JPH09208468A - Tablet containing p-chloro-n-(2-morpholinoethyl) benzamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a small-sized tablet having eluting property and stability, containing p-chloro-N-(2-morpholinoethyl)benzamide (moclobemide). SOLUTION: This tablet comprises >=60wt.% of moclobemide and <=40wt.% of an excipient, especially 65-69wt.% of moclobemide and 31-35wt.% of the excipient and especially having total weight of 50-300mg and 45-160mg of moclobemide. The excipient comprises 1-5wt.% of a binder (e.g. hydroxypropylcellulose), 5-20wt.% of a disintegrator (e.g. low-substituted hydroxypropylcellulose), 0.2-3wt.% of a lubricant and <=33.8wt.% of the other formulating component. Preferably, film coating is performed and tabletted because moclobemide has bitterness. The tablet keeps usual eluting property, stability and the effect of a medicine and can readily be administrated in spite of enriched contact of moclobemide and miniaturized tablet.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical preparation, and particularly p-chloro-N- (2-morpholinoethyl).
It relates to small tablets containing benzamide.

[0002]

2. Description of the Related Art JP-A-62-15547 and JP-A-1-2243
No. 18 discloses that p-chloro-N- (2-morpholinoethyl) benzamide is 50 mg and 50, 100 or 15 respectively.
Formulation examples containing 0 mg are described. However, the content of the compound is only 20 to 37.5% by weight, and in particular
Tablets containing 0 mg are large tablets with a total weight of 400 mg.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention p-Chloro-N- (2
-Morpholinoethyl) benzamide (hereinafter sometimes referred to as moclobemide or a main drug) is a benzamide derivative that selectively and reversibly inhibits A-type monoamine oxidase (MAO-A), and is used as an antidepressant in European countries. Including
Sold in over 40 countries. However, effective treatment as an antidepressant requires fairly high doses and is necessarily administered in the form of large tablets. Such a dosage form is difficult to take for a patient, especially for a child or an elderly patient, and thus is not a preferable dosage form. Therefore, it has been desired to develop a small tablet containing a sufficient amount of the active ingredient moclobemide.

The inventors of the present invention have increased the content of moclobemide, have the same dissolution property and biologically equivalent properties as the conventional large tablets, and are small in size, in which the stability of the contained components is sufficiently retained. As a result of intensive studies on tablets, a combination of a specific binder and a disintegrant was found, and a formulation of a small tablet meeting the above-mentioned object was found, and the present invention was completed.

[0005]

According to the present invention, (a) p-chloro-N- (2-morpholinoethyl) benzamide is contained in an amount of 60% by weight or more, and (b) (i) 1 to 5% by weight of a binder. Excipient consisting of (ii) 5 to 20% by weight of disintegrant, (iii) 0.2 to 3% by weight of lubricant, and (iv) 33.8% by weight or less of other formulation ingredients.
Tablets with a total weight of 50-300 mg consisting of up to 40% by weight are provided.

[0006] In the present specification, weight% means the ratio to the tablet (hereinafter also referred to as a tablet core) excluding the weight of the film layer. Excipients used in the tablets of the present invention include binders, disintegrants, lubricants and other formulation ingredients. Hereinafter, these will be described.

Examples of the binder include hydroxypropyl cellulose, pullulan, carmellose sodium and the like, and hydroxypropyl cellulose is preferable. Examples of the disintegrator include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, and partially pregelatinized starch, with low-substituted hydroxypropyl cellulose being preferred. Therefore, a combination using hydroxypropyl cellulose as the binder and low-substituted hydroxypropyl cellulose as the disintegrator is particularly preferable.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate and the like, with magnesium stearate being preferred. Other formulation ingredients include lactose, corn starch,
Examples include crystalline cellulose, bulking agents such as D-mannitol, and fluidizing agents such as Aerosil. Further, the tablet of the present invention can be colored by adding an appropriate dye.

The tablet of the present invention contains the active ingredient moclobemide.
Contains 60 wt% or more, preferably moclobemide 60 ~
Contains 75% by weight. More preferably moclobemide is 63
˜71% by weight, particularly preferably 65-69% by weight.
In other words, the tablet of the present invention contains not more than 40% by weight of excipients, preferably 25-40% by weight, more preferably 29-
It contains 37% by weight, particularly preferably 31 to 35% by weight.

The tablet of the present invention usually contains about 30 to about 280 mg of moclobemide, preferably about 30 mg to about 22 mg.
5 mg, particularly preferably about 45 mg moclobemide
Contains 160 mg.

Regarding the excipient contained in the tablet of the present invention, the binder is preferably 1.5 to 4.5% by weight, the disintegrant is 7 to 18% by weight, and the lubricant is 0.5 to 2.5% by weight, particularly preferably 2.5 to 2.5% by weight. 3.5 wt%, disintegrant 8-12 wt% and lubricant
It is 0.7 to 2% by weight.

In a particularly preferred form of the tablet of the present invention, (a) p-chloro-N- (2-morpholinoethyl) benzamide is contained in an amount of 65% by weight to 69% by weight and (b) (i) a binder of 2.5 to 3.5%. % By weight (ii) Disintegrator 8-12% by weight (iii) Lubricant 0.7-2% by weight (iv) Other formulation ingredients 13.5-24.3% by weight Excipients 31-35% and total weight Examples include tablets of 65 to 246 mg.

Since the tablet of the present invention has a bitter taste with moclobemide as an active ingredient, it is usually preferable to carry out film coating according to a conventional method. Further, the film layer can be colored by adding an appropriate dye.

Excipients used in the film layer include film coating agents, plasticizers, opacifying agents (or opacifying agents), and the coating agent is usually 62 to 70% by weight of the film layer, plasticizer. 15-19%, hiding agents 15-19%
It consists of the ratio of Examples of the coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose derivatives such as methylcellulose, and the like, and hydroxypropylmethylcellulose is preferable, and hydroxypropylmethylcellulose is particularly preferable.
2910 is preferred. Macrogol as a plasticizer
Examples include 1500, 4000 or 6000, polyoxyethylene (105) polyoxypropylene (5) glycol (trade name: PEP101), and the like, Macrogol 6000 is preferable. Examples of the masking agent include titanium oxide. Therefore, as a coating agent for the film layer, hydroxypropylmethyl cellulose 2910 is used.
, And Macrogol 6000 as a plasticizer and titanium oxide as a masking agent are particularly preferable.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION A patient usually receives moclobemide as an active ingredient in a proportion of 63 to 71% by weight, about 150 mg, about 100 m 2.
g, or in the form of tablets containing about 50 mg. Therefore,
The following three modes can be given as specific modes of the present invention.

(1) The weight of the tablet core is 197 to 253 mg,
It contains moclobemide 140-160 mg, which is film-coated and the total tablet weight is 202-260 mg.
(2) Tablet core weight is 129-171 mg, containing moclobemide 92-108 mg, which is film-coated, and the total tablet weight is 133-17
7mg tablets, and (3) tablet core weight 63-87mg, containing moclobemide 45-55mg, which is film-coated, the total tablet weight 66-92mg.
tablets that are mg.

Further, among the above specific forms, the following three forms are particularly preferable.

(1) A tablet having a tablet core weight of about 225 mg and moclobemide of about 150 mg, which is film-coated and has a total tablet weight of about 231 mg,

(2) A tablet having a tablet core weight of about 150 mg and moclobemide of about 100 mg, which is film-coated and has a total tablet weight of about 155 mg, and

(3) A tablet having a tablet core weight of about 75 mg and moclobemide of about 50 mg, which is film-coated and has a total tablet weight of about 79 mg.

The tablet of the present invention can be produced, for example, by the following method. First, the binder is dissolved in purified water, sprayed on the mixture of the main drug and other excipients (disintegrant and other formulation ingredients) using a granulator, then granulated and dried to form granules. obtain. The obtained granules are passed through a sieve having an appropriate mesh size, mixed with a lubricant, and the mixture is compressed into tablets using a conventional tableting machine. If necessary, the tablets are film-coated using a suitable coating device.

[0022]

[Example] Example 1

[Table 1] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Component weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 150 mg 66.7% ・ Hydroxypropyl cellulose (binder) 7 mg 3.1% ・ Low-substituted hydroxypropylcellulose (disintegrant) 22.5 mg 10.0% ・ Magnesium stearate (lubricant) 2.5 mg 1.1% ・ Lactose (bulking agent) 42 mg 18.7% ・ Aerosil (fluidizing agent) 1 mg 0.4 % ─────────────────────────────────── Above Tablet core 225 mg 100% ──────── ──────────────────────────── ・ Hydroxypropyl methylcellulose 2910 4 mg ・ Titanium oxide 1 mg ・ Macrogol 6000 1 mg ── ──────────────────────────────── Above Film layer 6 mg ────────────── ────────────────────── Total 231 mg ━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━

Fluid Bed Granulator Flow Coater FLO-5
Mocrobemide 3000 with (Freund Industrial Products)
A mixture of 140 g of hydroxypropylcellulose, 450 g of low-substituted hydroxypropylcellulose, 840 g of lactose and 20 g of aerosil was dissolved in 2400 g of purified water and spray-dried to obtain granules. This is sized with a twin sizing machine (screen; 16 mesh, manufactured by Hata Tekko Co., Ltd.) and then magnesium stearate.
Mix with 50 g and press the tablet press clean press 18K (Φ 9 m
m, manufactured by Kikusui Seisakusho Co., Ltd.) and tableted to produce about 20,000 tablet cores. Next, 400 g of hydroxypropylmethyl cellulose 2910 and 100 g of Macrogol 6000 were dissolved in 5000 g of purified water, and 100 g of titanium oxide was dispersed therein to prepare a film solution. Subsequently, 4.5 kg of moclobemide tablet core was charged into an aqua coater (Freund Industrial Product Co., Ltd.), and the film layer was sprayed at 6 mg per tablet, dried at 50 ° C for 16 hours, and a film containing 150 mg of moclobemide. A coated tablet was obtained.

Example 2--

[Table 2] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Component weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 100 mg 66.7% ・ Hydroxypropyl cellulose (binder) 4.66 mg 3.1% ・ Low-substituted hydroxypropylcellulose (disintegrant) 15 mg 10.0% ・ Magnesium stearate (lubricant) 1.68 mg 1.1% ・ Lactose (bulking agent) 28 mg 18.7% ・ Aerosil (fluidizing agent) 0.66 mg 0.4 % ─────────────────────────────────── Above Tablet core 150 mg 100% ─────── ──────────────────────────── ・ Hydroxypropyl methylcellulose 2910 3.3 mg ・ Titanium oxide 0.85 mg ・ Macrogol 6000 0.85 mg ─────────────────────────────────── Above Film layer 5 mg ────────── ────────────────────────── Total 155 mg ━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━

Tabletting machine clean press 1 in Example 1
Clean press 1 instead of punch and die for 8KΦ 9 mm
A film-coated tablet containing 100 mg of moclobemide was obtained by treating in the same manner as in Example 1 using a punch and die for 8KΦ8 mm.

Example 3--

[Table 3] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Component weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 50 mg 66.7% ・ Hydroxypropyl cellulose (binder) 2.33 mg 3.1% ・ Low-substituted hydroxypropylcellulose (disintegrant) 7.5 mg 10.0% ・ Magnesium stearate (lubricant) 0.84 mg 1.1% ・ Lactose (bulking agent) 14 mg 18.7% ・ Aerosil (fluidizer) 0.33 mg 0.4 % ─────────────────────────────────── Above Tablet core 75 mg 100% ─────── ──────────────────────────── ・ Hydroxypropyl methylcellulose 2910 2.64 mg ・ Titanium oxide 0.66 mg ・ Macrogol 6000 0.67 mg ・ Yellow ferric oxide 0.03 mg ─────────────────────────────────── Above film layer 4 mg ── ───────────────────────────────── Total 79.0 mg ━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━

Tabletting machine clean press 1 in Example 1
Clean press 1 instead of punch and die for 8KΦ 9 mm
Using a punch and die for 8KΦ 6 mm, the same treatment as in Example 1 was carried out to obtain a film-coated tablet containing 50 mg of moclobemide.

Example 4--

[Table 4] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Ingredient weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 150 mg 69.8% ・ Hydroxypropyl cellulose (binder) 8 mg 3.7% ・ Low-substituted hydroxypropylcellulose (disintegrant) 27.8 mg 12.9% ・ Magnesium stearate (lubricant) 3.2 mg 1.5% ・ Lactose (bulking agent) 25 mg 11.6% ・ Aerosil (fluidizing agent) 1 mg 0.5 % ─────────────────────────────────── Above Tablet core 215 mg 100% ──────── ──────────────────────────── ・ Hydroxypropyl methylcellulose 2910 4 mg ・ Titanium oxide 1 mg ・ Macrogol 6000 1 mg ── ──────────────────────────────── Above Film layer 6 mg ────────────── ────────────────────── Total 221 mg ━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━

Using the above formulation, the same treatment as in Example 1 was carried out to obtain a film-coated tablet containing moclobemide (150 mg).

Example 5--

[Table 5] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Component weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 150 mg 65.2% ・ Hydroxypropyl cellulose (binder) 4.6 mg 2.0% ・ Low-substituted hydroxypropylcellulose (disintegrant) 20.6 mg 9.0% ・ Magnesium stearate (lubricant) 1.8 mg 0.8% ・ Lactose (bulking agent) 52 mg 22.6% ・ Aerosil (fluidizing agent) 1 mg 0.4 % ─────────────────────────────────── Above Lock core 230 mg 100% ─────── ──────────────────────────── ・ Hydroxypropyl methylcellulose 2910 4 mg ・ Titanium oxide 1 mg ・ Macrogol 6000 1 mg ── ───────────────────────────────── Above Film layer 6 mg ───────────── ─────────────────────── Total 236 mg ━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━━

Using the above formulation, the same treatment as in Example 1 was carried out to obtain a film-coated tablet containing moclobemide (150 mg).

The thus-obtained tablet of the present invention has a suitable hardness and a suitable disintegration property. That is, the hardness is 3.0
It disintegrates within 30 minutes at 37 ° C in purified water in the range of kg to 15.0 kg.

The results of the hardness test, the disintegration test and the dissolution test of the tablets obtained in Examples 1 and 3 are shown below.

Test Example 1 : Hardness Test--The hardness of the tablets of Examples 1 and 3 was determined by Schleuniger Tester 6
The measurement was performed using a D type (Tablet Tester 6D, manufactured by Schleuniger).

The hardness of the tablets of Examples 1 and 3 are respectively
The hardness was 13 kg and 8 kg, and both had extremely good hardness.

Test Example 2 : Disintegration test--Using the tablets of Examples 1 and 3, the disintegration test method described in the Japanese Pharmacopoeia (12th edition) (test solution purified water 1000 ml; reciprocation number 30 reciprocations / min; temperature 37) C)).

The disintegration times of the tablets of Examples 1 and 3 were 9 to 13 minutes and 8 to 10 minutes, respectively, and both showed good disintegration time.

Test Example 3 : Dissolution test--Using the tablets of Examples 1 and 3, the paddle method described in the Japanese Pharmacopoeia (12th edition) (test solution purified water 900 ml; rotation speed 50 rp)
m .; Temperature 37 ° C; 150 mg and 50 mg equivalent amount). The collected liquid was filtered through a membrane filter (pore size 0.45 μm), and the filtrate was quantified by the UV method. Table 6 shows the results.

[0039]

[Table 6]

As is clear from Table 6, the tablets of the present invention
After 20 minutes, the elution rate almost reached 100%, indicating a good elution property.

As is clear from the above test, the tablet of the present invention has good hardness, good disintegration property and dissolution property, and excellent tablet properties.

In the tablets of Examples 1 and 3, the active ingredient, the active ingredient, was stable in the accelerated test (for 6 months) under heating and / or humidifying conditions.

Comparative Tests Below, the formulations of small tablets containing moclobemide other than the tablets of the present invention are given as comparative examples, and it is shown that the formulation characteristics of the tablets of the present invention are superior to the formulations of the following comparative examples.

Comparative Example 1 --Formulation without Addition of Low Displacement Hydroxypropyl Cellulose as Disintegrator

[0045]

[Table 7] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Component weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 150 mg 66.7% ・ Hydroxypropyl cellulose (binder) 1.8 mg 0.8% ・ Magnesium stearate (lubricant) 2.25mg 1.0% ・ Lactose (bulking agent) 69.82mg 31.0% ・ Aerosil (fluidizer) 1.13mg 0.5% ─────────────── ───────────────────── 225 mg 100% ━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━

The tablet of Comparative Example 1, which was produced in the same manner as in Example 1 using the formulation of Comparative Example 1 above, had a disintegration time of about 1 hour or longer in the disintegration test, and the tablet formulation characteristics were insufficient. It was a thing.

Comparative Example 2 --Formulation with Increased Content of Hydroxypropyl Cellulose as Binder

[0048]

[Table 8] Per tablet ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Component weight% by weight ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ・ Moclobemide (main drug) 150 mg 66.7% ・ Hydroxypropyl cellulose (binder) 17 mg 7.6% ・ Low-substituted hydroxypropylcellulose (disintegrant) 11.5 mg 5.1% ・ Magnesium stearate (lubricant) 2.5 mg 1.1% ・ Lactose (bulking agent) 43 mg 19.1% ・ Aerosil (fluidizer) 1 mg 0.4 % ─────────────────────────────────── 225 mg 100% ━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━

The tablet of Comparative Example 2 produced by the same method as that of Example 1 using the formulation of Comparative Example 2 described above had a disintegration time of about 1 hour or longer in the disintegration test, and the tablet formulation characteristics were insufficient. It was a thing.

[0050]

INDUSTRIAL APPLICABILITY The tablet of the present invention has the same dissolution property and biologically equivalent property as the conventional large-sized tablet, despite the increase in the content of moclobemide and the reduction in size. Since it is a small tablet with sufficient stability, it can be easily taken even by patients who are difficult to take with a large tablet, and the same drug effect as a large tablet can be obtained.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] April 24, 1997

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claim 3

[Correction method] Change

[Correction contents]

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction contents]

[0007] As the binder, hydroxyaldehyde cellulose, pullulan, carmellose Sodium like, hydroxyaldehyde cellulose is preferred. Disintegrants, low-substituted hydroxyaldehyde cellulose, carmellose, carmellose calcium, croscarmellose sodium, although partially pregelatinized starch, and the like, low-substituted hydroxyaldehyde cellulose is preferred. Therefore, as the binder, with a hydroxyaldehyde cellulose, combinations using low-substituted hydroxyaldehyde cellulose is particularly preferred as a disintegrant.

Front Page Continuation (72) Inventor Minoru Hiraishi 1-6 A-702, Yoshinishi Sawayoshi, Ibaraki-shi, Osaka

Claims (4)

[Claims] 1. Amount of (a) p-chloro-N- (2-morpholinoethyl) benzamide of 60% by weight or more and (b) (i) 1-5% by weight of binder (ii) 5-20% by weight of disintegrant. Excipient comprising (iii) 0.2 to 3% by weight of lubricant and (iv) 33.8% by weight or less of other formulation ingredients.
Tablets with a total weight of 50-300 mg consisting of up to 40% by weight. 2. The tablet according to claim 1, wherein the binder is hydroxypropyl cellulose. 3. The tablet according to claim 2, wherein the disintegrant is low-substituted hydroxypropyl cellulose. 4. The method according to claim 1, wherein the film coating is applied.
4. The tablet according to any one of 3 to 3.