KR101428018B1 - Orally disintegrating tablet containing aripiprazole and manufacturing method thereof - Google Patents

Abstract

The present invention relates to an orally disintegrating tablets comprising aripiprazole and a solid dispersion of aripiprazole and a hydrophilic polymer, more preferably a three-component solid dispersion of aripiprazole, a specific hydrophilic polymer and a sugar alcohol (preferably mannitol) Is used. The aripiprazole oral disintegration tablet according to the present invention has improved dissolution and absorption properties and is excellent in taste, foreign substance, and the like.

Description

[0001] The present invention relates to an oral disintegrating tablet containing aripiprazole and a manufacturing method thereof,

The present invention relates to an orally disintegrating tablet containing aripiprazole, which is improved in elution and absorption properties and improved in taste such as taste, foreign body sensation and the like.

Aripiprazole, a quinolinone derivative, is a potent partial agonist of the dopamine D ₂ receptor and the 5-HT _1A receptor and is termed a so-called 'dopamine-serotonin stabilizer'. Partially active agents block the receptor if the receptor is overstimulated and activate the receptor in the absence of stimulation.

Such aripiprazole is marketed as an antipsychotic agent under the trade name Abilify ^TM and is used for the treatment or amelioration of schizophrenia. Treatment of acute mania and mixed artifacts associated with bipolar disorder, and supplement therapy of major depressive disorder.

The properties of aripiprazole are eluted under acidic conditions depending on the use of hydrogen ion, but they are characterized by difficulty in elution under neutral to basic conditions. In addition, aripiprazole coagulates in the course of preparation and elution, There is a problem that the dissolution rate drops. In order to improve this, a solubilizing agent of a surfactant is generally used. However, in the case of a composition containing such a surfactant, when the preparation is made from a disintegrating tablet for oral cavity, taste and the like are so bad that the mouth feel is deteriorated, and there is a fear of toxicity when taking a long time, resulting in difficulty in use.

Accordingly, there is a need for a means for improving the mouthfeel such as taste, foreign substance and the like in the preparation of the disintegration tablet for oral cavity as well as solving problems such as deterioration of elution and cohesiveness of aripiprazole.

Accordingly, a problem to be solved by the present invention is to provide an orally disintegrating tablet containing aripiprazole which is excellent in elution, secures dissolution stability even in long-term storage, and has excellent mouthfeel such as taste and foreign body.

In order to solve the above problems, the present invention provides an orally disintegrating tablet (ODT) comprising aripiprazole as an active ingredient, wherein the tablet comprises a solid dispersion of aripiprazole and a hydrophilic polymer, Wherein the tablets contain sugar alcohols.

More preferably, in the oral disintegration tablet according to the present invention, part of the sugar alcohol is contained in a solid dispersion of aripiprazole and a hydrophilic polymer.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present inventors have tried various methods to solve the problems in the aripiprazole oral disintegration tablet described above, and have solved the above-mentioned problems by using aripiprazole, a three-component solid dispersion of a hydrophilic polymer (particularly, a specific hydrophilic polymer) It was a remarkable invention that it was very excellent.

As will be described later, when the sugar alcohol is included in the preparation of the solid dispersion, the flowability of the solid dispersion granules produced is remarkably improved to improve the filling efficiency of the tablet machine, the filling deviation is reduced, and the manufacturing efficiency can be greatly improved In addition to this flowability, in addition to the flowability, ODT in which the sugar alcohol is contained in the solid dispersion is more dissolved in the oral cavity than the ODT in which the sugar alcohol is not contained in the solid dispersion, and the foreign matter is much reduced and the initial elution deviation Less.

The aripiprazole ODT of the present invention can solve the conventional problems of aripiprazole by introducing the above-mentioned technical idea, and as a result, the oral disintegration tablet of the present invention is not substantially containing the surfactant capable of causing various problems .

In the present invention, "substantially free" means not more than about 2% by weight, preferably not more than about 1% by weight based on the total weight of the tablet, more preferably not more than 0.2% Means to contain not more than 1% by weight, and more preferably does not include at all.

In the aripiprazole ODT of the present invention, as the sugar alcohol, mannitol, xylitol, sorbitol, maltitol, erythritol or a mixture thereof may be used. In particular, Mannitol is preferred. For example, when sorbitol and maltitol are used, sticking may occur during tableting of the disintegration tablet, which is less suitable for mass production. In addition, when the sorbitol and maltitol are used, the moisture content of the solid dispersion is high and the stability may not be good. In the case of the oral disintegration tablet of aripiprazole using maltitol, the disintegration is relatively slow.

The content of the sugar alcohol (especially mannitol) in forming the three-component solid dispersion according to the present invention is preferably less than 3 parts by weight based on 1 part by weight of aripiprazole, more preferably 0.1 to 2.5 parts by weight Still more preferably 0.5 to 2 parts by weight.

In the aripiprazole ODT according to the present invention, hydrophilic polymers for forming a solid dispersion include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG ), Polyvinyl alcohol (PVA), sodium-carboxymethylcellulose (Na-CMC), xanthan gum, polymethacrylate, starch, starch derivative or mixtures thereof Among them, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) or a mixture thereof is more preferable for various purposes of the present invention, and the flowability, mouth feel, dissolution rate and disintegration time In many aspects, hydroxypropylmethylcellulose (HPMC) is most preferred.

The viscosity of the hydrophilic polymer (particularly, hydroxypropylmethylcellulose (HPMC)) for forming such a solid dispersion is in the range of 2.5 to 10 cps when measured using a conventional polymer viscosity measuring apparatus in a 2 wt% aqueous solution at 20 캜 More preferably 4 to 6 cps. When the viscosity of the hydrophilic polymer for solid dispersion formation is too high, disintegration in the oral cavity is slowed and a foreign body sensation is caused. If the viscosity is too low, the effect of improving the dissolution rate may be insignificant.

In consideration of the formation of the solid dispersion, the improvement of the dissolution rate, the disintegration time in the oral cavity, etc., the content of the hydrophilic polymer (especially HPMC) is preferably 0.3 to 0.04 part by weight relative to 1 part by weight of aripiprazole, To 0.04 parts by weight, more preferably 0.16 to 0.06 parts by weight.

The present invention also relates to a process for producing aripiprazole ODT according to the present invention, wherein d (0.9) of the solid dispersion is in the range of 10 - More preferably 10 to 30 占 퐉, and further preferably 10 to 25 占 퐉. The solid dispersion has a d (0.5) of preferably 5 to 20 μm, more preferably 5 to 10 μm.

The aripiprazole ODT according to the present invention may contain various additives in addition to the above-mentioned components, without impairing the object of the present invention. Disintegrating agents such as low-substituted hydroxypropylcellulose (L-HPC), crospovidone, croscarmellose sodium, starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose and the like; Lubricants such as magnesium stearate, talc, sodium stearyl fumarate, calcium stearate and silicon dioxide; Flavoring agents; coloring agent; Antioxidants, and the like, but the present invention is not limited to these kinds of additional components.

For the purpose of the present invention, the oral disintegration tablet of the present invention contains 7% by weight or less, preferably 5% by weight or less, of the insoluble component excluding the lubricant, based on the total weight of the oral disintegration tablet, Preferably 3% by weight or less. It is also preferable that the three-component solid dispersion of the present invention for preparing the oral disintegration tablet does not substantially contain an insoluble component.

The present invention also relates to a method for preparing a solution or suspension comprising (S1) a solution or suspension containing aripiprazole, a hydrophilic polymer and a sugar alcohol (preferably mannitol); And (S2) spray-drying the solution or suspension to prepare a solid dispersion. The method of manufacturing an orally disintegrating tablet containing aripiprazole according to claim 1, , The manufacturing method according to the present invention further comprises (S3) a step of mixing the solid dispersion thus prepared with sugar alcohol (preferably mannitol), and then (S4) do.

In the above production method according to the present invention, the content of the sugar alcohol (preferably mannitol) for forming the three-component solid dispersion is preferably less than 3 parts by weight based on 1 part by weight of aripiprazole, considering elution stability and flowability More preferably 0.1 to 2.5 parts by weight, still more preferably 0.5 to 2 parts by weight.

In the above production method according to the present invention, the viscosity of the hydrophilic polymer (particularly, hydroxypropylmethylcellulose (HPMC)) for forming the three-component solid dispersion is measured with a conventional polymer viscosity measuring device It is preferably 2.5 to 10 cps, more preferably 4 to 6 cps.

In the production method according to the present invention, the content of the hydrophilic polymer (particularly, HPMC) for forming the three-component solid dispersion is preferably 0.3 to 0.04 parts by weight, more preferably 0.25 to 0.04 parts by weight relative to 1 part by weight of aripiprazole And more preferably 0.16 to 0.06 part by weight.

In the manufacturing method according to the present invention, the spray drying may be performed using a spray-dryer or fluid-bed granulator commonly used in the field of the present invention, The present invention is not limited thereto.

In the preparation of the three-component solid dispersion granules according to the present invention, the spray drying method is preferable, and when the granules are produced by a general wet granulation method, disintegration is slowed, have. It is understood that the size of the granule in the manufacture of a general wet granule becomes larger as compared with the method of producing a spray-dried solid dispersion, and the size of the enlarged granule affects the melting rate, which slows down the disintegration rate of the tablet. It is not limited to this mechanism.

The present invention provides an aripiprazole-containing ODT excellent in absorption and dissolution rate and excellent in mouthfeel such as taste, foreign body and the like, and a method for producing the same.

1 is a graph showing the effect of improving the dissolution rate of the three-component solid dispersion according to the present invention.
2 is a graph showing a change in dissolution rate depending on a polymer used as a binder in the three-component solid dispersion according to the present invention.
FIG. 3 is a dissolution graph showing the effect of presence or absence of sugar alcohol on the dissolution rate of the tablet in the three-component solid dispersion according to the present invention.
4 is a dissolution graph showing the influence of the viscosity of the hydrophilic polymer used in the three-component solid dispersion according to the present invention on the dissolution rate.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Examples 1-3 > Effect evaluation of three-component solid dispersion

Using the ingredients and the contents shown in Table 1, tablets containing aripiprazole were prepared as follows.

First, Example 1 was prepared as follows. 72 g of D-mannitol and 8 g of HPMC were dissolved in 600 g of water. The resulting solution was suspended in 32 g of L-HPC and 24 g of aripiprazole while stirring with a mechanical stirrer. The obtained suspension was spray-dried using a spray dryer (Mini spray dryer, Buchi 290) at an inlet temperature of 130 to 135 ° C and an outlet temperature of 65 to 75 ° C to obtain a solid dispersion. Tablets containing 3 mg of Aripiprazole were prepared by mixing 104 g of the solid dispersion, 652 g of D-mannitol, and 12 g of magnesium stearate and then tableting with a single tablet machine (Killian SP300) at a weight of 100 mg per tablet.

Example 2 was prepared as follows. 72 g of D-mannitol was dissolved in 600 g of water. The resulting solution was suspended in 32 g of L-HPC and 24 g of aripiprazole while stirring with a mechanical stirrer. Using the obtained suspension, a solid dispersion was obtained in the same manner as in Example 1. Tablets containing 3 mg of Aripiprazole were prepared by mixing 104 g of the solid dispersion, 652 g of D-mannitol, and 12 g of magnesium stearate and then tableting with a single tablet machine (Killian SP300) at a weight of 100 mg per tablet.

Example 3 was prepared as follows. Tablets containing 3 mg of Aripiprazole were prepared by mixing 24 g of Aripiprazole, 30 g of L-HPC, 684 g of D-mannitol and 12 g of magnesium stearate and then tableting with a single tablet machine (Killian SP300) at a weight of 100 mg per tablet.

Function Composition Example 1 Example 2 Example 3 Spray Drying (w / HPMC) Spray Drying (w / o HPMC) Direct Compression (w / disintegrant) mg / T mg / T mg / T API Aripiprazole 3.0 3.0 3.0 Excipient D-Mannitol 9.0 9.0 - Binder HPMC (4.5 cps) 1.0 - - Disintegration L-HPC (NBD-022) 4.0 4.0 10.0 Excipient D-Mannitol 81.5 82.5 85.5 Lubricant Magnesium Stearate 1.5 1.5 1.5

The dissolution rates of the above Examples 1-3 were evaluated. Specifically, 900 ml of pH 5.0 sodium acetate buffer was used as the elution medium, and paddle method (75 rpm) was used. The dissolution test results are shown in Fig. As a positive control group, Abilify ^TM containing 3 mg of aripiprazole, OD was used.

As shown in FIG. 1, it was confirmed that the oral disintegration tablet containing the three-component aripiprazole solid dispersion according to the present invention was eluted very rapidly. In particular, the elution of Example 2 was very slow despite the fact that HPMC, a polymer used as a binder and used to hold each component, was not used. In the case of Example 3 prepared by the direct method, The elution was much slower than the three-component solid dispersion according to the present invention.

≪ Examples 4 to 8 > Effect evaluation according to kind of polymer

Using the components and contents described in Table 2, tablets containing aripiprazole were prepared as follows.

Specifically, 72 g of D-mannitol and 8 g of binder were dissolved in 600 g of water. The resulting solution was suspended with 24 g of aripiprazole while stirring with a mechanical stirrer. Using the obtained suspension, a solid dispersion was obtained in the same manner as in Example 1. A tablet containing 24 mg of Aripiprazole was prepared by mixing 104 g of the solid dispersion, 35 g of crospovidone, 205.8 g of D-mannitol, and 5.3 g of magnesium stearate, followed by tableting at a weight of 350 mg per tablet using a single tablet press (Killian SP300).

Function Composition Example 4 Example 5 Example 6 Example 7 Example 8 HPMC 3cps HPMC 4.5cps HPC-L HPC-SL PVP-k30 mg / T mg / T mg / T mg / T mg / T API Aripiprazole 24.0 24.0 24.0 24.0 24.0 Excipient D-Mannitol 72.0 72.0 72.0 72.0 72.0 Binder HPMC 3cps 8.0 HPMC 4.5cps 8.0 HPC-L 8.0 HPC-SL 8.0 PVP-K30 8.0 Disintegration Crospovidone 35.0 35.0 35.0 35.0 35.0 Excipient D-Mannitol 205.8 205.8 205.8 205.8 205.8 Lubricant Magnesium Stearate 5.3 5.3 5.3 5.3 5.3

The dissolution rates of the above Examples 4-8 were evaluated. Specifically, 900 ml of pH 5.0 sodium acetate buffer was used as the elution medium, and paddle method (75 rpm) was used. The dissolution test results are shown in Fig.

As shown in FIG. 2, HPC and HPMC are preferred as the polymer for forming the solid dispersion in the oral disintegration tablet containing the three-component aripiprazole solid dispersion according to the present invention, while those of PVP exhibit unsatisfactory elution The results are shown.

The particle diameters of the solid dispersions prepared in Example 4-8 were measured and the results are shown in Table 3 below. Helos (laser diffraction) instrument was used for particle size measurement. D (0.5) means a particle size distribution in which 50% of particles are smaller than or equal to the corresponding size, and d (0.9) means a particle size distribution in which 90% % Means that the particle size distribution is smaller than the corresponding size.

Formulation No. (Unit: μm) d (0.1) d (0.5) d (0.9) Aripiprazole 1.08 4.80 10.57 SD Granule (PVP) 7.11 20.54 44.47 SD Granule (HPC-SL) 1.39 5.12 14.43 SD Granule (HPMC 4.5 cps) 1.84 7.82 24.14 SD Granule (HPMC 3 cps) 1.71 7.17 39.19

As shown in Table 3, the sizes of the solid dispersion particles produced depending on the kind of the polymer used for forming the solid dispersion were different, which greatly influenced the degree of foreign matter, which is an important physical property of ODT.

In ODT according to the present invention, the d (0.9) of the solid dispersion is preferably in the range of 10 to 50 占 퐉, taking into account the sensation of foreign substance, solubility, etc., and taking into account the ease of production such as flowability during the production process. More preferably 10 to 30 占 퐉, and further preferably 10 to 25 占 퐉. The solid dispersion has a d (0.5) of preferably 5 to 20 μm, more preferably 5 to 10 μm.

Examples 9 to 10 Evaluation according to presence or absence of mannitol in the solid dispersion

Using the ingredients and the contents shown in Table 4, a disintegration tablet containing aripiprazole was prepared in the same or similar manner as in Example 1.

Function Composition Example 9 Example 10 (w / o mannitol in SD) (w mannitol in SD) mg / T mg / T Solid dispersion API Aripiprazole 24.0 24.0 Excipient D-Mannitol 48.0 Binder HPMC (4.5 cps) 2.0 2.0 After mixing Disintegration Crospovidone 10.5 10.5 Disintegration HPS (Hydroxypropyl starch) 24.5 24.5 Excipient D-Mannitol 230.5 278.5 Lubricant Colloidal Silica Dioxide 3.5 3.5 Lubricant Sodium Stearyl Fumarate 7.0 7.0

Flowability was measured using pre-tablet granulation of the mixture prepared in Examples 9 and 10 above. As a method for measuring the flowability of the powder, an angle of repose, which is the angle of the inclined slope of the powder passing through the funnel, was measured. The larger the powder particle, the more angular the angle of repose increases, the greater the angle of repose, the less fluidity, and the smaller the powderiness, the better the fluidity. The results are shown in Table 5 below.

Example 9 Example 10 Angle of repose value 48.37 [deg.] 40.36 DEG

As shown in Table 5, the flowability of Example 10 containing mannitol, which is a sugar alcohol at the time of preparing the solid dispersion, was much better than that of Example 9. As a result, if the sugar alcohol is included in the solid dispersion, ODT The packing efficiency is improved and the filling deviation is reduced, so that the manufacturing efficiency can be remarkably improved.

In addition to the flowability, the ODT containing sugar alcohol in the solid dispersion was better melted in the oral cavity than the ODT containing no sugar alcohol in the solid dispersion, and the foreign matter was much reduced.

The dissolution results of Examples 9 and 10 are shown in Fig. As shown in FIG. 3, it can be seen that the inclusion of sugar alcohol in the aripiprazole solid dispersion results in a small deviation in filling of the solid dispersion during tableting, and a small variation in individual dissolution rate.

≪ Examples 11 to 15 > Evaluation according to changes in the content of mannitol in the solid dispersion

Using the ingredients and the contents shown in Table 6, a disintegration tablet containing aripiprazole was prepared in the same or similar manner as in Example 1.

 (mg / T) Function Composition Example 11 12 13 14 15 Solid dispersion API Aripiprazole 24 24 24 24 24 Excipient D-Mannitol 120 72 48 24 0 Binder HPMC 645 (4.5 cps) 4 4 4 4 4 After mixing Disintegration Crospovidone 10.5 10.5 10.5 10.5 10.5 Disintegration HPS 24.5 24.5 24.5 24.5 24.5 Excipient D-Mannitol 156.5 204.5 228.5 252.5 276.5 Lubricant Colloidal Silica Dioxide 3.5 3.5 3.5 3.5 3.5 Lubricant Sodium Stearyl Fumarate 7.0 7.0 7.0 7.0 7.0

The elution stability of Examples 11 to 15 was evaluated as follows, and the results are shown in Table 7 below. Specifically, tablets were prepared as described above and packaged in Alu-Alu, a packaging substrate having excellent airtightness, and stored at 60 ° C / 80% RH for 2 weeks. Before and after the stability test, the sample was eluted with paddle method (75 rpm) using 900 ml of pH 5.0 sodium acetate buffer as the elution medium.

Example 11 12 13 14 15 Dissolution% at 15min
(Initial) 93.2 89.1 89.6 85.6 89.2 Dissolution% at 15 min (60 ° C / 80% RH, 2 weeks) 53.0 73.0 88.7 88.3 88.8

As shown in Table 7, when the content of mannitol was 3 parts by weight or more based on 1 part by weight of aripiprazole, the elution stability of ODT could not be secured. Therefore, the content of mannitol relative to 1 part by weight of aripiprazole is preferably less than 3 parts by weight, more preferably 0.1 to 2.5 parts by weight, and still more preferably 0.5 to 2 parts by weight.

≪ Examples 16 to 19 > Evaluation according to viscosity change of HPMC in solid dispersion

Using the ingredients and the contents shown in Table 8, a disintegration tablet containing aripiprazole was prepared in the same or similar manner as in Example 1.

(mg / T) Function Composition Example 16 17 18 19 Solid dispersion API Aripiprazole 24 24 24 24 Excipient D-Mannitol 48 48 48 48 Binder HPMC 2
(3 cps) 2
(4.5 cps) 2
(6 cps) 2
(15 cps) After mixing Disintegration Crospovidone 10.5 10.5 10.5 10.5 Disintegration HPS 24.5 24.5 24.5 24.5 Excipient D-Mannitol 230.5 230.5 230.5 230.5 Lubricant Colloidal Silica Dioxide 3.5 3.5 3.5 3.5 Lubricant Sodium Stearyl Fumarate 7.0 7.0 7.0 7.0

The viscosity of the HPMC is measured by a 2 wt% aqueous solution at 20 캜.

The disintegration time (sec) in the mouth of the oral disintegration tablets prepared in Examples 16 to 19 was measured and shown in Table 9 below.

Unit: second Example 16 17 18 19 Disintegration (in vivo) 25 seconds 27 seconds 45 seconds 60 seconds or more

As shown in Table 9, when the viscosity of the hydrophilic polymer for forming a solid dispersion of aripiprazole exceeds 6 cps, the disintegration in the oral cavity becomes too slow, resulting in a problem of causing a lot of foreign bodies when taken.

The dissolution results of Examples 16 to 18 are shown in Fig. The elution test was carried out in the same manner as in Example 9. As shown in FIG. 4, when the viscosity of the HPMC used for forming the solid dispersion was less than 3 cps, the effect of improving the dissolution rate was lowered.

Therefore, in the oral disintegration tablet according to the present invention, the viscosity of the hydrophilic polymer (particularly, hydroxypropylmethyl cellulose (HPMC)) for forming a solid dispersion is measured by using a conventional polymer viscosity measuring apparatus in an aqueous 2 wt% solution at 20 ° C , It is preferably 2.5 to 10 cps, more preferably 4 to 6 cps.

≪ Examples 20 to 23 > Evaluation according to changes in the content of HPMC in the solid dispersion

Using the components and the contents shown in Table 10, a disintegration tablet containing aripiprazole was prepared in the same or similar manner as in Example 1.

(mg / T) Function Composition Example 20 21 22 23 Solid dispersion API Aripiprazole 24 24 24 24 Excipient D-Mannitol 48 48 48 48 Binder HPMC (4.5 cps) 8 4 3 2 After mixing Disintegration Crospovidone 10.5 10.5 10.5 10.5 Disintegration HPS 24.5 24.5 24.5 24.5 Excipient D-Mannitol 224.5 228.5 229.5 230.5 Lubricant Colloidal Silica Dioxide 3.5 3.5 3.5 3.5 Lubricant Sodium Stearyl Fumarate 7.0 7.0 7.0 7.0

The viscosity of the HPMC is measured by a 2 wt% aqueous solution at 20 캜.

The disintegration time (sec) and the tablet hardness of the oral disintegration tablets prepared in Examples 20 to 23 were measured and shown in Table 11 below.

Unit: second Example 20 21 22 23 Disintegration (in vivo) 90 seconds 40 seconds 33 seconds 27 seconds Tablet Hardness 32 to 38 N 32 to 38 N 32 to 39 N 30 to 35 N

As shown in Table 11, when the content of the hydrophilic polymer for forming a solid dispersion of aripiprazole is more than 0.3 parts by weight relative to 1 part by weight of aripiprazole, disintegration in the oral cavity becomes too slow, resulting in a lot of foreign bodies . As a result, the inventors of the present invention found that the oral disintegration time of the aripiprazole oral disintegration tablet was within at least one minute, which was suitable for oral disintegration properties.

Therefore, when the total amount of the hydrophilic polymer (particularly, HPMC) is 0.3 to 0.04 parts by weight based on 1 part by weight of aripiprazole, taking into account the formation of solid dispersion, improvement of dissolution rate, securing hardness of proper tablet, More preferably from 0.25 to 0.04 part by weight, still more preferably from 0.16 to 0.06 part by weight.

≪ Examples 24 to 27 > Effect evaluation according to kinds of sugar alcohols

Using the ingredients and the contents shown in Table 12, a disintegration tablet containing aripiprazole was prepared in the same or similar manner as in Example 1.

(mg / T) Function Composition Example 24 25 26 27 Solid dispersion API Aripiprazole 24 24 24 24 Excipient Sugar alcohol Mannitol
24 Sorbitol
24 Maltitol
24 Microcrystalline cellulose
24 Binder HPMC (4.5 cps) 2 2 2 2 After mixing Disintegration Crospovidone 10.5 10.5 10.5 10.5 Disintegration HPS 24.5 24.5 24.5 24.5 Excipient D-Mannitol 254.5 254.5 254.5 254.5 Lubricant Colloidal Silica Dioxide 3.5 3.5 3.5 3.5 Lubricant Sodium Stearyl Fumarate 7.0 7.0 7.0 7.0

The viscosity of the HPMC is measured by a 2 wt% aqueous solution at 20 캜.

The particle size of the granules was measured using a Loss on Drying (Halden Moisture Analyzer (Metter / Toledo) apparatus, no weight change after 10 minutes at 105 ° C) of the solid dispersion granules prepared in Examples 24 to 27 (d (0.9), using HELOS instrument) and disintegration time (sec) and refined hardness of oral disintegration tablet were measured and shown in Table 13 below.

Unit: second Example 24 25 26 27 SD Granule L.O.D 0.75% 2.55% 2.70% 1.54% SD particle size (d (0.9), m) 14.7 29.86 13.57 55.6 Disintegration (in vivo) 38 seconds 26 seconds 2 minutes 11 seconds 2 minutes Tablet Hardness 30 ~ 35N 29 ~ 33N 32 ~ 38N 32 ~ 35N

As shown in Table 13, the solid dispersion using sorbitol and maltitol had a high LOD, which was highly likely to stick during tableting. On the other hand, in the case of the solid dispersion granules using sorbitol, the particle size was large and the agglomerates were formed, resulting in a low degree of mixing in the post-mixing process and giving rise to a foreign sensation when administered. The disintegration of the oral disintegration tablet of aripiprazole using maltitol was slow.

On the other hand, in Example 27 in which microcrystalline cellulose, which is an insoluble filler commonly used in place of sugar alcohol, was used, the LOD was high and the particle size of the solid dispersion granules was very large and the disintegration time in the oral cavity was very slow. Furthermore, oral disintegration tablets using insoluble microcrystalline cellulose were very poorly assessed by the subjects because of a very pronounced sensation of foreign body sensation. As a result, the oral disintegration tablet of the present invention contains 7% by weight or less, preferably 5% by weight or less, more preferably 3% by weight or less of the insoluble component with respect to the total weight of the oral disintegration tablet. It is also preferable that the three-component solid dispersion of the present invention for preparing the oral disintegration tablet does not substantially contain an insoluble component.

Claims (21)

In an orally disintegrating tablet comprising aripiprazole as an active ingredient,
Wherein the tablet comprises aripiprazole and a solid dispersion of a hydrophilic polymer, wherein the solid dispersion comprises an insoluble component in an amount of 1% by weight or less based on the total weight of the tablet,
Wherein said tablet comprises sugar alcohols. The oral cavity disintegrating tablet according to claim 1, wherein a part of the sugar alcohol is contained in the solid dispersion. 3. The oral disintegration tablet according to claim 1 or 2, wherein the sugar alcohol is mannitol, xylitol, sorbitol, maltitol, erythritol or a mixture thereof. The oral disintegration tablet according to claim 3, wherein the sugar alcohol is mannitol. The oral disintegration tablet according to claim 4, wherein the content of mannitol contained in the solid dispersion is less than 3 parts by weight based on 1 part by weight of aripiprazole. The method of claim 1, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol Characterized in that it is carboxymethylcellulose (Na-CMC), xanthan gum, polymethacrylate, starch, starch derivative or a mixture thereof. The oral disintegration tablet according to claim 6, wherein the hydrophilic polymer is hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), or a mixture thereof. The oral disintegration tablet according to claim 7, wherein the viscosity of the hydrophilic polymer is 2.5 to 10 cps as measured with a 2 wt% aqueous solution at 20 ° C. The oral disintegration tablet according to claim 7, wherein the content of the hydrophilic polymer is 0.3 to 0.04 parts by weight relative to 1 part by weight of aripiprazole. The oral disintegration tablet according to claim 7, wherein the hydrophilic polymer is hydroxypropyl methylcellulose (HPMC). The oral disintegration tablet according to claim 1, wherein the oral disintegration tablet contains an insoluble component in an amount of 5% by weight or less based on the total weight of the oral disintegration tablet. (S1) preparing a solution or suspension containing aripiprazole, a hydrophilic polymer and a sugar alcohol; And
(S2) spray-drying the solution or suspension to prepare a solid dispersion,
Wherein the solid dispersion comprises an insoluble component in an amount of 1% by weight or less based on the total weight of the tablets. 13. The method of claim 12, wherein said method further comprises: (S3) mixing said solid dispersion with a sugar alcohol. The method according to claim 12 or 13, wherein the sugar alcohol is mannitol, xylitol, sorbitol, maltitol, erythritol or a mixture thereof. 15. The method according to claim 14, wherein the sugar alcohol is mannitol. 16. The method according to claim 15, wherein the content of mannitol contained in the solid dispersion is less than 3 parts by weight based on 1 part by weight of aripiprazole. The method of claim 12, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol Characterized in that it is carboxymethylcellulose (Na-CMC), xanthan gum, polymethacrylate, starch and starch derivatives or mixtures thereof. 18. The method according to claim 17, wherein the hydrophilic polymer is hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), or a mixture thereof. The method according to claim 18, wherein the viscosity of the hydrophilic polymer is 2.5 to 10 cps as measured with a 2 wt% aqueous solution at 20 캜. The method according to claim 18, wherein the content of the hydrophilic polymer is 0.3 to 0.04 parts by weight relative to 1 part by weight of aripiprazole. 19. The method of claim 18, wherein the hydrophilic polymer is hydroxypropyl methylcellulose (HPMC).

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