WO2016108507A2 - Composite tablet for oral administration comprising melatonin and sertraline - Google Patents

Abstract

The present invention provides a composite tablet for oral administration and a method for manufacturing the same, the composite tablet for oral administration comprising: a sustained release layer including melatonin or a pharmaceutically acceptable salt thereof, and a gel-forming polymer as a sustained release agent; and an immediate release layer including sertraline or a pharmaceutically acceptable salt thereof.

Description

Oral Combination Tablets Containing Melatonin and Sultraline

The present invention relates to an oral complex tablet comprising melatonin and sulfalin as active ingredients, and more particularly, to a complex tablet comprising a sustained release layer of melatonin and a rapid release layer of sulfaline.

Melatonin is a hormone secreted from the pineal gland of the brain having the structure of 5-methoxy-N-acetyl-tryptamine and plays a major role in induction and regulation of sleep. Melatonin is effective in the treatment of sleep disorders resulting from abnormal production of melatonin due to aging-related diseases or the use of certain agents (eg, beta adrenoceptor blockers). Melatonin is known to reduce the time it takes to fall asleep and to improve sleep quality and daytime activity. Melatonin is standing kadin ^® (Circadin ^®) are commercially available as a product name of a sustained release oral sex tablets (tablet) forms. Circadine ^® is a sustained release matrix in the form of a matrix containing Eudragit RSPO (Ammonio Methacrylate Copolymer, Type B) corresponding to acrylic resin as a sustained release agent. Melatonin has a short half-life of 35 to 50 minutes, which is not sufficient, but circadine increases the half-life to 3.5 to 4 hours due to the sustained release technology, which can release a certain amount for 8 to 10 hours. . Circadine is a dissolution test for the release of melatonin from 25 to 50% by weight for 1 hour, 40 to 65% by weight for 2 hours, and 80% by weight for 8 hours. It is a standard.

Sultralin is a selective serotonin reuptake inhibitor (SSRI) having a structure of the following formula and is widely used as an antidepressant drug.

[Formula 1]

Sertraline is primarily used in the form of the hydrochloride to the solubility increases, the sertraline hydrochloride are commercially available in the form Zoloft ^® (Zoloft ^®) tablets for oral use (tablet) in the immediate release of a product name. Zoloput ^® is used to treat depression, panic disorder, obsessive compulsive disorder, or post traumatic stress disorder.

Night Eating Syndrome (NES) was the first disease published in 1955 by Dr. Albert Stunkard of the United States. After 7 o'clock, the meal accounts for more than 50% of the total daily intake, which is represented by insomnia. People with this condition usually skip breakfast or eat small amounts, eat roughly lunch, and eat more than half of their daily intake only in the evening. In addition, people sleep at night for more than three days a week or wake up, or often do not have symptoms that fall asleep. The cause is not yet clear, but psychological and psychological problems such as abnormal reactions to stress, depression and anxiety, and loss of confidence are known. Supper reduces melatonin, a sleep hormone to half of normal levels, and also reduces the secretion of leptin, a hormone that suppresses appetite. This leads to a vicious cycle of not getting enough sleep at night and not eating appetite.

There are many studies showing that patients with late night syndrome have low levels of melatonin (Non Patent Literatures 1 and 2). Exogenous melatonin lowers the gastric emptying rate (GER). It has been reported to be effective (Non Patent Literature 3). In addition, agomelatine, a melatonin agonist, has been reported to be effective in treating late night syndrome by controlling sleep cycle and appetite (Non-Patent Document 4).

Sultraline has also been shown to be effective in the treatment of late night syndrome (Non Patent Literatures 5 and 6), and improved serotonin function is associated with alleviation of symptoms of late night syndrome. The use of SSRI (Selective Serotonin Reuptake Inhibitor) has been reported to be recommended (Non-Patent Document 7).

[Preceding technical literature]

[Non-Patent Documents]

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.

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

3. 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.

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

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.

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

It is an object of the present invention to provide oral combined tablets of melatonin and sultraline having sustained release of melatonin and immediate release of sultraline.

Another object of the present invention is to provide a method for preparing oral complex tablets of melatonin and sulfalin.

One aspect of the invention

A sustained release layer containing melatonin or a pharmaceutically acceptable salt thereof, and a gelling polymer as a sustained release agent; And

Provided is an oral combined tablet comprising an immediate release layer containing sulfalin or a pharmaceutically acceptable salt thereof.

Another aspect of the invention

Preparing melatonin granules containing melatonin or a pharmaceutically acceptable salt thereof and a gel forming polymer as a sustained release carrier;

Preparing a granulline granule comprising a sulfalline or a pharmaceutically acceptable salt thereof; And

It provides a method for producing an oral complex tablet according to an aspect of the present invention, comprising the step of preparing the bilayer tablet by the tableting the sulfaline granules in a bilayer tablet press, and then adding the melatonin granules. .

The oral combination tablet according to the present invention forms a gel matrix of the gel-forming polymer present in the melatonin-containing sustained release layer upon administration into the body, and due to the viscosity of the gel matrix, the slow release layer and The phenomenon that the matrix of the sustained release layer of the interface portion between the immediate release layer is not broken does not occur, and thus the melatonin sustained release of the sustained release layer can be maintained without being impaired. Therefore, the combination tablet according to the present invention can simultaneously administer melatonin and sulfalin as one unit dosage form, while having the same release properties as each active ingredient, and thus have the same efficacy as when each is administered as a separate unit dosage form. Can be exercised. Therefore, in the treatment of a patient having a disease requiring a combination administration of melatonin and sulfalin, such as a night-time syndrome, it is possible to effectively treat a single unit dosage form while effectively treating the patient, thereby improving patient compliance.

1 is a schematic diagram of a bilayer tablet according to an aspect of the present invention, and a drug release pattern of the same melatonin sustained release layer and sulfalline immediate release double layer tablet as in the conventional single formulation.

Figure 2 is a graph showing the results of measuring the dissolution rate of sulftralin of bilayer tablet of Comparative Example 1 in pH 1.2, 4.0, 6.8, or distilled water over time.

3 is a graph showing the results of measurement of the dissolution rate of sulftralin in bilayer tablet of Example 1 in pH 1.2, 4.0, 6.8, or distilled water over time.

4 is a graph showing the results of measuring the dissolution rate of melatonin of the bilayer tablet of Comparative Example 1 in pH 1.2, 4.0, 6.8, or distilled water over time.

5 is a graph showing the results of measuring the dissolution rate of melatonin of the bilayer tablet of Example 1 in pH 1.2, 4.0, 6.8, or distilled water over time.

All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

One aspect of the invention

A sustained release layer containing melatonin or a pharmaceutically acceptable salt thereof, and a gelling polymer as a sustained release agent; And

Provided is an oral combined tablet comprising an immediate release layer containing sulfalin or a pharmaceutically acceptable salt thereof.

The oral complex tablet may be in the form of a two-layer tablet including a sustained release layer and an immediate release layer. Hereinafter, the oral composite tablet will be described by dividing it into a sustained release layer, an immediate release layer, and a bilayer tablet.

(i) Western layer

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

As used herein, “melatonin or a pharmaceutically acceptable salt thereof” is understood to include melatonin, melatonin analogs, pharmaceutically acceptable salts or esters thereof, or prodrugs thereof known in the art. In one embodiment, the melatonin or a pharmaceutically acceptable salt thereof is a melatonin free base.

The combined tablet may contain about 1-8 mg of melatonin free base per unit dosage form, for example 2 mg per unit dosage form.

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

The gel forming polymer may be any gel forming polymer known in the art as a sustained release agent. The gel-forming polymer is, for example, hydroxypropyl methyl cellulose (HPMC), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carbomer (carbomer), hydroxypropyl cellulose (HPC), methylcellulose (MC), carboxymethylcellulose sodium (CMC-Na), propylene oxide (PO), and any combination thereof. In one embodiment, the gelling polymer is a gelling polymer having a viscosity of 4,000-100,000 cps, more specifically a gelling polymer having 4,000-15,000 cps. In another embodiment the gel-forming polymer is hydroxypropylmethylcellulose. In another embodiment, the hydroxypropylmethylcellulose has a viscosity of 4,000-100,000 cps. In another embodiment, the gelling polymer is HPMC 2910 (4000 cps).

The gel-forming polymer may be contained in an amount of 20 to 70 parts by weight, specifically about 20 to 50 parts by weight, relative to 1 part by weight of melatonin or a pharmaceutically acceptable salt thereof.

The gel-forming polymer enables the sustained release of melatonin or a pharmaceutically acceptable salt thereof, which is the active ingredient of the sustained release layer in the composite tablet of the present invention. As a result of the experiment, using a Eudragit RSPO, a methacryl-based copolymer, a sustained-release agent contained in the cadcarine sustained-release tablet, a two-layer including a sustained-release layer of the same prescription as circadine sustained-release tablet and a sulfalline-containing immediate release layer of the same prescription as zolopute Elution test of melatonin after preparing tablets showed that sustained release of melatonin was not obtained, and the dissolution rate of melatonin was remarkably faster than that of circadine. In contrast, the sustained-release composite tablet according to the present invention was prepared by introducing a gel-forming polymer instead of Eudragit RSPO in the preparation of a sustained release layer, and found to have a sustained release property very similar to that of the conventional circadine sustained-release tablet ( See Test Examples 1-2.

The sustained release layer may further comprise a pharmaceutically acceptable additive selected from the group consisting of diluents, 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 one embodiment, the diluent is a combination of lactose and calcium hydrogen phosphate. The diluent may be contained in an amount of 15 to 45 parts by weight relative to 1 part by weight of melatonin or a pharmaceutically acceptable salt thereof.

The disintegrant is a group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolate, starch, and any combination thereof. It may be selected from, but is not limited thereto. The disintegrant may be contained in an amount of 10 to 40 parts by weight based on 100 parts by weight of melatonin or a pharmaceutically acceptable salt thereof.

The glidants include calcium stearate, silicon dioxide, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene It may be selected from the group consisting of glycol, sodium benzoate, talc and any combination thereof, but is not limited thereto. In one embodiment, the glidant is a combination of magnesium stearate and silicon dioxide. The glidant may be contained in an amount of 0.5-4 parts by weight, specifically 0.7-3 parts by weight, based on 1 part by weight of melatonin or a pharmaceutically acceptable salt thereof.

(ii) immediate release

The immediate release layer contains, as active ingredient, sulfalin or a pharmaceutically acceptable salt thereof.

As used herein, “sultraline or pharmaceutically acceptable salts thereof” refers to those known in the art, such as those used in the art, including, but not limited to, saltralines, sulftraline analogs, pharmaceutically acceptable salts or esters thereof, or prodrugs thereof. It is to be interpreted as including.

Pharmaceutically acceptable salts of the sulfalins include addition salts and include, for example, salts of hydrochloric acid, salts of salts of salt, salts of salts of salts such as salts of salts such as salts of salts such as salts of salts. In one embodiment, the pharmaceutically acceptable salt of sultraline is sultraline hydrochloride.

The multi-tablet may contain about 25-200 mg of sulfalin free base per unit dosage form. In one embodiment, 50 mg or 100 mg is contained per unit dosage form, which corresponds to 55.95 mg or 111.9 mg, respectively, as sulfalin hydrochloride.

The immediate release layer may be formed by tableting granules of a mixture comprising sulfalin or a pharmaceutically acceptable salt thereof, the granules comprising dry or wet granules. In one embodiment, the granules are wet granules.

The immediate release layer may comprise, in addition to the active ingredient, any pharmaceutically acceptable additives known in the art for the preparation of the granules. The pharmaceutically acceptable additive may be selected from the group consisting of diluents, binders, disintegrants, glidants, 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 one embodiment, the diluent is a combination of lactose and calcium hydrogen phosphate. The diluent may be contained in an amount of 100 to 180 parts by weight, specifically 120 to 150 parts by weight, relative to 100 parts by weight of the sulfalin or a pharmaceutically acceptable salt thereof.

The binder may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone (PVP), pregelatinized starch, and any combination thereof, but is not limited thereto. In one embodiment, the binder is hydroxypropylcellulose. The binder may be contained in an amount of 0.4-3 parts by weight, specifically 0.7-2 parts by weight, relative to 100 parts by weight of the sulfalin or a pharmaceutically acceptable salt thereof.

The disintegrant may be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolate, starch and mixtures thereof. However, the present invention is not limited thereto. In one embodiment, the disintegrant is sodium starch glycolate. The disintegrant may be contained in an amount of 10 to 30 parts by weight, specifically 15 to 20 parts by weight, relative to 100 parts by weight of the sulfaline or a pharmaceutically acceptable salt thereof.

The glidants include calcium stearate, silicon dioxide, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene It may be selected from the group consisting of glycol, sodium benzoate, talc and any combination thereof, but is not limited thereto. In one embodiment, the glidant is a combination of magnesium stearate and silicon dioxide. The glidant may be contained in an amount of 3 to 10 parts by weight, specifically 3 to 8 parts by weight, relative to 100 parts by weight of the sulfaline or a pharmaceutically acceptable salt thereof.

(iii) two-story tablet

The bilayer tablet comprises granules of the mixture containing the melatonin or a pharmaceutically acceptable salt thereof, and a gel-forming polymer as a sustained release agent as the first layer (the sustained release layer), and a sulfaline or a pharmaceutically acceptable salt thereof. It can be formed by tableting in the form of a bilayer tablet, using the granules of the mixture as a second layer (the immediate release layer). The bilayer tablet may include both a melatonin-containing sustained release layer and a sultraline-containing immediate release layer in one formulation, thereby achieving both a sustained effect of melatonin and a rapid effect of sultraline due to the sustained release of melatonin (Test Examples 1 to 2). 3).

In contrast, when the sustained-layer layer was prepared by containing Eudragit RSPO, a sustained-release agent contained in conventional cadcardine sustained-release tablets rather than gel-forming polymers, the bilayer tablet showed a significantly faster melatonin dissolution rate than circadine sustained-release information and thus did not exhibit desired sustained release properties. can not do it. In order to prepare a bilayer tablet showing sustained release of melatonin and immediate release of sultanaline, the present inventors have introduced each tablet formulation of zoloft, which is a single agent of melatonin, which is a commercially available melatonin, and a single formulation of sultraline. After granulating each of them, an attempt was made to manufacture a double layer tablet with a double layer tablet press (see Comparative Example 1). However, when the bilayer tablet was prepared by such a prescription, it was shown that the sustained release of melatonin in the sustained release layer did not maintain the sustained release of circadine (see Test Example 1). As a result of the study, when a gel-forming polymer was introduced as a sustained release agent instead of the methacryl sustained release agent used in circadine, a sustained release layer was prepared, but the sustained release of melatonin was maintained similar to that of circadine. (See Test Example 1). In order to maintain a single tablet without separating the immediate release layer and the sustained release layer in the two-layered tablet, a close bond between the immediate release layer and the sustained release layer is required, and a sustained release layer containing a methacrylate-based sustained release agent such as Eudragit RSPO In case of disintegration of the immediate release layer in the body, the interface of the release layer, which is in close contact with the release layer, is broken due to the effect of the release layer, thereby increasing the dissolution rate of the melatonin drug in the release layer (see FIG. 1A). The sustained release layer containing the polymer appears to be due to the fact that the gel formed rapidly by the gel-forming polymer before the impact of the disintegration of the immediate release layer in the body can surround the interface of the sustained release layer to protect the sustained release layer from the effect of the immediate release layer. (See B of FIG. 1). The breakage of the interface of the sustained release layer is believed to widen or enlarge the drug release channel of the methacrylate structure of Eudragit RSPO, which is a sustained release agent forming a sustained release matrix, upon the disintegration of the immediate release layer.

In methacrylate copolymer sustained release agents such as Eudragit RSPO, the drug is slowly released while the drug in the matrix is gradually diffused while the matrix form is maintained, whereas sustained release agents such as gel-forming polymers are formed in the gel form by the absorption of the matrix. As it grows, the drug in the matrix diffuses and is released, while the surface of the matrix slowly melts and releases slowly. Therefore, when the matrix of Eudragit RSPO contained in the sustained release layer is broken by the disintegration of the immediate release layer, the sustained release pattern of the sustained release drug through the matrix is not maintained but a large amount is released (A in FIG. 1A). Since the matrix of the gel-forming polymer contained in the sustained release layer is formed rapidly by moisture absorption, the gel matrix is not damaged due to the disintegration of the immediate release layer due to the viscosity, so that the sustained release pattern of the sustained release drug is maintained. (See B in FIG. 1). Such, the schematic diagram of the drug release pattern of the two-layered tablet according to an aspect of the present invention (Fig. 1A) and the drug release pattern of the two-layered tablet prepared by introducing into the sustained-release layer and immediate release layer of the conventional single formulation as it is. Is shown in FIG.

In one embodiment, the bilayer tablets are eluted at 50 rpm in an aqueous buffer solution at 37 ± 0.5 ° C., pH 4.0 according to the second method paddle method according to the USP. At a dissolution rate of 40-65% by weight for 2 hours, at least 75% by weight for 8 hours, and sulfalin at least 75% by weight for 45 minutes.

The two-layered tablet can maintain the sustained release of the conventional melatonin monotherapy and the immediate release of the sulfaline mono formulation while maintaining the melatonin mono- and sulfalin mono-forms as one unit. The drug can be retained as it is. Therefore, if it is necessary to take two unit dosage forms, only one combination tablet according to one aspect of the present invention can be administered, thereby increasing patient compliance.

The two-layered tablet may further include a film coating layer on the outer surface. The film coating layer may include any film coating agent and colorant exhibiting rapid release. The film coating agent may be a mixture of HPC and HPMC, or a mixture of polyvinyl alcohol (PVA) and PEG (polyethylene glycol), but is not limited thereto. The colorant includes titanium dioxide, iron oxide, and the like, but is not limited thereto. A commercially available representative film coating agent is Opadry. The film coating layer may serve to mask the taste and to impart stability to the final composite tablet.

In one embodiment, the double-layered tablet may be used for the treatment or amelioration of late night syndrome, and the double-layered tablet may be administered as a dosage administered to treat the late night syndrome for the treatment or amelioration of the late night syndrome. Depending on the gender, age, weight, race, and severity of the disease, it may increase or decrease at the discretion of the expert. In one embodiment, the bilayer tablet may be administered once a day, twice a day, three times a day, or four times a day.

Another aspect of the invention

Preparing melatonin granules containing melatonin or a pharmaceutically acceptable salt thereof and a gel forming polymer as a sustained release carrier;

Preparing a granulline granule comprising a sulfalline or a pharmaceutically acceptable salt thereof; And

The tablet of the oral tablet according to an aspect of the present invention, comprising the step of forming the immediate release layer by tableting the sulfalin granules in a two-layer tableting machine, and then adding the melatonin granules to tableting. It provides a manufacturing method.

Details of the method for producing a composite tablet may be applied to the description of the composite tablet according to the aspect of the present invention.

When tableting the bilayer tablet, changing the tableting order of the tablets of the sultraline granules and the melatonin granules, it is possible to increase the mixing of the granules in the immediate release and the granules in the sustained release at the interface of the bilayer tablet. As the incorporation increases, the sustained release matrix of the interface may be more affected by the disintegration of the immediate release layer, and thus the initial dissolution rate of the sustained release drug may increase.

 In one embodiment, the step of preparing the melatonin granules

Associating and drying melatonin or a pharmaceutically acceptable salt thereof with the pharmaceutical additives excluding the gelling polymer and the lubricant to form granules; And

The formed granules may be mixed with the gel forming polymer and then the lubricant is mixed.

In the step of preparing the bilayer tablet, the tableting of the sulfallin granules may be performed at 1.5-6 kp, and the tableting of the melatonin granules may be performed at 8-16 kp. As described above, in order for each layer of the two-layered tablet not to be separated from each other and the two-layered tablet is formed properly, the interface between the sustained-release layer and the immediate release layer must be closely coupled. When the tableting pressure is too large during the tableting of the immediate release layer, even after the sustained release granules are added and tableted, the immediate release layer and the sustained release layer tend to be separated from each other without bonding to each other. In addition, when the tableting pressure is too small during the tableting of the immediate release layer, the formation of the immediate release layer may not be performed properly. In addition, when the tablet of the sustained release layer is harder than the tableting pressure of the immediate release layer, the interface between the sustained release layer and the immediate release layer may be tightly coupled.

The process of each step involved in the preparation of the composite tablet may be carried out based on a conventional bilayer tablet manufacturing process performed in the art.

EXAMPLE

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Comparative Example 1 Preparation of a Composite Formulation Having the Same Melatonin Sustained Release Layer and Sultraline Immediate Release Layer as in the Previous Single-Formulation

The fast-release layer granules were prepared according to the composition of Table 1 below, the sustained-release layer granules were prepared according to the composition of Table 2, and then double-layered tablets were prepared.

For the preparation of immediate release granules, sulfalin (or a salt thereof), calcium hydrogen phosphate, lactose, and sodium starch glycolate are mixed and combined and dried using a binder solution made by dissolving hydroxypropyl cellulose in water. Granules were prepared and then silicon dioxide and magnesium stearate were mixed.

For the production of sustained-layer granules, eudragit, calcium hydrogen phosphate, and lactose are mixed, combined and dried using a binder solution made of a mixture of melatonin and methanol to prepare granules, and then the granules are Eudragit RSPO was added and mixed, followed by silicon dioxide and magnesium stearate.

First, the immediate release layer granules were first tableted to a hardness of 2.0 kp, followed by secondary tableting by filling the sustained layer granules thereon to prepare a double-layered tablet.

Example 1 Preparation of a Composite Formulation Having a Melatonin Sustained Release Layer and a Sultraline Immediate Release Layer (1)

It is the same as the preparation method of Comparative Example 1, except that instead of using the Eudragit RSPO of Comparative Example 1 as a sustained release base in the preparation of the sustained-layer granules hydroxypropylmethylcellulose (HPMC 2910, 4000 cps) Except, prepared in the same way

Example 2 Preparation of a Composite Formulation Having a Melatonin Sustained Release Layer and a Sultraline Immediate Release Layer (2)

The same method as the preparation method of Comparative Example 1, except for using the polyethylene oxide (PEO) instead of using the Eudragit RSPO of Comparative Example 1 as a sustained release base when preparing the sustained-layer granules, It was.

Example 3 Preparation of a Composite Formulation Having a Melatonin Sustained Release Layer and a Sultraline Immediate Release Layer (3)

Same as the preparation method of Comparative Example 1, except for using the polyvinylpyrrolidone (PVP) instead of using the Eudragit RSPO of Comparative Example 1 as a sustained release base in the production of sustained-layer granules It was prepared by the method.

Example 4 Preparation of a Composite Formulation Having a Melatonin Sustained Release Layer and a Sultraline Immediate Release Layer (4)

In the same manner as in Preparation Method of Comparative Example 1, except that polyvinyl alcohol (PVA) was used instead of Eudragit RSPO of Comparative Example 1 as a sustained release base when preparing sustained-layer granules. Prepared.

Example 5 Preparation of a Composite Formulation Having a Melatonin Sustained Release Layer and a Sultraline Immediate Release Layer (5)

It was prepared in the same manner as in Preparation Method of Comparative Example 1, except that carbomer was used instead of Eudragit RSPO of Comparative Example 1 as a sustained release base when preparing sustained-layer granules.

The formulation of Comparative Example 1 and Example 1-5 are summarized in Tables 1 and 2 below.

TABLE 1

TABLE 2

Example 6 Preparation of a Composite Formulation Having a Melatonin Sustained Release Layer and a Sultraline Immediate Release Layer (6)

It is the same as the preparation method of Example 1, but using the HPMC 15,000cps instead of using the Eudragit HPMC 4000 cps of Example 1 as a sustained release base in the production of sustained-layer granules and using the prescription of Table 3 below Except for the same method.

TABLE 3

Test Example 1: Comparative Dissolution Test

pH 1.2 (buffer prepared with hydrochloric acid and sodium chloride with a concentration of about 0.1 mol / L hydrochloric acid as the first solution of the Korean Pharmacopoeia Disintegration Test Method), 4.0 (0.05 mol / L Sodium Acetate buffer), or 6.8 (Korea Pharmacopoeia Disintegration) 12 complex tablets of Comparative Example 1 or Example 1 in a buffer of distilled water or a buffer of 0.2 mol / L potassium dihydrogen phosphate solution and a buffer prepared by using 0.2 mol / L sodium hydroxide solution Into, the dissolution test was carried out under the conditions of about 37 ℃, 50 rpm according to the paddle method of the Korean Pharmacopoeia 2 method. The results of measuring the dissolution rate of sulfallin over time are shown in Table 4 and FIG. 2 (Comparative Example 1) and FIG. 3 (Example 1). In addition, the results of measuring the dissolution rate of melatonin over time are shown in Table 5, and Figure 4 (Comparative Example 1), Figure 5 (Example 1).

TABLE 4

TABLE 5

According to the results of the experiment, the dissolution rate of sulfallin was shown to have a rapid release or more equivalent to the zolofute as a reference drug in all pH conditions in Comparative Example 1 and Example 1.

On the contrary, the melatonin dissolution rate was found to be significantly faster than the comparative drug circadian sustained-release tablet melatonin dissolution rate, whereas in Example 1, the melatonin dissolution rate was very similar to the circadine sustained-release tablet.

Test Example 2 Dissolution Test of Two-Layered Tablet According to Kind of Gel-forming Polymer

To 900 mL of pH 4.0 buffer (0.05 mol / L sodium acetate buffer solution), the test drug was added, and the composite tablets of Comparative Example 1 and Example 1-5 were treated at 37 ° C. and 50 rpm in accordance with the method of the Korean Pharmacopoeia 2 method. A dissolution test was performed.

The dissolution rate was measured after 45 minutes for the active ingredient of rapid release layer, and the results are shown in Table 6 below.

Melatonin, the active ingredient of the sustained release layer, measured the dissolution rate after 1 hour, 2 hours, and 8 hours, and the results are shown in Table 7 below.

TABLE 6

TABLE 7

According to the experimental results, Comparative Example 1 and Example 1-5 was found to have a rapid release of the sulfalline dissolution rate similar to the zolofute as a reference.

On the other hand, while the melatonin dissolution rate was shown to be significantly faster than Comparative Example 1, the circadian sustained release tablet, Example 1-5 has a very similar sustained release to the circadine sustained release tablet, Appeared to match.

Test Example 3 Dissolution Test of Two-Layered Tablet According to Viscosity

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

TABLE 8

According to the experimental results, the melatonin elution rate of Example 1 and Example 6 both had a sustained release very similar to the circadian sustained-release tablet, the control drug, it was found to meet the sustained-release elution criteria of circadine sustained-release tablet.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (17)

1. A sustained release layer containing melatonin or a pharmaceutically acceptable salt thereof, and a gelling polymer as a sustained release agent; And

   An oral combined tablet comprising an immediate release layer containing sulfalin or a pharmaceutically acceptable salt thereof.
2. According to claim 1, wherein the sustained release layer and the immediate release layer is formed by tableting granules, respectively, oral complex tablets.
3. The oral combined tablet according to claim 1, wherein the granules are wet granules.
4. The oral complex tablet according to claim 1, wherein the oral complex tablet is a bilayer tablet including the sustained release layer and the immediate release layer.
5. The oral combined tablet of claim 1, wherein the gelling polymer is a gelling polymer having a viscosity of 4,000-15,000 cps.
6. The method of claim 1, wherein the gel-forming polymer is hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carbomer, hydroxy Oral complex tablets selected from the group consisting of propyl cellulose (HPC), methyl cellulose (MC), sodium carboxymethyl cellulose (CMC-Na), propylene oxide (PO), and any combination thereof.
7. According to claim 1, wherein the sustained release layer is an oral combination tablet further comprises a pharmaceutical additive selected from the group consisting of diluents, disintegrants, lubricants, and any combination thereof.
8. The method of claim 7, wherein

   The diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate, and any combination thereof,

   The disintegrant is a group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolate, starch, and any combination thereof. Is selected from,

   The lubricant is calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene Oral combination tablet selected from the group consisting of glycol, sodium benzoate, silicon dioxide, talc and any combination thereof.
9. The oral complex tablet according to claim 1, wherein the immediate release layer is selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any combination thereof.
10. The method of claim 9,

    The diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate, and any combination thereof,

    The binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone (PVP), pregelatinized starch, and any combination thereof,

    The disintegrant is a group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolate, starch, and any combination thereof. Is selected from,

    The glidants include calcium stearate, silicon dioxide, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene Oral combination tablet selected from the group consisting of glycol, sodium benzoate, talc, and any combination thereof.
11. According to claim 1, when the dissolution test at 50 rpm in an aqueous buffer of 37 ± 0.5 ℃, pH 4.0 according to the second method paddle method according to the USP

    Melatonin has a dissolution rate of 25-50 wt% for 1 hour, 40-65 wt% for 2 hours, 75 wt% or more for 8 hours,

    The oral combination tablet of which sulfallin shows an elution rate of 75% by weight or more for 45 minutes.
12. The oral combination tablet according to claim 1, wherein the melatonin is contained in an amount of 1-8 mg per unit dosage form as the melatonin free base.
13. The oral combination tablet according to claim 1, wherein the sulfalin is salt of sulfaline hydrochloride and is contained in an amount of 25-200 mg per unit dosage form as a salt of salt.
14. The oral combination tablet of claim 1, wherein the oral combined tablet is for treating or improving late night syndrome.
15. Preparing melatonin granules containing melatonin or a pharmaceutically acceptable salt thereof and a gel forming polymer as a sustained release carrier;

    Preparing a granulline granule comprising a sulfalline or a pharmaceutically acceptable salt thereof; And

    According to any one of claims 1 to 14, comprising the step of preparing the immediate release layer by the tableting of the salt of granules in a two-layer tableting machine, and then by adding the melatonin granules to tableting. Method for preparing oral complex tablets.
16. The method of claim 15, wherein preparing the melatonin granules

    Associating and drying melatonin or a pharmaceutically acceptable salt thereof with the pharmaceutical additives excluding the gelling polymer and the lubricant to form granules;

    Mixing the formed granules together with the gel-forming polymer, and then mixing the lubricants.
17. 16. The method according to claim 15, wherein in the step of preparing the bilayer tablet, the tableting of the salt of granules is carried out at 1.5 6 kp, and the tableting after adding the melatonin granules is performed at 8-16 kp.

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