TW201626990A - An oral composite tablet containing melatonin and sertraline - Google Patents

Abstract

An oral composite tablet and a method of preparing the oral composite tablet are provided. The oral composite tablet includes: a sustained-release layer containing melatonin or a pharmaceutically acceptable salt thereof, and a gel-forming polymer as a release-sustaining agent; and a immediate-release layer containing sertraline or a pharmaceutically acceptable salt thereof.

Description

Oral complex lozenge containing melatonin and sertraline

The present disclosure relates to an oral complex lozenge comprising melatonin and sertraline as an active ingredient, and more particularly to a composite lozenge comprising a melatonin sustained release layer and a sertraline immediate release layer.

Melatonin, also known as 5-methoxy-N-ethinylamine, is a hormone secreted by the pineal gland of the brain, which plays an important role in sleep induction and regulation. Melatonin is effective in treating sleep disorders caused by abnormal production of melatonin, which is attributed to aging-related diseases or the use of specific drugs (for example, β-adrenergic receptor blockers). Melatonin is known to reduce sleep time and improve sleep quality and daytime activity. Melatonin may be administered orally sustained release tablets (sustained-release tablet) in the form of Circadin ^® product name is obtained. Circadin ^® resin comprising an acrylic-based Eudragit RSPO (ammonio methacrylate copolymer, type B) of a matrix sustained-release tablets, the system acts as a release Eudragit RSPO maintaining agent (release-sustaining agent) of. Melatonin has a half-life of about 35 to 50 minutes that is too short to produce sufficient efficacy, but this half-life can be extended to about 3.5 to 4 hours due to sustained release techniques to allow a constant release of about 8 to 10 hours for the entire Stable performance during sleep time. Circadin ^® having a dissolution test standard, which requires over one hour from about 25 to about 50wt% in quality control sustained release of, within 2 hours from about 40wt% to about 65wt% and a period of 8 hours to about 80wt%, or 80wt% The above melatonin dissolution rate is measured by a dissolution test at pH 4.0.

The sertraline having the structure represented by Formula 1 is widely used as a selective serotonin reuptake inhibitor (SSRI) for an antidepressant.

Sertraline is mainly used in the form of hydrochloride to increase solubility. Sertraline hydrochloride may be administered orally in the form of immediate release tablets commercially available under the product name Zoloft ^®. Zoloft ^{® is} used to treat depression, panic disorder, obsessive-compulsive disorder or post-traumatic stress disorder (PTSD).

Night eating syndrome (NES) is a disease first published in 1955 by Dr. Albert Stunkard of the United States, in which about 50% of the daily food intake occurs after 7 pm and the disease is usually accompanied by insomnia. Most people with this syndrome do not eat breakfast or eat very little breakfast, eat lunch casually during busy periods, and more than half of the daily Food intake occurs at night. Normally, these people may sleep normally for more than three days in a week, or they may have difficulty falling asleep unless they eat. Although the cause is not yet clear, it is known that psychological and mental problems, such as abnormal reactions to stress, depression, anxiety, and loss of confidence, may mostly lead to nocturnal eating syndrome. Eating at night can reduce the level of sleep hormone melatonin to one-half of normal, and also reduce the secretion of the appetite-suppressing hormone leptin. For these reasons, there is a possibility of a continuous vicious cycle of nighttime sleep deprivation and nighttime eating caused by uncontrolled appetite.

Many studies have shown that patients suffering from nocturnal eating syndrome have lower melatonin levels (Non-Patent Document 1 and Non-Patent Document 2). It has been reported that exogenous melatonin can reduce gastric emptying rate, and as a result of animal testing, it has also been found to be effective for treating nocturnal eating syndrome (Non-Patent Document 3). In addition, agomelatine, a melatonin agonist, has been reported to be effective in treating nocturnal eating syndrome by controlling sleep cycle and appetite (Non-Patent Document 4).

As a result of many clinical tests, it has been found that sertraline is effective for treating nocturnal eating syndrome (Non-Patent Document 5 and Non-Patent Document 6). It has also been found that the improved function of serotonin is associated with an improvement in nocturnal eating syndrome, and therefore it is recommended to use a selective serotonin reuptake inhibitor (SSRI) such as sertraline to treat nocturnal eating syndrome (Non-Patent Document 7).

[Previous Technical Literature]

[Non-patent literature]

1. LA Pawlowl et al., Night eating syndrome: Effects of brief relaxation training on stress, mood, hunger, and eating patterns, International Journal of Obesity (2003) 27, 970-978.

2. Grethe St a Birketvedt et al., Behavioral and Neuroendocrine Characteristics of the Night-Eating Syndrome, JAMA. 1999; 282(7): 657-663.

3. Ö. KASIMAY et al., EXOGENOUS MELATONIN DELAYS GASTRIC EMPTYING RATE IN RATS: ROLE OF CCK2 AND 5-HT3 RECEPTORS, JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2005, 56, 4, 543-553.

4. Walter Milano et al., Hindawi Publishing Corporation Case Reports in Medicine Volume 2013, Article ID 867650, 5 pages.

5. John P. O’Reardon et al., A Randomized, Placebo-Controlled Trial of Sertraline in the Treatment of Night Eating Syndrome, Am J Psychiatry 163:5, May 2006.

6. John P. O’Reardon et al., Clinical trial of sertraline in the treatment of night eating syndrome, Int J Eat Disord. 2004 Jan; 35(1): 16-26.

7. Saeed Shoar et al, Prophylactic diet: A treatment for night eating syndrome, Hypothesis 2012, 10(1): e5, doi: 10.5779/hypothesis.v10i1.241 (2012).

The present disclosure provides an oral complex lozenge comprising melatonin and sertraline having sustained release properties of melatonin and immediate release properties of sertraline.

The present disclosure also provides a method of preparing an oral complex lozenge comprising melatonin and sertraline.

According to one aspect of the present disclosure, there is provided an oral composite lozenge comprising: a sustained release layer comprising melatonin or a pharmaceutically acceptable salt thereof, and a gel-forming polymer as a release maintenance agent; An immediate release layer containing sertraline or a pharmaceutically acceptable salt thereof.

According to another aspect of the present disclosure, there is provided a method of preparing an oral complex lozenge comprising: preparing a gel-forming polymer comprising melatonin or a pharmaceutically acceptable salt thereof, and as a release maintenance agent Melatonin granules; preparing sertraline granules comprising sertraline or a pharmaceutically acceptable salt thereof; and compressing the sertraline granules to form an immediate release layer using a two-layer tablet press, adding fading thereto The black hormone particles, and the resulting mixture is tableted, thereby forming a bilayer tablet.

According to one or more embodiments of the present disclosure, an oral complex lozenge may comprise a gel-forming polymer in a sustained release layer comprising melatonin, wherein when the oral complex lozenge is administered to the body, the gel-forming layer may Forming a gel matrix, thus preventing the release of the melatonin-containing sustained release layer from the immediate release layer containing sertraline due to the viscosity of the gel matrix The matrix is destroyed so that the sustained release properties of melatonin in the sustained release layer containing melatonin can be maintained without deterioration. Thus, an oral complex lozenge according to any of the embodiments, as a single unit dosage form for simultaneous administration of melatonin and sertraline, can have the desired release properties of each of the two active ingredients and exhibit as an active ingredient Separate the efficacy of a single unit dosage form when administered. Therefore, patients who require a combination therapy of melatonin and sertraline can be effectively treated by administering only a single unit dosage form of the oral complex lozenge, such as a patient suffering from nocturnal eating syndrome, which can be improved. Patient's drug compliance.

1 is a drug release mode of a bilayer tablet according to an embodiment and a drug release mode of a bilayer tablet comprising a melatonin sustained release layer and a sertraline immediate release layer prepared using a conventional single formulation. schematic diagram.

2 illustrates a graph of sertraline dissolution rate versus time in a double-layer tablet of Comparative Example 1 in a buffer at pH 1.2, pH 4.0, or pH 6.8, or in distilled water.

Figure 3 illustrates a graph of sertraline dissolution versus time for a bilayer tablet of Example 1 in a buffer at pH 1.2, pH 4.0 or pH 6.8, or in distilled water.

Figure 4 is a graph showing the melatonin dissolution rate versus time in the bimodal tablet of Comparative Example 1 in a buffer at pH 1.2, pH 4.0 or pH 6.8, or in distilled water.

Figure 5 illustrates melatonin dissolution rate in a double layer tablet of Example 1 in a buffer at pH 1.2, pH 4.0 or pH 6.8, or in distilled water. A chart relative to time.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although exemplary methods or materials are listed herein, other similar or equivalent methods or materials are also within the scope of the invention. All publications disclosed herein are hereby incorporated by reference in their entirety.

The aspect of the present disclosure provides an oral complex lozenge comprising: a sustained release layer comprising melatonin or a pharmaceutically acceptable salt thereof, and a gel-forming polymer as a release maintenance agent; An immediate release layer of the forest or a pharmaceutically acceptable salt thereof.

The oral complex lozenge can be a bilayer tablet comprising a sustained release layer and an immediate release layer. In the following, sustained release layers, immediate release layers and bilayer tablets are individually described in more detail for oral complex lozenges.

(i) sustained release layer

The sustained release layer may include melatonin or a pharmaceutically acceptable salt thereof, and a gel forming polymer as a release maintenance agent.

As used herein, the phrase "melatonin or a pharmaceutically acceptable salt thereof" may mean melatonin, melatonin analog, a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof. In some embodiments, melatonin or a pharmaceutically acceptable salt thereof can be melatonin free base.

In some embodiments, an oral complex lozenge can include from about 1 to about 8 mg of melatonin in the form of melatonin free base per single unit dosage form. For example, the amount of melatonin in the form of melatonin free base can be about 2 mg per single unit dosage form.

The sustained release layer can be formed by tableting a mixture in the form of particles comprising melatonin or a pharmaceutically acceptable salt thereof, and a gel forming polymer. The granules may comprise dry granules or wet granules.

The gel forming polymer can be any gel forming polymer known in the art as a release maintenance agent. For example, the gel-forming polymer may be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyethylene oxide (PEO), polyvinylpyrrolidone (polyvinylpyrrolidone; PVP). ), polyvinyl alcohol (PVA), carbomer, hydroxypropyl cellulose (HPC), methyl cellulose (MC), sodium carboxymethyl cellulose (CMC- Na), propylene oxide (PO) and any combination thereof. In some embodiments, the gel forming polymer can be a gel forming polymer having a viscosity of from about 4,000 cps to about 100,000 cps, and in some embodiments from about 4,000 cps to about 15,000 cps. In some other embodiments, the gel forming polymer can be hydroxypropyl methylcellulose (HPMC), for example, having a viscosity of from about 4,000 cps to about 100,000 cps. For example, the gel forming polymer can be HPMC 2910 (4000 cps).

The gel forming polymer may be in an amount of from about 20 parts by weight to about 70 parts by weight, based on 1 part by weight of melatonin or a pharmaceutically acceptable salt thereof, and in some embodiments, about 20 parts by weight to about 50 parts by weight.

The gel-forming polymer can achieve sustained release of melatonin or a pharmaceutically acceptable salt thereof as an active ingredient in the sustained release layer of an oral complex lozenge. According to the respective comprises melatonin sustained release layer and an immediate release sertraline tablets bilayer execution of melatonin melatonin dissolution test results of layers, wherein the melatonin in the sustained release layer of Circadin available as a single unit dosage form ^® sustained release tablets are prepared as in release of the agent is maintained methyl acrylate copolymer Eudragit RSPO, and sertraline immediate release layer was prepared according to the same composition Zoloft ^® lozenges, troches found bilayer sustained due Circadin ^® The release of the tablet is significantly higher than the melatonin dissolution rate without the sustained release properties of melatonin. However, it was found to form a polymer gel according to prepare instead Eudragit RSPO melatonin sustained release layer of a composite oral lozenge of Example embodiment has Circadin ^® conventional sustained-release tablets of sustained release of their properties are very similar Sustained release properties (Refer to Test Case 1 and Test Case 2).

The sustained release layer of the oral complex lozenge may further comprise a pharmaceutically acceptable additive selected from the group consisting of a diluent, a disintegrant, a lubricant, and any combination thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate, and any combination thereof, but is not limited thereto. In some embodiments, the diluent can be a combination of lactose and dibasic calcium phosphate. The amount of the diluent may be from about 15 parts by weight to about 45 parts by weight relative to 1 part by weight of melatonin or a pharmaceutically acceptable salt thereof.

The disintegrant can be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, and crospovidone. , pregelatinized starch, sodium starch glycolate, starch, and any combination thereof, but are not limited thereto. The amount of the disintegrant may be from about 10 parts by weight to about 40 parts by weight relative to 100 parts by weight of melatonin or a pharmaceutically acceptable salt thereof.

The lubricant may be selected from the group consisting of calcium stearate, ceria, glyceryl monostearate, palmitoyl stearate, magnesium stearate, sodium lauryl sulfate, sodium stearate Zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and any combination thereof, but are not limited thereto. In some embodiments, the lubricant can be a combination of magnesium stearate and ceria. The amount of lubricant may range from about 0.5 parts by weight to about 4 parts by weight, and in some embodiments, from about 0.7 parts by weight to 1 part by weight of melatonin or a pharmaceutically acceptable salt thereof. About 3 parts by weight.

(ii) immediate release layer

The immediate release layer may comprise sertraline or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the phrase "sertraline or a pharmaceutically acceptable salt thereof" may mean sertraline, a sertraline analog, a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof.

The pharmaceutically acceptable salts of sertraline may include acid addition salts, for example, sertraline hydrochloride, sertraline acetate, sertraline lactate, and koji Lin Tiandong amine and so on. In some embodiments, the pharmaceutically acceptable salt of sertraline is sertraline hydrochloride.

Oral complex lozenges can include from about 25 mg to about 200 mg of sertraline in the form of the sertraline free base per single unit dosage form. In some embodiments, an oral complex lozenge can comprise about 50 mg or about 100 mg of sertraline per single unit dosage form, which corresponds to about 55.95 mg or about 111.9 mg of sertraline hydrochloride, respectively.

The immediate release layer can be formed by ingot tableting a mixture comprising sertraline or a pharmaceutically acceptable salt thereof. The granules may comprise dry granules or wet granules. In some embodiments, the particles can be wet particles.

In addition to the above active ingredients, the immediate release layer may further comprise any of the known pharmaceutically acceptable additives used in the art for the preparation of granules. Pharmaceutically acceptable additives can be selected from the group consisting of diluents, binders, disintegrants, lubricants, and any combination thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate, and any combination thereof, but is not limited thereto. In some embodiments, the diluent can be a combination of lactose and dibasic calcium phosphate. The amount of diluent may range from about 100 parts by weight to about 180 parts by weight, and in some embodiments, from about 120 parts by weight to about 150 parts by weight based on 100 parts by weight of sertraline or a pharmaceutically acceptable salt thereof. .

The binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone (PVP), pregelatinized starch, and any combination thereof. But it is not limited to this. In some embodiments, the binder can be hydroxypropyl cellulose. The amount of the binder may range from about 0.4 parts by weight to about 3 parts by weight, and in some embodiments, from about 0.7 parts by weight to about 2 parts by weight relative to 100 parts by weight of sertraline or a pharmaceutically acceptable salt thereof. Share.

The disintegrant can be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatin Starch starch, sodium starch glycolate, starch, and any combination thereof, but are not limited thereto. In some embodiments, the disintegrant can be sodium starch glycolate. The amount of disintegrant may range from about 10 parts by weight to about 30 parts by weight, and in some embodiments, from about 15 parts by weight to about 20 parts by weight based on 100 parts by weight of sertraline or a pharmaceutically acceptable salt thereof. Share.

The lubricant may be selected from the group consisting of calcium stearate, ceria, glyceryl monostearate, palmitoyl stearate, magnesium stearate, sodium lauryl sulfate, sodium stearate Zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and any combination thereof, but are not limited thereto. In some embodiments, the lubricant can be a combination of magnesium stearate and ceria. The amount of lubricant may range from about 3 parts by weight to about 10 parts by weight, and in some embodiments, from about 3 parts by weight to about 8 parts by weight, based on 100 parts by weight of sertraline or a pharmaceutically acceptable salt thereof. .

(iii) Bilayer tablets

The bilayer tablet can be used as a first layer (i.e., a sustained release layer) by including particles comprising melatonin or a pharmaceutically acceptable salt thereof, and a gel forming polymer as a release maintaining agent, and Sertraline or its medicinal The particles of the acceptable salt are formed as a second layer (i.e., an immediate release layer). Double-layer tablets provide both a sustained (long-acting) effect of melatonin and an immediate effect of sertraline due to the simultaneous inclusion of a sustained release layer containing melatonin and the immediate presence of sertraline in a single formulation. Release layer (refer to Test Case 1 to Test Case 3).

However, a maintaining agent comprising as the release Eudragit RSPO in conventional sustained release Circadin ^® lozenges, troches bilayer rather than the gel-forming polymer of melatonin sustained release layer may not exhibit the desired sustained release characteristics, Circadin ^® attributed to the sustained release tablets compared to fade significantly melatonin's fast dissolution rate. In order to prepare a bilayer tablet having a sustained release property of melatonin and an immediate release property of sertraline, the inventors of the present disclosure use a bilayer tablet for testing, and the tablet is prepared by melatonin and sertraline woods each individually granulated so as to have the same composition as the melatonin and, respectively, sertraline may utilize the conventional Circadin ^® and Zoloft ^® lozenges single formulation, and treated with lozenges The agent presses the two kinds of granules to prepare a bilayer tablet (refer to Comparative Example 1). However, this was found to have faded bilayer tablets of the composition of melatonin sustained release layer described above does not maintain the same sustained-release characteristics of Circadin ^® (Reference Test Example 1). According to the results, we have found that a gel-forming material as a sustained release coating material, instead of using a methacrylate in the sustained release coating Circadin ^® prepared melatonin sustained release layer remains with bilayer tablets formulated Circadin ^® single The sustained release properties of melatonin in the form of a bilayer tablet similar in sustained release of the substance (Reference Test Example 1). This can be attributed to the following reasons. In a bilayer tablet comprising an immediate release layer and a sustained release layer, the immediate release layer and the sustained release layer are strongly bonded so as not to be separated from one another, thus maintaining a single lozenge form. However, in a bilayer tablet having a sustained release layer comprising a methacrylate release maintenance agent such as Eudragit RSPO, the interface of the sustained release layer and the immediate release layer in close contact with each other can be broken after the immediate release layer disintegrates in the body. And, inevitably, the melatonin dissolution rate in the sustained release layer can be increased (refer to A in Fig. 1). Meanwhile, in a bilayer tablet having a sustained release layer including a gel-forming polymer, the gel-forming polymer can rapidly form a gel to be coated before the sustained release layer is destroyed due to disintegration of the immediate release layer in the body. The cloth continues to release the interface of the layer, thereby protecting the sustained release layer from the collapse of the immediate release layer (refer to B in Figure 1). Destruction of the sustained release layer can result in broadening or broadening of the drug release channel in the methacrylate structure of Eudragit RSPO used as a matrix to release the maintenance agent to form a sustained release layer.

A methacrylate copolymer such as Eudragit RSPO as a release maintenance agent can cause sustained release of the drug via slow drug diffusion within the matrix while maintaining the structure of the matrix. However, the gel-forming polymer used as a release-preventing agent can form an increased matrix in the form of a gel by moisture absorption and cause sustained release of the drug or slow dissolution of the substrate surface itself by diffusion of the drug in the matrix. . Therefore, at the junction with the immediate release layer, when the matrix of the Eudragit RSPO in the sustained release layer is broken due to the disintegration of the immediate release layer, the sustained release of the drug via the matrix is no longer ensured, so that a large amount of the drug can be released quickly (Reference) A) in Figure 1. At the same time, the gel-forming polymer in the sustained release layer can be absorbed by moisture absorption. The gel matrix is rapidly formed, wherein the gel matrix can be destroyed by the disintegration of the immediate release layer due to its viscosity so that the sustained release mode of the drug in the sustained release layer can be maintained (refer to B in Fig. 1). 1 is a drug release mode of a bilayer tablet in accordance with an embodiment (B in FIG. 1) and a bilayer tablet comprising a sustained release layer and an immediate release layer prepared using a conventional single formulation. Schematic diagram (A in Figure 1).

In some embodiments, the bilayer tablet is evaluated using a USP dissolution test II (blade method) according to the US Pharmacopoeia (USP) in an aqueous buffer solution at pH 4.0 at about 37 ± 0.5 ° C and about 50 rpm. It may have a dissolution test of about 25 wt% to about 50 wt% for about 1 hour, a dissolution test for about 2 hours of about 40 wt% to about 65 wt%, and a dissolution test for about 8 hours of about 75 wt% or more of melatonin dissolution rate; and dissolution The dissolution rate of sertraline of about 75 wt% or more was tested for about 45 minutes.

A bilayer tablet according to any of the above embodiments can include melatonin and a conventional single formulation of sertraline in a single unit dosage form, while at the same time maintaining the same blackening as the conventional single formulation. The sustained release properties of the hormone and the immediate release properties of sertraline, and thus the same efficacy as when administering a conventional single formulation. Thus, a bilayer tablet according to any of the above embodiments may improve patient's drug compliance, as it is not necessary to take two separate single formulations.

The bilayer tablet according to any of the above embodiments may further comprise a film coating layer on its outer surface. The film coating layer may include a film coating agent and a colorant having immediate release properties. The film coating agent may be a mixture of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC), or polyvinyl alcohol (PVA) and polyethylene glycol ( A mixture of polyethylene glycol; PEG), but is not limited thereto. The colorant may be titanium dioxide or iron oxide, but is not limited thereto. A representative example of a currently available film coating agent is Opadry ^® . The film coating layer provides a drug taste masking effect and improves the stability of the final composite tablet.

In some embodiments, a bilayer tablet according to any of the above embodiments can be used to treat or ameliorate nighttime consumption at a dose administered to each of the conventional single formulations for treating or ameliorating nocturnal eating syndrome. Syndrome. The dosage of the bilayer tablet for treating or ameliorating the nocturnal eating syndrome may vary with the particularist's judgment, depending on the gender, age, weight, race and condition of the patient. In some embodiments, the bilayer tablet according to any of the above embodiments can be administered once, twice, three times or four times a day.

Another aspect of the present disclosure provides a method of preparing an oral complex lozenge according to any of the above embodiments, the method comprising: preparing a gel comprising melatonin or a pharmaceutically acceptable salt thereof, and as a release maintenance agent Glue forming polymer melatonin particles; preparing sertraline particles comprising sertraline or a pharmaceutically acceptable salt thereof; and compressing the sertraline particles to form an immediate release layer using a two-layer tablet press Melatonin granules are added thereto, and the resulting mixture is tableted, thereby forming a bilayer tablet.

The above detailed description of the oral complex lozenge according to any of the above examples can be applied to the description of the method of preparing an oral composite lozenge.

If the sertraline granules are pressed in the process of forming the bilayer tablet and then the order of the melatonin granules is transformed, the particles in the layer are immediately released. The particles in the sustained release layer may be more likely to be mixed together at the interface of the two layers in the bilayer tablet. The more the mixing occurs, the more likely the matrix of the sustained release layer in the joint region with the immediate release layer is affected by the disintegration of the immediate release layer, and the more the initial drug release rate in the sustained release layer can be increased.

In some embodiments, the preparation of melatonin particles can include granulating melatonin or a pharmaceutically acceptable salt thereof with a pharmaceutical additive that does not include a gel forming polymer and a lubricant, and the resulting product Drying to form granules; and the formed granules are mixed with a gel forming polymer and then mixed with a lubricant.

In the formation of the bilayer tablet, the tablet of the sertraline particles can be carried out at a pressure of from about 1.5 kp to about 6 kp, and the tablet after the addition of the melatonin particles can be carried out at a pressure of from about 8 kp to about 16 kp. As described above, in order to prepare a bilayer tablet comprising a sustained release layer and an immediate release layer which are not separated from each other, the sustained release layer and the immediate release layer need to be strongly bonded to each other at their interfaces. When the tablet for forming the immediate release layer is performed under the pressure of the high pressure ingot, the immediate release layer can be easily separated from the sustained release layer formed by injecting the particles for forming the sustained release layer without being strong Ground combination. On the other hand, when the tablet for forming the immediate release layer is performed under the pressure of the low pressure ingot, the immediate release layer may be improperly formed. In addition, the tablet used to form the sustained release layer can be performed at a higher pressure of the tablet than the immediate release layer to ensure a strong bond between the sustained release layer and the immediate release layer at its interface.

The process involved in each step of preparing the oral composite lozenge according to any of the above examples can be carried out according to conventional procedures for preparing bilayer tablets known in the art.

Example

One or a plurality of embodiments of the present disclosure will now be described in detail with reference to the following examples. However, these examples are for illustrative purposes only and are not intended to limit the scope of one or a plurality of embodiments.

Comparative Example 1: Preparation of a composite formulation comprising the same melatonin sustained release layer and a sertraline immediate release layer as those of the conventional single formulations

After preparing the immediate release layer particles according to the composition of Table 1 and preparing the sustained release layer particles according to the composition of Table 2, a bilayer tablet was prepared.

In order to prepare the particles of the immediate release layer, sertraline (or a salt thereof), calcium hydrogen phosphate, lactose and sodium starch glycolate are mixed together, and a binder solution prepared by dissolving hydroxypropylcellulose in water is used. Co-granulation is carried out and then dried to obtain granules of the immediate release layer. The granules are then mixed with cerium oxide and magnesium stearate.

To prepare the particles of the sustained release layer, calcium hydrogen phosphate and lactose are co-mixed, co-granulated using a binder solution prepared by mixing melatonin with methanol, and then dried to obtain particles of the sustained release layer. The granules are then mixed with Eudragit RSPO as a release maintenance agent and then mixed with cerium oxide and magnesium stearate.

The pellets of the layer are immediately released to a hardness of about 2.0 kp (first tablet), and then the particles of the sustained release layer are loaded onto the immediate release layer and pressed (second ingot) to form a bilayer tablet.

Example 1: Preparation of a composite formulation comprising a melatonin sustained release layer and a sertraline immediate release layer (1)

A bilayer tablet was prepared in the same manner as in Comparative Example 1, except that instead of Eudragit RSPO used as a release maintenance agent, hydroxypropylmethylcellulose (HPMC 2910, 4000 cps) was used to form particles of the sustained release layer.

Example 2: Preparation of a composite formulation comprising a melatonin sustained release layer and a sertraline immediate release layer (2)

The bilayer tablet was prepared in the same manner as in Comparative Example 1, except that instead of Eudragit RSPO used as a release maintenance agent, polyethylene oxide (PEO) was used to form particles of the sustained release layer.

Example 3: Preparation of a composite formulation comprising a melatonin sustained release layer and a sertraline immediate release layer (3)

The bilayer tablet was prepared in the same manner as in Comparative Example 1, except that instead of Eudragit RSPO used as a release maintenance agent, polyvinylpyrrolidone (PVP) was used to form particles of the sustained release layer.

Example 4: Preparation of a composite formulation comprising a melatonin sustained release layer and a sertraline immediate release layer (4)

The bilayer tablet was prepared in the same manner as in Comparative Example 1, except that instead of Eudragit RSPO used as a release maintaining agent, polyvinyl alcohol (PVA) was used to form particles of the sustained release layer.

Example 5: Preparation of a composite formulation comprising a melatonin sustained release layer and a sertraline immediate release layer (5)

The bilayer tablet was prepared in the same manner as in Comparative Example 1, except that instead of the Eudragit RSPO used as a release maintaining agent, carbomer was used to form particles of the sustained release layer.

The compositions of the bilayer tablets according to Comparative Example 1 and Examples 1 to 5 are shown in Tables 1 and 2.

Example 6: Preparation of a composite formulation comprising a melatonin sustained release layer and a sertraline immediate release layer (6)

A bilayer tablet was prepared in the same manner as in Example 1, except that instead of using hydroxypropylmethylcellulose (Eudragit HPMC 2910, 4000 cps) as a release maintenance agent, HPMC (15,000 cps) was used to form a sustained release layer. The particles, and the composition was changed as shown in Table 3.

Test Example 1: Comparative dissolution test

1.2 buffer at 12 kinds of composite lozenges each of Comparative Example 1 and of Example 1 into about 900M l of pH (in the Korean Pharmacopoeia disintegration test method used in the first solution, having about 0.1 Mol/L HCl concentration hydrochloric acid solution and sodium chloride to prepare buffer solution), pH 4.0 buffer (0.05 mol/L sodium acetate buffer solution), pH 6.8 buffer (disintegration test method in Korean Pharmacopoeia) After using the second solution, using a buffer solution prepared with about 0.2 mol/L potassium dihydrogen phosphate reagent and about 0.2 mol/L sodium hydroxide reagent) or distilled water, the dissolution test is performed at about 37 ° C and 50 rpm according to the Korean Pharmacopoeia. The dissolution method II (blade method) is carried out. The results of measuring the dissolution rate of sertraline with respect to time are shown in Table 4, Figure 2 (Comparative Example 1) and Figure 3 (Example 1). The results of measuring the melatonin dissolution rate with respect to time are shown in Table 5, Figure 4 (Comparative Example 1) and Figure 5 (Example 1).

According to test results, compared with reference to their use as Zoloft ^® tablets of the immediate release nature of the drug, found Comparative Example 1 and Example 1 composite tablets each having the equal or better of immediate release properties at all tested pH conditions .

However, Circadin ^® sustained release melatonin compared to the dissolution rate of the tablets, the compound was found in Comparative Example 1 agent of melatonin significantly higher dissolution rate, and in the example compound in the tablets of melatonin 1 Hormone dissolution rates are very similar.

Test Example 2: Dissolution test for a bilayer tablet using a different gel to form a polymer

4.0 900M l of buffer at about pH (about 0.05mol / L of sodium acetate buffer solution) at about about 37 [deg.] C at 50rpm according to the Korean Pharmacopoeia dissolution method II (paddle method), Comparative Example 1 and Example A dissolution test was performed on each of the composite tablets of 1 to 5.

The dissolution rate of sertraline as an active ingredient of the immediate release layer was measured after 45 minutes. The results are shown in Table 6.

The dissolution rate of melatonin as an active ingredient of the sustained release layer was measured after 1 hour, 2 hours, and 8 hours. The results are shown in Table 7.

According to test results, found that Comparative Example 1 and Examples 1 to 5 of the composite tablets having the drug as a reference of their Zoloft ^® tablets of similar sertraline dissolution rate similar to an immediate release properties.

However, as the reference drug of Circadin ^® compared to sustained release lozenges, troches found comparison compound of Example 1 has significantly higher dissolution rate melatonin, troches and the compound of Examples 1 to 5 having a sustained release lozenges Circadin ^® the agents of their very similar sustained release characteristics, corresponding to the desired sustained release Circadin ^® sustained release properties of the content of the lozenges.

Test Example 3: In view of the viscosity test for the dissolution of the double-layer tablet

The melatonin dissolution test was performed on the composite tablets of Examples 1 and 6 in the same manner as Test Example 1 at pH 4.0. The dissolution test results are shown in Table 8.

According to the test result, a composite Example 1 and Example 6 of the lozenges have very similar properties as the reference sustained release of the medicament Circadin ^® sustained release tablets of sustained release of their nature, corresponding to Circadin ^® sustained release tablets of The desired level of sustained release properties.

Although the present invention has been particularly shown and described with respect to the preferred embodiments of the present invention, it will be understood by those of ordinary skill in the art Spirit and scope. The disclosed embodiments should be considered in a descriptive sense only and not for the purpose of limitation. Therefore, the scope of the invention is defined by the appended claims and the claims

Claims (17)

An oral complex lozenge comprising: a sustained release layer comprising melatonin or a pharmaceutically acceptable salt thereof, and a gel forming polymer as a release maintenance agent; and an immediate release layer comprising Sertraline or a pharmaceutically acceptable salt thereof. The oral composite lozenge of claim 1, wherein the aforementioned sustained release layer and the aforementioned immediate release layer are formed by ingoting respective particles thereof. The oral composite tablet according to claim 1, wherein the particles are wet particles. The oral complex lozenge according to claim 1, wherein the oral composite lozenge comprises a bilayer tablet of the aforementioned sustained release layer and the immediate release layer. The oral complex lozenge of claim 1, wherein the gel-forming polymer has a gel-forming polymer having a viscosity of from about 4,000 cps to about 15,000 cps. The oral complex tablet according to claim 1, wherein the gel-forming polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), and polyvinylpyrrolidone ( PVP), polyvinyl alcohol (PVA), carbomer, hydroxypropyl cellulose (HPC), methyl cellulose (MC), sodium carboxymethyl cellulose (CMC-Na), propylene oxide (PO) and Any combination. The oral composite tablet according to claim 1, wherein the sustained release layer further comprises a pharmaceutically acceptable additive selected from the group consisting of a diluent, a disintegrant, a lubricant, and any of them. combination. The oral complex lozenge according to claim 7, wherein the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and dibasic calcium phosphate. Any combination thereof; the aforementioned disintegrant is selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, and cross-complex Ketone, pregelatinized starch, sodium starch glycolate, starch, and any combination thereof; the aforementioned lubricant is selected from the group consisting of calcium stearate, glyceryl monostearate, palmitoyl stearate, hard Magnesium citrate, sodium lauryl sulfate, sodium stearate, sodium stearate, stearic acid, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, cerium oxide, talc, and any combination thereof. The oral complex lozenge of claim 1, wherein the immediate release layer further comprises a pharmaceutically acceptable additive selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any of them combination. The oral complex lozenge according to claim 9, wherein the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, sucrose, Lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate, and any combination thereof; the foregoing binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone ( PVP), pregelatinized starch and any combination thereof; the aforementioned disintegrant is selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, crosslinked carboxymethyl Cellulose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, starch, and any combination thereof; the aforementioned lubricant is selected from the group consisting of calcium stearate, cerium oxide, glyceryl monostearyl Acid esters, palmitoyl glyceryl stearate, magnesium stearate, sodium lauryl sulfate, sodium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and its Any combination. The oral composite lozenge according to claim 1, wherein the oral composite lozenge has the aforementioned one as evaluated using a USP dissolution test II (blade method) in an aqueous buffer solution of pH 4.0 at about 37 ± 0.5 ° C and about 50 rpm. The dissolution test is about 25 wt% to about 50 wt% for about 1 hour, the dissolution test is about 40 wt% to about 65 wt% for about 2 hours, and the dissolution rate of one of the aforementioned melatonins is about 75 wt% or more for about 8 hours in the aforementioned dissolution test; The aforementioned dissolution test measures the dissolution rate of one of the aforementioned sertraline of about 75 wt% or more for about 45 minutes. The oral complex lozenge of claim 1, wherein the aforementioned amount of the melatonin in the form of melatonin free base is from about 1 mg to about 8 mg per single unit dosage form. The oral complex lozenge according to claim 1, wherein the aforementioned sertraline is sertraline hydrochloride, and the aforementioned amount of the sertraline in the form of a sertraline free base is about 25 mg per single unit dosage form. Up to about 200mg. The oral complex lozenge according to claim 1, wherein the oral complex lozenge is used for treating or improving nocturnal eating syndrome (NES). A method of preparing an oral complex lozenge according to any one of claims 1 to 14, comprising the steps of: preparing melatonin particles, including melatonin or a pharmaceutically acceptable salt thereof, and maintaining as a release Gel forming polymer; preparing sertraline particles, including sertraline or a pharmaceutically acceptable salt thereof; and injecting the aforementioned sertraline particles into an immediate release layer using a two-layer tablet press The aforementioned melatonin particles are added thereto, and a resulting mixture is tableted, thereby forming a bilayer tablet. The method of claim 15, wherein the preparing melatonin particles comprises: granulating melatonin or a pharmaceutically acceptable salt thereof with a pharmaceutical additive not comprising the gel forming polymer and a lubricant; And drying a resultant product to form granules; mixing the aforementioned granules with the aforementioned gel forming polymer And then mixed with the aforementioned lubricant. The method of claim 15, wherein in the foregoing formation of the bilayer tablet, the aforementioned tablet of the sertraline particles is performed at about 1.5 kp to about 6 kp, and the aforementioned tablet after the addition of the aforementioned melatonin particles Executed at about 8kp to about 16kp.