KR102090784B1 - Pharmaceutical formulation for oral administration comprising atomoxetine having a rapid dissolution rate and method for preparation thereof - Google Patents

Abstract

The present invention is 1) atomoxetine or a pharmaceutically acceptable salt thereof; 2) starch having a particle D ₉₀ of 50 to 200 μm and a span value of 1 to 2; And 3) a pharmaceutical preparation for oral use, and a preparation method thereof, comprising a pharmaceutically acceptable additive selected from the group consisting of a disintegrant, a lubricant, and a mixture thereof, wherein the pharmaceutical preparation of the present invention has an improved disintegration rate and dissolution rate. Since it exhibits excellent absorption rate in the body, it can be usefully used as a preventive or therapeutic agent for attention deficit / hyperactivity disorder (ADHD).

Description

Pharmaceutical preparations for oral use containing atomoxetine that exhibits a rapid dissolution rate and a method of manufacturing the same PHARMACEUTICAL FORMULATION FOR ORAL ADMINISTRATION COMPRISING ATOMOXETINE HAVING A RAPID DISSOLUTION RATE AND METHOD FOR PREPARATION THEREOF}

The present invention relates to an oral pharmaceutical preparation for the prevention or treatment of attention deficit / hyperactivity disorder (ADHD) containing atomoxetine, which exhibits a rapid dissolution rate and a high absorption rate in the body, thereby improving therapeutic effect and productivity, and a method for manufacturing the same.

Attention-Deficit / Hyperactivity Disorder (ADHD), one of the most common mental disorders first seen in childhood, can occur throughout childhood and adulthood. It has been reported that about 4.1% of infants aged 9 to 17 years suffer from ADHD. Infants with ADHD cannot concentrate on anything, cannot sit quietly, act impulsively, and cannot complete their activities. Therefore, if ADHD is not treated, the infant's injury rate is higher, and it has a long-term negative effect on the ability of friends to make friends and the ability of children in school. Infants with ADHD are more likely to develop depression, self-esteem, and other emotional problems over time. In most cases, infants and adults with ADHD are treated with psychostimulants such as amphetamine, methylphenidate and pemoline. However, treatment with these drugs has serious side effects and high drug dependence.

Atomoxetine (chemical name: (R)-(-)-N-methyl-3- (2-methylphenoxy) -3-phenylpropylamine) is commonly used in the treatment of ADHD in the form of hydrochloride. As a norepinephrine reuptake inhibitor, the atomoxetine activation mechanism is described in Gehrert, DR, et al. , Neuroscience Letters , 157, 203-206 (1993). Atomoxetine is very active in function and further lacks any other central nervous system activity at concentrations or doses that effectively inhibit norepinephrine reuptake. Therefore, it has few side effects and is used as a selective drug.

Atomoxetine is a very stable drug, and due to its improved safety, the therapeutic effect on ADHD is excellent in both adults and children. In addition, atomoxetine can be administered once a day because it is medicinal and safe even when administered in relatively low amounts. Thus, the difficulty created by multiple administrations can be solved, especially for pediatric patients and adult patients with low attention.

Atomoxetine can be produced in a clean and stable crystalline form, which can be easily prepared by oral formulations such as tablets, capsules, suspensions, and the like. In addition, since it is easily absorbed orally and requires only once a day administration, there is no reason to administer by means other than oral administration. In addition, preparations in the form of injection solutions, depot injections, suppositories, etc. are also known to those skilled in the art and can be usefully administered in other formulations. However, it is more preferable to administer atomoxetine as a tablet or capsule.

Existing capsules containing atomoxetine use liquid lubricants, which are inconvenient to produce during production, and have a disadvantage in that mixing is less than that of powder lubricants.

Thus, the present inventors have shown an improved dissolution rate and absorption rate in the body, and as a result of diligent research to develop a pharmaceutical formulation containing atomoxetine with improved therapeutic effect and productivity, the particle size of starch as a disintegrant, lubricant, and excipient is an important factor The present invention was completed by discovery.

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Gehlert, D.R., et al., Neuroscience Letters, 157, 203-206 (1993)

Accordingly, an object of the present invention is to provide an oral pharmaceutical formulation containing atomoxetine that is rapidly disintegrated and absorbed in the body and a method for manufacturing the same.

In order to achieve the above object, the present invention

1) Atomoxetine or a pharmaceutically acceptable salt thereof;

2) starch having a particle D ₉₀ of 50 to 200 μm and a span value of 1 to 2; And

3) A pharmaceutically acceptable additive selected from the group consisting of disintegrants, lubricants and mixtures thereof

It provides an oral pharmaceutical preparation for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), including.

In order to achieve the above other object, the present invention

Granules prepared by mixing starch having a D ₉₀ of 50 to 200 μm and a span value of 1 to 2 with a disintegrant, and then adding and mixing atomoxetine or a pharmaceutically acceptable salt and lubricant thereof Provided is a method of preparing an oral pharmaceutical preparation for the prevention or treatment of attention deficit hyperactivity disorder, which includes formulation.

The pharmaceutical preparation for oral use of the present invention is useful for the prevention or treatment of ADHD because it exhibits a rapid dissolution rate and rapidly absorbed in vivo without entailing a reduction in the quality due to the enlargement of the preparation or the interaction of the active ingredient with the disintegrant. Can be used.

1 shows the measurement results of particle size distribution and particle size of pregelatinized starch.
2 to 4 is a graph showing the dissolution rate of atomoxetine over time of the capsules prepared in Examples and Comparative Examples.

The present invention is 1) atomoxetine or a pharmaceutically acceptable salt thereof; 2) starch having a particle D ₉₀ of 50 to 200 μm and a span value of 1 to 2; And 3) a pharmaceutically acceptable additive selected from the group consisting of disintegrants, lubricants, and mixtures thereof, to provide an oral pharmaceutical preparation for the prevention or treatment of attention deficit hyperactivity disorder.

Atomoxetine or a pharmaceutically acceptable salt thereof used as the active ingredient in the present invention is preferably in the form of particles, and the size of the particles of atomoxetine affects the disintegration and dissolution of pharmaceutical preparations, thus affecting the clinical effect. It is considered to be an important parameter influencing. Accordingly, atomoxetine may have a particle size (D ₉₀ ) of about 1 μm to about 10 μm, preferably about 5 μm to about 7 μm.

The atomoxetine or a pharmaceutically acceptable salt thereof may be included in an amount of 15 to 65% by weight, preferably 15 to 30% by weight based on the total weight of the formulation.

The effective dosage of atomoxetine for ADHD is from about 5 mg to about 100 mg per unit dosage form. A preferred adult dosage is about 10 mg to about 30 mg and a more preferred adult dosage is about 20 mg to about 60 mg. The pediatric dosage is, of course, less, about 5 mg to about 70 mg, more preferably about 10 mg to about 60 mg, very preferably about 10 mg to about 50 mg. The optimal dosage for each patient should be determined by the attending physician, taking into account the patient's volume, other medications required for the patient, the severity of the disease and other circumstances of the patient, as in the usual case.

The starch used as an excipient in the present invention may be selected from the group consisting of corn starch, potato starch, pregelatinized starch and mixtures thereof, and pregelatinized starch is preferred. Starch may be included in an amount of 30 to 80% by weight, preferably 65 to 80% by weight based on the total weight of the formulation.

Starch is D ₉₀ of the particle (Here, D ₉₀ is a means a diameter of particles corresponding to 90%, based on the volume) up to about 200 μm as the largest dimension, and preferably 50 to 200μm, for example, about 150 μm The effect of the invention can be exhibited only when the one is used. The particle represents the uniformity as a span value, and the span value is calculated as (X ₉₀ -X ₁₀ ) / X ₅₀ in the particle distribution (where X ₁₀ , X ₅₀ and X ₉₀ are 10%, 50%, and 90%). It shows the particle size showing cumulative distribution), and the smaller the span value, the narrower the size distribution. The starch used in the present invention preferably has a span value of less than 5, preferably 1 to 2.

According to the present invention, only when the pregelatinized starch used as an excipient exhibits a constant particle size distribution, it exhibits a rapid disintegration time and a rapid dissolution rate.

In the present invention, as a pharmaceutically acceptable additive, it may include a component selected from the group consisting of disintegrants, lubricants, and mixtures thereof. The use of the lubricant increases the mixing degree of the active ingredient and excipients, and the use of the disintegrant increases the disintegration power. Therefore, in the present invention, it is preferable that both a disintegrant and a lubricant are present. The pharmaceutical formulation according to the present invention can promote the dispersion and dissolution of atomoxetine when ingested, resulting in an increase in productivity and bioavailability.

The disintegrant may be selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, sodium carboxymethylcellulose, and mixtures thereof, 3 to 15% by weight based on the total weight of the formulation, preferably 4 to 8% by weight.

The lubricant may be selected from the group consisting of sodium stearyl fumarate, polyethylene glycol, talc, and mixtures thereof, and may be included in an amount of 0.6 to 5% by weight, preferably 0.7 to 3% by weight, based on the total weight of the formulation. have.

Particularly, when the lubricant according to the present invention is used, not only can the glidability be increased, but also the degree of mixing with the active ingredient is increased, uniform content uniformity is exhibited, and as a result, productivity is increased.

The pharmaceutical preparation according to the present invention may be a solid preparation such as granules, granules, tablets, capsules, etc., preferably granules, granules, or capsules filled with them.

Atomoxetine is a drug that is rapidly absorbed in vivo with a C _max reaching time of about 1 hour. The pharmaceutical formulation of the present invention containing such atomoxetine is 85% or more in 5 minutes, 90% or more in 10 minutes, 95% or more in 15 minutes in a dissolution test using 0.1N HCl solution as an eluent according to the USP paddle method. The dissolution rate can be indicated.

In addition, the present invention is mixed with a starch having a D ₉₀ of 50 to 200 μm and a span value of 1 to 2 of a particle with a disintegrant, followed by addition of atomoxetine or a pharmaceutically acceptable salt and lubricant thereof. It provides a method for preparing the oral pharmaceutical preparation, comprising the formulation of one granule.

Before mixing the atomoxetine with the excipient, mixing the excipient and disintegrant first and then mixing the atomoxetine a second time, followed by mixing the lubricant, is not only effective in providing the desired bioavailability, but also the mixing Or it has been found to be advantageous in solving problems related to the cohesiveness and mixing degree of the main component and lubricant during compounding. This can be obtained by uniformity of mixing due to reduced aggregation of excipients, etc. through secondary mixing of atomoxetine, which uniformity is particularly important in formulating unit dosage forms such as capsules or tablets.

In addition, the manufacturing method of the present invention can contribute to the rapid dissolution rate of pharmaceutical preparations by simple granulation, not wet or dry granulation.

The pharmaceutical preparation according to the present invention can increase the mixing degree of granules and improve productivity by using a specific lubricant, and improve the bioavailability by increasing the disintegrating power of the pharmaceutical preparation using a specific disintegrant. The pharmaceutical formulation of the present invention suppresses hyperactivity, attention deficit, and impulsivity by including acemoxetine as an active ingredient, thereby exhibiting a therapeutic effect on ADHD, thereby solving psychosocial disorders, including learning disabilities in children, and in the long term. It can prevent expected adolescent misconduct or deviant behavior and drug abuse and crime in adulthood.

[Example]

The present invention will be described in more detail through the following examples. These examples are intended to illustrate the present invention more specifically, but the present invention is not limited thereto.

Example 1: Preparation of atomoxetine hydrochloride capsules

According to the composition shown in Table 1, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (imported from: Roquette, D ₉₀ : Granules were prepared by uniformly mixing 174.6 μm, span value: 1.67), croscarmellose sodium and sodium stearyl fumarate. The granules thus prepared were filled in No. 3 capsules (capsule manufacturer: Seoheung Capsule) according to a conventional method to prepare capsules. When mixing, pregelatinized starch and croscarmellose sodium were first placed in a mixer (importer: Sejong), mixed thoroughly, and then mixed by adding atomoxetine hydrochloride. Then, sodium stearyl fumarate was added and mixed for 10 minutes to prepare a capsule.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 71.9 148.89 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Example 2

According to the composition shown in Table 2, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (imported from: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), crospovidone and sodium stearyl fumarate were uniformly mixed to prepare granules. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. As described in Example 1, as described in Example 1, the disintegrant and pregelatinized starch were first mixed, and the main component, atomoxetine hydrochloride, was separately added, followed by post-mixing of sodium stearyl fumarate.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 71.9 148.89 Crospovidone 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Example 3

According to the composition shown in Table 3, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (imported from: Roquette, D ₉₀ : Granules were prepared by uniformly mixing 174.6 μm, span value: 1.67), sodium carboxymethylcellulose and sodium stearyl fumarate. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. As described in Example 1, as described in Example 1, the disintegrant and pregelatinized starch were first mixed, and the main component, atomoxetine hydrochloride, was separately added, followed by post-mixing of sodium stearyl fumarate.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 71.9 148.89 Sodium carboxymethylcellulose 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Example 4

According to the composition shown in Table 4, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (imported from: Roquette, D ₉₀ : Granules were prepared by uniformly mixing 174.6 μm, span value: 1.67), sodium starch glycolate and sodium stearyl fumarate. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. As described in Example 1, as described in Example 1, the disintegrant and pregelatinized starch were first mixed, and the main component, atomoxetine hydrochloride, was separately added, followed by post-mixing of sodium stearyl fumarate.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 71.9 148.89 Sodium starch glycolic acid 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Comparative example  One

Atomoxetine hydrochloride (D ₉₀ : 34.5 μm), pregelatinized starch (received by: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), croscarmellose, according to the composition shown in Table 5 below Granules were prepared by uniformly mixing sodium and sodium stearyl fumarate. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. As described in Example 1, as described in Example 1, the disintegrant and pregelatinized starch were first mixed, and the main component, atomoxetine hydrochloride, was separately added, followed by post-mixing of sodium stearyl fumarate.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride (micro x) 22.1 45.71 Pregelatinized starch 71.9 148.89 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Comparative example  2

According to the composition shown in Table 6, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch that does not exhibit a uniform particle size (import: Colorcon, D ₉₀ : 148.0 μm, span value: 2.34), cross camel Granules were prepared by uniformly mixing los sodium and sodium stearyl fumarate. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. At this time, the mixing procedure was as described in Example 1, the disintegrant and pregelatinized starch were first mixed, and the main component, atomoxetine hydrochloride, was separately added, followed by post-mixing of sodium stearyl fumarate.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch (uniform x granularity) 71.9 148.89 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Comparative example  3

According to the composition shown in Table 7, the atomoxetine hydrochloride (D ₉₀ : 5.8 μm), D-mannitol (D ₉₀ : 145.6 μm, span value: 1.82), croscarmellose sodium and sodium stearyl fumarate were uniformly mixed. Granules were prepared. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. At this time, D-mannitol was used that shows a uniform particle size distribution that does not pass through the No. 70 sieve and passes through the No. 70 sieve, and the mixing sequence is first mixed with a disintegrant and D-mannitol, and the main component of atomoxetine hydrochloride is separately After addition, sodium stearyl fumarate was post-mixed.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 D-mannitol 71.9 148.89 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Comparative example  4

According to the composition shown in Table 8, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), microcrystalline cellulose (D ₉₀ : 151.4 μm, span value: 1.77), croscarmellose sodium and sodium stearyl fumarate were uniformly mixed. Granules were prepared. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. At this time, the microcrystalline cellulose was used to show a uniform particle size distribution that does not pass through the sieve No. 70 and no sieve No. 200. In the order of mixing, the disintegrant and the microcrystalline cellulose are first mixed, and the main component, atomoxetine hydrochloride, is separately used. After addition, sodium stearyl fumarate was post-mixed.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Microcrystalline cellulose 71.9 148.89 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Comparative example  5

According to the composition shown in Table 9, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (import: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), and sodium fumarate stearyl uniformly Mixing to prepare granules. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. With a composition without adding a disintegrant, the order of mixing was to add predominantly starch atomoxetine hydrochloride, followed by sodium stearyl fumarate.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 76.9 159.29 Sodium stearyl fumarate 1.0 2.00 gun 100.0 207.00

Comparative example  6-1

According to the composition shown in Table 10, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (import: Roquette, D ₉₀ : 174.6 μm, span value: 1.67) and croscarmellose sodium were uniformly mixed. Granules were prepared. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. With a composition without adding a lubricant, the mixing order was first mixed with a disintegrant and pregelatinized starch, as in the order described in Example 1, and the main component, atomoxetine hydrochloride, was separately added.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 72.9 150.89 Croscarmellose sodium 5.0 10.40 gun 100.0 207.00

Comparative Example 6-2

According to the composition shown in Table 11, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (import: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), croscarmellose sodium and fumaric acid stearyl Granules were prepared by uniformly mixing sodium. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. With the composition added by varying the ratio of the lubricant, the mixing order is as described in Example 1, first disintegrating agent and pregelatinized starch are mixed first, and the main component, atomoxetine hydrochloride, is separately added, and then sodium stearyl fumarate is added. After mixing.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 72.4 149.89 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 0.5 1.00 gun 100.0 207.00

Comparative Example 6-3

According to the composition shown in Table 12, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (import: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), croscarmellose sodium and fumaric acid stearyl Granules were prepared by uniformly mixing sodium. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. With the composition added by varying the ratio of the lubricant, the mixing order is as described in Example 1, first disintegrating agent and pregelatinized starch are mixed first, and the main component, atomoxetine hydrochloride, is separately added, and then sodium stearyl fumarate is added. After mixing.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 70.9 146.69 Croscarmellose sodium 5.0 10.40 Sodium stearyl fumarate 2.0 4.20 gun 100.0 207.00

Comparative Example 7-1

According to the composition shown in Table 13, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (import: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), croscarmellose sodium and magnesium stearate The granules were prepared by mixing uniformly. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. As for the mixing procedure, as shown in Example 1, the predominant starch and disintegrant were separately added with the main component, atomoxetine hydrochloride, and then magnesium stearate was post-mixed.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 71.9 148.89 Croscarmellose sodium 5.0 10.40 Magnesium stearate 1.0 2.00 gun 100.0 207.00

Comparative Example 7-2

According to the composition shown in Table 14, atomoxetine hydrochloride (D ₉₀ : 5.8 μm), pregelatinized starch (import: Roquette, D ₉₀ : 174.6 μm, span value: 1.67), croscarmellose sodium and stearic acid were uniform. The mixture was mixed to prepare granules. The granules thus prepared were filled into capsules according to the method described in Example 1 to prepare capsules. As for the mixing procedure, stearic acid was post-mixed after the predominant starch and disintegrant were separately added with the main component, atomoxetine hydrochloride, as described in Example 1.

ingredient weight(%) mg / capsule Atomoxetine hydrochloride 22.1 45.71 Pregelatinized starch 71.9 148.89 Croscarmellose sodium 5.0 10.40 Stearic acid 1.0 2.00 gun 100.0 207.00

Test example  1: particle size analysis test

The particle size distribution and particle size of pregelatinized starch used in the present invention are measured using a particle size analyzer (HELOS, Sympatec) under a pressure of 3.5 bar.

Test example  2 : Atomoxetine  Homogeneity test of capsules containing hydrochloride

The capsules containing the atomoxetine hydrochloride of Examples 1 to 4 and Comparative Examples 1 to 7-2 of the present invention were tested for content uniformity according to the Pharmacopoeia formulation uniformity test method. The results are shown in Tables 15 to 17 below. The lower the determination number, the more uniform the particles.

Example 1 Example 2 Example 3 Example 4 Content average (%) 99.8 100.4 98.9 100.2 Deviation 0.58 1.21 0.78 0.82 Judgment 1.4 2.9 1.9 2.0

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Content average (%) 99.7 100.6 99.9 100.2 98.8 Deviation 0.83 0.74 0.64 0.77 0.68 Judgment 2.0 1.8 1.5 1.8 1.6

Comparative Example 6-1 Comparative Example 6-2 Comparative Example 6-3 Comparative Example 7-1 Comparative Example 7-2 Content average (%) 9.5 100.4 100.3 99.1 98.7 Deviation 3.76 3.47 2.61 3.62 4.51 Judgment 9.0 8.3 6.3 8.7 10.8

As shown in Tables 15 to 17, Examples 1 to 4 showed uniform content uniformity compared to Comparative Examples 6-1 to 6-3, 7-1 and 7-2.

Test Example 3: Disintegration test of capsules containing atomoxetine hydrochloride

The disintegration time was measured for the capsules containing atomoxetine hydrochloride obtained in Examples 1 to 4 and Comparative Examples 1 to 7-2, and the results are shown in Tables 18 to 20 below. The disintegration time was measured as the time at which the capsule contents were all dispersed.

Furtherance Example 1 Example 2 Example 3 Example 4 Disintegration time (sec) 53 63 57 68

Furtherance Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Disintegration time (sec) 65 74 137 334 284

Furtherance Comparative Example 6-1 Comparative Example 6-2 Comparative Example 6-3 Comparative Example 7-1 Comparative Example 7-2 Disintegration time (sec) 58 55 84 68 71

As shown in Tables 18 to 20, the capsules of Examples 1 and 3 had a disintegration time rapidly disintegrating within 60 seconds, whereas Comparative Examples 1 to 5 and 6-3, 7-1 and 7-2 It was found that the case exhibits a remarkably slow disintegration time.

Test Example 4: Dissolution test of capsules containing atomoxetine hydrochloride

The capsules containing atomoxetine hydrochloride obtained in Examples 1 to 4 and Comparative Examples 1 to 7-2 were tested for dissolution of atomoxetine according to the dissolution conditions and analysis conditions described below. The results are shown in Tables 21 and 22 below and FIGS. 3 to 5.

-Elution conditions-

Eluent: 1000 mL of 0.1 N-HCl solution

Apparatus: USP paddle method, 50 rpm

Temperature: 37 ℃

-Analysis condition-

Column: L7 column for liquid chromatograph of 3.5 μm (column particle size) in a stainless tube with an inner diameter of 4.6 mm and a length of about 75 mm or similar column

Mobile phase: acetonitrile: 0.03 M potassium dihydrogen phosphate buffer (38: 62, v / v)

Detector: ultraviolet absorption photometer (measurement wavelength: 220 nm)

Flow rate: 1.5 mL / min

Injection volume: 10 μL

Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes Example 1 91.4 96.8 98.1 98.9 Example 2 85.4 93.4 95.6 97.5 Example 3 87.4 94.6 95.5 96.5 Example 4 85.5 95.4 97.7 97.8

Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes Comparative Example 1 62.7 75.6 84.3 96.8 Comparative Example 2 54.3 76.4 83.5 94.7 Comparative Example 3 37.3 52.6 71.4 87.3 Comparative Example 4 33.8 45.3 52.4 64.3 Comparative Example 5 24.7 43.7 73.5 90.3 Comparative Example 6-1 89.4 95.8 97.3 97.7 Comparative Example 6-2 90.6 93.5 96.3 98.3 Comparative Example 6-3 65.7 76.8 84.4 95.4 Comparative Example 7-1 88.4 91.5 93.3 93.7 Comparative Example 7-2 86.9 90.3 94.2 95.2

In general, the dissolution rate of atomoxetine measured at 50 rpm was measured by using a 0.1 N HCl solution, which is a liquid similar to the gastrointestinal tract, as the eluent, using the paddle method, which is the dissolution test condition most evaluated in oral pharmaceutical preparations. As shown in Tables 21 and 22, and FIGS. 3 to 5, the capsules of Examples 1 to 4 release 85% or more in 5 minutes, 90% or more in 10 minutes, and 95% or more in 15 minutes, Comparative Example 1 It was found that the dissolution rate was significantly higher than that of the capsules 5 to 6-3.

Claims (13)

1) Atomoxetine or a pharmaceutically acceptable salt thereof;
2) starch having a particle D ₉₀ of 50 to 200 μm and a span value of 1 to 2; And
3) contains a pharmaceutically acceptable additive selected from the group consisting of disintegrants, lubricants and mixtures thereof,
The atomoxetine or a pharmaceutically acceptable salt thereof has a particle size (D ₉₀₎ of 1 μm to 10 μm,
The disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, carboxymethylcellulose sodium and mixtures thereof,
The lubricant is sodium stearyl fumarate, characterized in that it is contained in an amount of 0.6 to 1% by weight based on the total weight of the formulation, oral pharmaceutical preparation for the prevention or treatment of attention deficit hyperactivity disorder.
According to claim 1,
The pharmaceutical preparation, characterized in that the atomoxetine or a pharmaceutically usable salt thereof is contained in an amount of 5 mg to 100 mg per unit dosage form.
delete According to claim 1,
The starch is a pharmaceutical preparation characterized in that it is selected from the group consisting of corn starch, potato starch, pregelatinized starch and mixtures thereof.
delete delete delete According to claim 1,
Pharmaceutical preparation characterized in that the starch is contained in an amount of 30 to 80% by weight based on the total weight of the formulation.
According to claim 1,
The pharmaceutical preparation, characterized in that the disintegrant is contained in an amount of 3 to 15% by weight based on the total weight of the formulation.
According to claim 1,
The pharmaceutical formulation, characterized in that eluting at least 85% of atomoxetine within 5 minutes.
According to claim 1,
The pharmaceutical preparation, characterized in that the pharmaceutical preparation is a granule, granule, capsule or tablet.
After mixing the starch having a D ₉₀ of 50 to 200 μm and a span value of 1 to 2 with a disintegrant selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, sodium carboxymethylcellulose and mixtures thereof , Here fumosanstea contained in an amount of 0.6 to 1% by weight based on the total weight of the formulation as atomoxetine or a pharmaceutically acceptable salt and lubricant thereof having a particle size (D ₉₀₎ of 1 μm to 10 μm A method for preparing an oral pharmaceutical preparation according to claim 1, comprising formulating granules prepared by mixing by adding aryl sodium.
The method of claim 12,
The granules, characterized in that formed by simple mixing, the manufacturing method.

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