KR20220085746A - Double layer tablet for controlled release of clomipramine hydrochloride and preparation method thereof - Google Patents

Abstract

The present invention relates to a double tablet having clomipramine hydrochloride as an active ingredient for the treatment of premature ejaculation, wherein the core tablet is a sustained-release tablet and the outer layer is a fast-disintegrating tablet, and a method for preparing the same. The rapid drug release from the double tablet sok-disintegrating tablet shortens the drug effect expression time, and after the active ingredient is rapidly released to a certain amount in the initial stage, the remaining active ingredient is continuously released for a long time. The controlled drug release properties of the double tablet of the present invention can suppress the side effects caused by the rapid release of an active ingredient for premature ejaculation, such as clomipramine hydrochloride, from the immediate-release tablet or the fast-disintegrating tablet.

Description

Double layer tablet for controlled release of clomipramine hydrochloride and preparation method thereof

The present invention relates to a double tablet for controlled release of clomipramine hydrochloride and a method for preparing the same, and more particularly, to a double tablet having the advantages of rapid expression of efficacy and sustained efficacy of clomipramine hydrochloride.

Premature ejaculation refers to ejaculation that occurs abnormally faster than desired by a man or his partner during sexual intercourse. These symptoms are common sexual dysfunction that 30% of the total adult population often suffers from, and it is known that most of the causes are psychological factors. WHO considers premature ejaculation when the intravaginal latency time (ILT) is less than 60 seconds during intercourse. It is known that premature ejaculation is related to brain signaling, and stimulation of 5HT _2C , 5-HT _1B and 5-HT ₇ receptors in 5-hydroxytrpytamine (5-HT, serotonin) is a desirable approach for improving premature ejaculation. (Francois Giuliano, TRENDS in Nurosciences Vol. 30, No. 2, (2007)).

As an oral treatment for premature ejaculation, products such as Priligy, which use dapoxetine hydrochloride, a selective serotonin reuptake inhibitor (SSRI) as an active ingredient, are being prescribed at home and abroad. Although the effect of dapoxetine hydrochloride for ejaculation control and delay of ejaculation is positive, there is a problem with low medication compliance due to the inconvenience of having to take the drug 60 to 180 minutes before sexual intercourse because the onset of drug effect is delayed.

Clomipramine hydrochloride is an anti-compulsive drug belonging to the dibenzazepine TCA group known as tricyclic antidepressant agents (TCAs). Currently, oral capsules of 25, 50 and 75 mg are available under the trade name Anafranil. The chemical name of clomipramine hydrochloride is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5Hdibenz[b,f]azepine monohydrochloride. Studies have been conducted to apply the inhibition of serotonin reuptake of clomipramine hydrochloride to the treatment of premature ejaculation.

However, the release and absorption rate control of clomipramine through an oral fast-disintegrating formulation, which is expected to exhibit rapid drug effect, or a double tablet having both a fast-disintegration layer and a sustained-release layer, etc. was not specifically presented. By controlling the release of SSRI drugs such as clomipramine hydrochloride, on-demand administration is possible, immediate and sustained release of the drug is possible, and side effects can be reduced. effort is required for

Accordingly, the problem to be solved by the present invention relates to a pharmaceutical double tablet for controlled release of clomipramine hydrochloride and a method for preparing the same, wherein the double tablet has a fast disintegrating tablet of clomipramine hydrochloride as an outer layer, and contains clomipramine hydrochloride. The Western government is the nuclear layer. In the present invention, after the drug is rapidly released within a few minutes of the initial drug release, the drug is slowly released for several hours, so that the drug effect can be rapidly expressed and the drug effect can be sustained. Another object of the present invention to be solved is to provide a double tablet capable of reducing the risk of side effects due to excessive release of the drug and a method for manufacturing the same.

In order to solve the above problems, the present invention provides a double tablet containing clomipramine or a pharmaceutically acceptable salt thereof, preferably a double tablet containing clomipramine hydrochloride.

The present invention is a double tablet comprising clomipramine or a salt thereof as an active ingredient,

The double tablet provides a sustained-release core tablet comprising clomipramine or a salt thereof as an active ingredient, and a double tablet comprising an outer layer surrounding the core tablet and containing clomipramine or a salt thereof as an active ingredient.

The outer layer preferably has a faster disintegration rate than the core tablet, for example, the outer layer has fast disintegration, and the fast disintegration property is understood to mean that the disintegration rate is fast, in the present specification, deionized water or It can be understood to mean that 90 to 100% of the total weight disintegrates within 1 minute under the conditions of the dissolution test solution having a pH of 1.2, 4.0 and 6.8, respectively. The core tablet has sustained-release properties, and the sustained-release properties indicate that drug release proceeds slowly, and in the present specification, the active ingredient is 30 to 75 in deionized water or in a dissolution test solution having a pH of 1.2, 4.0 and 6.8, respectively, in 150 to 180 minutes. It can be understood that % is eluted.

Hereinafter, the present invention will be described in detail.

The drug is released from the dosage form as it passes through the gastrointestinal tract, and finally dissolved and absorbed. In order for a drug to be absorbed, it must first be eluted and dissolved in the body fluid at the site of absorption. It is known that the pH of the stomach is 1-3, the pH of the duodenum is 5-7, the pH of the ascending colon is 7-8, and the pH of the jejunum is 6.5. Clomipramine hydrochloride of the present invention exhibits an immediate medicinal effect, and it is preferable that the duration of the medicinal effect is maintained for at least 1 hour.

The formulation for oral administration of clomipramine according to the present invention comprises a fast-disintegrating outer layer comprising clomipramine or a salt thereof (preferably hydrochloride), a disintegrant, a binder, an excipient, and a lubricant, and clomipramine Min or a salt thereof (preferably hydrochloride), an excipient, a disintegrant, a release controlling agent, and granules containing a binder solution are mixed with a binder, a disintegrant, and a lubricant; .

Preferably, the double tablet may be prepared by first preparing a core tablet, placing the core tablet in a tableting machine, and compression molding by adding a composition for forming a double tablet thereon. Since the composition for forming an outer layer does not surround the bottom portion of the core tablet, the double tablet prepared in this way may be obtained in a form in which a part of the core tablet is exposed in the double tablet. This type of double tablet can have rapid disintegration and sustained release at the same time as the drug passes through the gastrointestinal tract, so both rapid and sustained release of the drug can be expected. In addition, side effects caused by the rapid release of the active ingredient can also be suppressed.

In order to simultaneously satisfy the rapid expression of pharmacological activity of an oral preparation containing clomipramine hydrochloride and the continuation of the pharmacological activity for more than 1 hour, the present invention provides a fast-disintegration layer that rapidly disintegrates the drug and a sustained-release layer that allows the drug to be slowly released. When preparing a double tablet made of, ethyl acrylic acid-methylmethacrylic acid-trimethylaminoethylmethacrylic acid chloride copolymer and/or hydroxypropylmethylcellulose (HPMC) are used in an appropriate ratio as a release controlling agent for sustained-release core tablets having different pH It is possible to control the dissolution rate and/or residence time in the gastrointestinal tract at each site in the gastrointestinal tract, and preferably hydroxypropylmethylcellulose (HPMC) may be used.

The ethylacrylic acid-methylmethacrylic acid-trimethylaminoethylmethacrylic acid chloride copolymer may include Eudragit RL PO, Eudragit RS PO, or a mixture thereof, preferably the Eudragit RL PO and Eudragit RL PO and Eudragit RL PO. a mixture of dragit RS PO. The HPMC is preferably 1 to 100 kDa, preferably HPMC having a molecular weight of 10 to 50 kDa may be used. Preferably, the controlled-release agent may be included in an amount of 20 to 40% by weight, preferably 25 to 35% by weight, based on the total weight of the sustained-release core tablet. In the above content range, clomipramine or a salt thereof may have a constant lasting effect for 1 hour.

The outer layer may use F-melt M as a disintegrant to promote rapid disintegration. Since the F-melt M has abundant pores, the water absorption rate is fast and as a result, the tablet manufactured by tableting has the advantage that it can be disintegrated by a small amount of moisture in the oral cavity. The F-melt M consists of hydroxypropylmethylcellulose, microcrystalline cellulose, lactose, polyvinylpyrrolidone, crospovidone, and magnesium stearate. The disintegrant may be included in an amount of from 60 to 80% by weight based on the total weight of the outer layer composition, and more preferably from 65 to 78% by weight based on the total weight of the composition. In the above content range, it can bring about rapid disintegration of the tablet while having good tabletting properties.

The active ingredient of the present invention, clomipramine or a salt thereof, may be included in an amount of 15 to 35% by weight, preferably 20 to 30% by weight, based on the weight of the formulation. The pharmacological effect is excellent in the above range.

The disintegrant absorbs moisture to promote disintegration of the formulation and is used to improve dissolution of clomipramine or a salt thereof. In addition to the F-melt M, non-limiting examples of disintegrants that can be used in the present invention are each independently croscamellose sodium, sodium starch glycolate, microcrystalline cellulose ), crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidone (Polyvinylpyrrolidone, PVP, Povidone), low-substituted hydroxypropylcellulose (Hydroxypropylcellulose, low substituted), alginic acid, It may be powdered cellulose, starch, sodium alginate, or a mixture thereof. The disintegrant may be additionally added in a pharmaceutically acceptable method by adding it to the oral solid formulation, and a secondary disintegrant may be additionally used for the purpose of more rapid release of the formulation. It is preferable to use the disintegrant in an amount of 10 to 30% by weight based on the total weight, and most preferably 20 to 30% by weight may be used. Non-limiting examples of excipients used in the fast-disintegration layer and the sustained-release layer in the present invention may each independently be microcrystalline cellulose, lactose, mannitol, glucose, sorbitol, dextrin, sucrose, or a mixture thereof.

In the present invention, as a water-soluble polymer in the fast-disintegration layer and the sustained-release layer, a binder that is soluble in an organic solvent and serves to increase the binding force of the formulation can be used. Non-limiting examples of binders that can be used may include polyvinylpyrrolidone (also called povidone). The polyvinylpyrrolidone used in the rapidly disintegrating layer may have a molecular weight of preferably 40,000 to 60,000 g/mol, more preferably 45,000 to 55,000 g/mol. The polyvinylpyrrolidone used in the sustained-release layer may preferably have a molecular weight of 100,000 to 150,000 g/mol, more preferably 110,000 to 135,000 g/mol. When having the molecular weight as described above, it is possible to achieve the desired rapid disintegration and / or sustained release.

Non-limiting examples of the lubricant usable in the fast-disintegration layer and the sustained-release layer in the present invention may each independently be light anhydrous silicic acid, silicon dioxide, talc, stearic acid, magnesium stearate, or a mixture thereof. The lubricant can improve the fluidity of the granular material and facilitate the compression and release of the tablet.

The present invention is a pharmaceutical preparation having both sustained-release and immediate-release properties of clomipramine hydrochloride in the form of a two-layer tablet comprising a fast-disintegration layer and a sustained-release layer.

The formulation for oral administration of clomipramine according to the present invention may be prepared by mixing, kneading and/or granulating the sustained-release layer and the fast-disintegrating layer, respectively, and then tableting. Controlled release of the drug can be advantageous when via a granulation process. As the tableting method, a general pharmaceutical tableting method may be used, but the double tablet of the present invention has a form in which the core tablet is exposed on the surface of the tablet. For example, a core tablet is placed on the bottom and the composition for forming an outer layer is wrapped thereon, so that the core tablet corresponding to the bottom part can be exposed from the double tablet. This type of double tablet may have an excellent structure for sustained release of clomipramine hydrochloride.

According to the present invention, a dissolution test was carried out by the paddle method at 50 revolutions per minute (Korean Pharmacopoeia 10 revision, dissolution test 2nd method) using 900 ml of the dissolution solution for double tablets consisting of a fast-disintegration layer and a sustained-release layer containing the same active ingredient according to the present invention. at 37°C pH 4.0, 6.8. 1.2, and the following dissolution profile in the water eluate may be satisfied.

1) Under the conditions of pH 4.0, pH 1.2 and water eluate, 90-100% of the total weight of the active ingredient was dissolved within 10 minutes.

2) 90-100% of the total weight of the active ingredient is eluted for 10 minutes to 1 hour under the pH 6.8 dissolution condition.

In one embodiment, the core tablet of the present invention includes clomipramine hydrochloride, povidone and crospovidone, the outer layer includes clomipramine hydrochloride and F-melt M, and the clomipramine hydrochloride is a core tablet and the outer layer may contain the same amount.

Preferably, the double tablet may be effective at 0.5 to 4 hours, 1 to 3.5 hours, and 0.5 to 3 hours after administration.

The present invention provides a method for preparing double tablets of clomipramine comprising the following steps.

(S1) comprising clomipramine or a salt thereof, and preparing a sustained-release core tablet composition comprising hydroxypropylmethylcellulose as a release controlling agent;

(S2) preparing a core tablet by tableting the composition of step (S1);

(S3) comprising clomipramine or a salt thereof, and preparing a composition for forming an outer layer comprising a fast disintegrant consisting of mannitol, xylitol, microcrystalline cellulose, crospovidone, and magnesium aluminometasilicate; and

(S4) adding the composition of step (S3) to the core tablet compressed in step (S2) and compression molding to obtain a double tablet; It provides a method for preparing a double tablet comprising, respectively, clomipramine or a salt thereof in the core tablet and the outer layer, comprising: The manufacturing method may further include (S5) obtaining a double tablet in which the core tablet is exposed on the surface of the double tablet.

The clomipramine preferably includes clomipramine hydrochloride.

The additives or excipients used in the preparation method of the present invention have excellent compatibility with clomipramine or a salt thereof (preferably clomipramine hydrochloride).

In the step (S1), when hydroxypropylmethylcellulose is included as a release controlling agent, it may be easy to manufacture a core tablet, and it may help to control continuous release. Therefore, side effects due to rapid release can be reduced. In the step (S1), the sustained-release core tablet composition contains, in addition to clomipramine or a salt thereof and hydroxypropylmethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, lactose, polyvinylpyrrolidone, crospovidone, and stear. It may further include magnesium acid. A core tablet obtained from the composition comprising or consisting of the above component may be stably formed, and the tablet may be stably formed without being broken or crushed when the outer layer composition is partially coated on the core tablet and then tableted. In addition, it may be advantageous to achieve the intended dissolution rate in the present invention.

Preferably, the composition contains 10 to 15 wt% (preferably 11 to 14 wt%) of clomipramine or a salt thereof, and 20 to 40 wt% (preferably 25 to 40 wt%) of the hydroxypropylmethylcellulose, based on the total weight of the core tablet composition. 35% by weight), 20 to 28% by weight of microcrystalline cellulose (preferably 22 to 26% by weight), 15 to 20% by weight of polyvinylpyrrolidone (preferably 16 to 19% by weight), 10 to 15% by weight of lactose % (preferably 11 to 14% by weight), 15 to 20% by weight of polyvinylpyrrolidone (preferably 16 to 19% by weight), 1.5 to 3.5% by weight of crospovidone (preferably 2 to 3% by weight), and 0.5 to 1.5 wt% (preferably 0.8 to 1.3 wt%) of magnesium stearate. When it has the above content range, it may be advantageous to achieve the object of the present invention, and it may be possible to manufacture stable core tablets.

The composition for forming the outer layer of step (S3) includes a fast disintegrant, and the fast disintegrant is F-melt M (trade name), which consists of mannitol, xylitol, microcrystalline cellulose, crospovidone, and magnesium aluminometasilicate. . The fast disintegrant has an abundance of pores, so the water absorption rate is fast and as a result, the tablet prepared by tableting has the advantage that it can be disintegrated by a small amount of moisture in the oral cavity. It is advantageous and has excellent compatibility with other components.

The composition for forming the outer layer of step (S3) may further include polyvinylpyrrolidone, sodium hydrogen carbonate and magnesium stearate.

The composition for forming the outer layer contains 15 to 35% by weight of clomipramine or a salt thereof (preferably 20 to 30% by weight), 60 to 80% by weight (65 to 78% by weight) of a disintegrant, based on the total weight of the composition; 0.5 to 1.5 wt% (preferably 0.8 to 1.2 wt%) of polyvinylpyrrolidone, 2-3 wt% (2.2 to 2.8 wt%) of sodium hydrogen carbonate, and 0.3 to 1 wt% (0.4 wt%) of magnesium stearate to 0.8% by weight) may be included. When it has the above content range, it may be advantageous for achieving the object of the present invention, and it may be advantageous for stable formation of the formulation, compatibility, and the like.

In step (S4), after adding the composition of step (S3) to the core tablet compressed in step (S2), compression molding may be performed to obtain a double tablet, wherein compression molding is wet granulation method/dry granulation method/direct A powder compression method may be used without limitation, but the direct powder compression method may be used in consideration of the process of adding the composition of step (S3) thereto, preferably in the presence of the core tablet. In the above step, the surface of the core tablet in contact with the bottom may be exposed to the outside in the double tablet. For example, when a core tablet is made in the form of a flat cylinder, the other side and side surfaces except for one side (bottom) of the cylinder may be manufactured in a form surrounded by an outer layer. A tablet of this type is illustrated in FIG. 1 .

The double tablet made by the above manufacturing method is designed so that one side of the inner core tablet is exposed to the outside, so that the drug is released from the inner core tablet after all drug release from the outer layer tablet is completed, so that the continuous release of the drug is not interrupted.

The present invention relates to a double tablet in which the core tablet is a sustained-release tablet and the outer layer is a fast-disintegrating tablet for controlling the release of the active ingredient, clomipramine hydrochloride, and a method for preparing the same. The rapid drug release from the fast-disintegrating tablet of the outer layer of the double tablet may enable rapid on-demand drug expression required for the treatment of premature ejaculation. In addition, the double tablet has the characteristic that the active ingredient is rapidly released at the beginning up to a certain amount, and then the remaining active ingredients are continuously released for a long time, thereby suppressing the side effects caused by the rapid release of the active ingredient from the immediate-release tablet or the fast-disintegrating tablet. can

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical spirit of the present invention together with the above-described content of the invention, so the present invention is limited to the matters described in those drawings It should not be construed as being limited.
1 is a schematic diagram of a double tablet of clomipramine hydrochloride in which the core tablet is a sustained-release tablet and the outer layer is a fast-disintegrating tablet.
Figure 2 shows the dissolution rate according to the pH of the dissolution test solution of clomipramine hydrochloride sokbung.
Figure 3 shows the dissolution rate according to the pH of the dissolution test solution of clomipramine hydrochloride sustained-release tablet.
Figure 4 shows the dissolution rate according to the pH of the dissolution test solution of clomipramine hydrochloride double tablet.
Figure 5 shows the dissolution rate according to the pH of the dissolution test solution of clomipramine hydrochloride immediate-release tablet.

Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.

<Example 1> Sokbung tablet of clomipramine hydrochloride

Clomipramine hydrochloride fast-disintegrating tablets were prepared as fast-disintegrating tablets by using a tablet press (Geumseong, Korea) after weighing the raw materials shown in Table 1 according to the amount and mixing them evenly. At this time, the weight of one fast-disintegrating tablet was 500 mg, and the diameter of the tablet was 10 mm. Table 1 below shows the composition of the rapidly disintegrating tablet of clomipramine hydrochloride.

classification Raw material name Serving Size (mg) chief ingredient Clomipramine hydrochloride 12.5 disintegrant F-melt 462.5 sweetener aspartame 5 acidifying agent citric acid 10 excipient sodium bicarbonate 5 lubricant magnesium stearate 5 1 tablet weight 500

<Example 2> granular fast disintegrating tablet of clomipramine hydrochloride

Clomipramine hydrochloride granular fast disintegrating tablet is prepared by completely dissolving povidone in Table 2 in ethanol, the binding solution, by adding clomipramine hydrochloride, lactose and sodium hydrogen carbonate, mixing evenly for about 3 minutes, and using a mixer. After mixing, it was lowered through a sieve of No. 40, dried at 45° C., and the granule mixture prepared by adding F-melt M, aspartame and magnesium stearate to mixing was prepared by tableting using the tablet press of Example 1. Table 2 below shows the composition of the granular fast-disintegrating tablet of clomipramine hydrochloride.

classification Raw material name Serving Size (mg) < Preparation of granules > chief ingredient Clomipramine hydrochloride 25 excipient lactose 21 excipient sodium bicarbonate 2.5 binder Kollidon® 30 (polyvinylpyrrolidone (molecular weight 50,000 g/mol)) 2 binder ethanol 8 < Mix > fast disintegrant F-melt M 93.8 sweetener aspartame 4.5 lubricant magnesium stearate 1.2 1 tablet weight 150

<Example 3> Granular sustained-release tablet of clomipramine hydrochloride

For the granular sustained-release tablet of clomipramine hydrochloride, clomipramine hydrochloride, microcrystalline cellulose, lactose, Eudragit RS PO and Eudragit RL PO of Table 3 were evenly mixed, and then ethanol as a binding solution was added to the mixture in small amounts. The mixture prepared by adding it according to the weight was lowered through a sieve No. 20, dried at 45° C., crospovidone, povidone (90F) and magnesium stearate were added and mixed to prepare a granule mixture prepared by tableting using the tableting machine of Example 1. Table 3 below shows the composition of the granular sustained-release tablet of clomipramine hydrochloride.

classification Raw material name Serving Size (mg) < Preparation of granules > chief ingredient Clomipramine hydrochloride 25 disintegrant Microcrystalline Cellulose 45 disintegrant lactose 35 sustained release agent Eudragit RS PO 15 sustained release agent Eudragit RL PO 15 binder ethanol 20 < Mix > disintegrant crospovidone 7.5 binder Kollidon® 90F (polyvinylpyrrolidone (molecular weight 125,000 g/mol)) 6.0 lubricant magnesium stearate 1.5 1 tablet weight 150

<Example 4> Double tablet of clomipramine hydrochloride

Double tablet of clomipramine hydrochloride was prepared using the composition of the fast-bung tablet composition of Table 4 and the composition of the granular sustained-release tablet of Table 5. All components in Table 4 were mixed evenly for about 5 to 10 minutes to prepare a fast-disintegrating tablet composition. Clomipramine hydrochloride of Table 5, microcrystalline cellulose, lactose and HPMC were evenly mixed, and then ethanol as a binding solution was added according to the weight and mixed using a mixer. The prepared mixture was lowered through a No. 20 sieve, dried at 45° C., povidone (90F), crospovidone, and magnesium stearate were added and mixed to prepare. The sustained-release granule mixture prepared according to the composition of Table 5 was compressed with a punch of 6 mm in diameter at low strength using the tableting machine of Example 1, and the sustained-release tablet was injected into a punch of 7 mm in diameter, and placed on the sustained-release tablet of 6 mm in diameter. A double tablet of clomipramine hydrochloride in the form shown in FIG. 1 was prepared by adding the fast-disintegrating tablet composition prepared according to the composition of 4 to fit the weight and then tableting. Table 4 below shows the composition of clomipramine hydrochloride rapidly disintegrating tablets.

classification Raw material name Serving Size (mg) chief ingredient Clomipramine hydrochloride 12.5 fast disintegrant F-melt M 35.5 binder Kollidon® 30 (polyvinylpyrrolidone (molecular weight 50,000 g/mol)) 0.5 excipient sodium bicarbonate 1.2 lubricant magnesium stearate 0.3 1 tablet weight 50

Table 5 below shows the composition of the sustained-release tablet of clomipramine hydrochloride granules.

classification Raw material name Serving Size (mg) < Preparation of granules > chief ingredient Clomipramine hydrochloride 12.5 disintegrant Microcrystalline Cellulose 24 excipient lactose 12.5 release control agent HPMC (80-120 cP, 2% in water at 20 ^o C) 30 binder ethanol 42 < Mix > binder Kollidon® 90F (polyvinylpyrrolidone (molecular weight 125,000 g/mol)) 17.5 disintegrant crospovidone 2.45 lubricant magnesium stearate 1.05 core tablet weight 100

The F-melt M may have the following composition.

Furtherance range (%) Sujae Pharmacopoeia D-mannitol 50 - 66 USP-NF/JP/EP xylitol 2 - 10 USP-NF/JP/EP Microcrystalline Cellulose 10 - 20 USP-NF/JP/EP crospovidone 5 - 9 USP-NF/JP/EP Magnesium Aluminometasilicate 2 - 9 USP-NF/JP/EP

<Comparative Example 1> Clomipramine hydrochloride immediate-release tablet

Clomipramine hydrochloride immediate-release tablets were prepared as immediate-release tablets using a tablet press (Geumseong, Korea) after the raw materials shown in Table 6 were weighed according to the amount and mixed evenly. At this time, the weight of one immediate-release tablet was 150 mg, and the diameter of the tablet was 7 mm. Table 7 below shows the composition of the immediate-release tablet of clomipramine hydrochloride.

classification Raw material name Serving Size (mg) chief ingredient Clomipramine hydrochloride 25 disintegrant Microcrystalline Cellulose 60 excipient lactose 50 disintegrant crospovidone 7.5 binder Kollidon® 30 (polyvinylpyrrolidone (molecular weight 50,000 g/mol)) 6.0 lubricant magnesium stearate 1.5 1 tablet weight 150

<Experimental Example 1> Disintegration test

The disintegration test for the tablets of Examples 1 to 4 and Comparative Example 1 was performed according to the disintegration test method of the Korean Pharmacopoeia general test method, after filling a 1L glass beaker with 800 mL of deionized water, and disintegration tester at 37±2 ° C. was operated to measure the time required for the tablet to completely disintegrate at a rotation speed of 31 rpm, and the experimental results are shown in Table 8. Table 8 below shows the disintegration time according to the formulation of clomipramine hydrochloride.

sample Disintegration time (min) Sokbung dissolving tablet (Example 1) <1 Granular fast disintegrating tablet (Example 2) <1 Extended release tablet (Example 3) 20 Double Tablet (Example 4) 120 Immediate release tablet (Comparative Example 1) 5

As shown in Table 8, the fast-disintegrating tablet of clomipramine hydrochloride prepared according to the composition of Table 1 of Example 1 and the granular fast-disintegrating tablet of clomipramine hydrochloride prepared according to the composition of Table 2 of Example 2 were 1 It completely disintegrated within minutes. In addition, the sustained-release tablet of clomipramine hydrochloride prepared according to the composition of Table 3 of Example 3 completely disintegrated after 20 minutes, and double tablet of clomipramine hydrochloride prepared according to the compositions of Tables 4 and 5 of Example 4 was completely disintegrated after 120 minutes. On the other hand, the immediate-release tablet of clomipramine hydrochloride prepared according to the composition of Table 7 of Comparative Example 1 completely disintegrated after 5 minutes.

<Test Example 2> Dissolution test

The dissolution test of clomipramine hydrochloride on the tablets prepared in Examples 3, 4 and Comparative Example 1 was performed according to the dissolution test method of the Korean Pharmacopoeia general test method after starting the test at 0, 5, 10, 15, 30, 60, After taking a sample of the eluate at 120, 180, 240, 360 and 480 minutes, it was filtered through a 0.45 μm filter and analyzed by HPLC. As the eluent used in the dissolution test, a solution having a pH of 1.2, 4.0 and 6.8 and deionized water were used, and the volume of the dissolution test solution per tablet was 900 mL, and the stirring speed was 50 rpm. Samples were taken at 0, 5, 10, 15, 30 and 60 min after the start of the dissolution experiment, filtered through a 0.45 μm filter, and analyzed by HPLC. The HPLC analysis was performed under the conditions of uBondapackTM (C18, 10 um, 125 Å, 3.9 mm 30 cm), analysis wavelength of 254 nm, flow rate of 1 mL/min, and sample injection volume of 10 uL according to the USP NF test method. did The sodium 1-heptanesulfonate solution, which is the mobile phase used in the HPLC analysis, was prepared and used as follows. In a 100 mL volumetric flask, 5.5 g of sodium 1-heptanesulonafate was added, 50 mL of deionized water was added, and the remaining volume was filled with glacial acetic acid to prepare. 20 mL of the solution was collected and placed in a 500 mL volumetric flask, 2 mL of triethylamine was added, and the remaining volume was filled with deionized water. Transfer the prepared solution to a 1L volumetric flask, adjust the pH of the solution to 3.2±0.1 using phosphoric acid, fill the remaining volume with acetonitrile, mix the solution using sonication or a stirrer, and remove air bubbles. prepared.

On the other hand, the dissolution test of clomipramine hydrochloride from the tablets prepared in Examples 1 and 2 was performed at 0, 5, 10, 15, 30, 45 and 60 minutes after the start of the dissolution test according to the dissolution test method among the general test methods of the Korean Pharmacopoeia. After taking a sample of the eluate, it was filtered through a 0.45 μm filter, and the absorbance was measured and analyzed at the maximum absorption wavelength of 254 nm according to the ultraviolet and visible absorbance measurement method among the general test methods of the Korean Pharmacopoeia.

The results of the dissolution test of the clomipramine hydrochloride rapidly disintegrating tablet prepared in Example 1 are shown in FIG. 2 . As shown in FIG. 2 , 100% of the drug was released within 5 minutes in all of the eluates at pH 1.2, 4.0 and 6.8, and about 100% of the drug was released within 10 minutes in deionized water.

The results of the dissolution test of the sustained-release tablet of clomipramine hydrochloride prepared in Example 3 are shown in FIG. 3 . As shown in FIG. 3 , the drug release rate of 79% was the fastest at 180 minutes at pH 4.0, which was similar to the drug release rate in deionized water. The release pattern was shown, and 80% dissolution was exhibited in 8 hours in the pH 6.8 dissolution test solution, indicating the slowest dissolution rate among the dissolution test solutions.

The results of the dissolution test of the double tablets of clomipramine hydrochloride prepared in Example 4 are shown in FIG. 4 . As shown in FIG. 4, the double tablets of clomipramine hydrochloride prepared in Example 4 showed drug release of 26% to 42% at 5 minutes and 40±5% at 30 minutes in dissolution test solutions of pH 1.2, 4.0 and 6.8. After showing drug release, it showed sustained release drug release at a constant rate.

The dissolution test result of the immediate-release tablet of clomipramine hydrochloride prepared in Comparative Example 1 is shown in FIG. 5 . As shown in FIG. 5 , 100% of the drug was released within 5 minutes at pH 1.2 and 4.0, and 85% of the drug was released within 10 minutes at pH 6.8 and deionized water.

Claims (9)

(S1) comprising clomipramine or a salt thereof, and preparing a sustained-release core tablet composition comprising hydroxypropylmethylcellulose as a release controlling agent;
(S2) preparing a core tablet by tableting the composition of step (S1);
(S3) comprising clomipramine or a salt thereof, and preparing a composition for forming an outer layer comprising a fast disintegrant consisting of mannitol, xylitol, microcrystalline cellulose, crospovidone, and magnesium aluminometasilicate; and
(S4) adding the composition of step (S3) to the core tablet compressed in step (S2) and compression molding to obtain a double tablet; containing,
A method for manufacturing a double tablet comprising clomipramine or a salt thereof in the core tablet and the outer layer, respectively. The method according to claim 1, wherein the clomipramine is clomipramine hydrochloride. The method according to claim 1, wherein the sustained-release core tablet composition in step (S1) contains, in addition to clomipramine or a salt thereof and hydroxypropylmethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, lactose, polyvinylpyrrolidone, A method for manufacturing double tablets, characterized in that it further comprises crospovidone and magnesium stearate. According to claim 3, wherein the composition comprises 10 to 15% by weight of clomipramine or a salt thereof, 20 to 40% by weight of hydroxypropylmethylcellulose, 20 to 28% by weight of microcrystalline cellulose, based on the total weight of the core tablet composition; 15 to 20% by weight of polyvinylpyrrolidone, 10 to 15% by weight of lactose, 15 to 20% by weight of polyvinylpyrrolidone, 1.5 to 3.5% by weight of crospovidone, and 0.5 to 1.5% by weight of magnesium stearate %, a double tablet manufacturing method comprising: The method according to claim 1, wherein the composition for forming the outer layer in step (S3) further comprises polyvinylpyrrolidone, sodium hydrogen carbonate and magnesium stearate. The composition of claim 5, wherein the composition for forming the outer layer contains 15 to 35% by weight of clomipramine or a salt thereof, 60 to 80% by weight of a disintegrant, and 0.5 to 1.5% by weight of polyvinylpyrrolidone, based on the total weight of the composition. %, sodium bicarbonate 2 to 3% by weight, and magnesium stearate 0.3 to 1% by weight of the double tablet manufacturing method characterized in that it contains. A double tablet containing clomipramine or a salt thereof, prepared by any one of the methods selected from claims 1 to 6. The double tablet according to claim 7, wherein the double tablet satisfies the following dissolution profile at 37° C. pH 1.2, 4, 6.8 and water dissolution according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia.
1) Under the conditions of pH 4.0, pH 1.2 and water eluate, 90-100% of the total weight of the active ingredient was dissolved within 10 minutes.
2) 90-100% of the total weight of the active ingredient is eluted for 10 minutes to 1 hour under the pH 6.8 dissolution condition. The double tablet according to claim 7, wherein the double tablet is administered 0.5 to 4 hours before sexual intercourse.

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