-soluble diluent, based on the total weight of the preparation. Formulation.
7. The method of any one of claims 1 to 6, wherein the aqueous diluent is selected from the group consisting of dextrin, lactose, sodium alginate, methylcellulose, saccharose, sodium carboxymethylcellulose, glucose, fructose, polyvinylpyrrolidone, hydroxypropylmethylcellulose , Hydroxyethyl cellulose, calcium monohydrogen phosphate, propylene glycol, sodium chloride, casein, dicalcium phosphate and sodium hydrogencarbonate.
The method according to any one of claims 1 to 6, wherein the mucoadhesive adhesive polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, polyvinylpyrrolidone / vinyl Polyacrylic acid, polymethacrylic acid, polymethacrylic acid, polymethacrylate, povidone, alginic acid, sodium alginate, xanthan gum, gum arabic, chitosan, starch, dextrin, propylene glycol and glycol derivatives Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, succinate, fumarate, malate, glutarate, adipate, pimelate, maleate, malate , Tartrate, acetate, nicotinate, or addition salt thereof.
7. The preparation according to any one of claims 1 to 6, wherein the preparation further comprises at least one pharmaceutically acceptable additive selected from the group consisting of a binder, a disintegrant and a glidant.
The pharmaceutical composition according to any one of claims 1 to 6, characterized in that the formulation releases 15 to 70% of racosamide at 2 hours after administration and 70 to 100% at 8 hours. Formulation.

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