KR20160082640A - Pharmaceutical composition comprising granules containing an active ingredient with adjusted diameter size - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising a compound represented by chemical formula I or a pharmaceutically acceptable salt thereof, wherein (A) the active ingredient (A) has a particle size distribution in which D90 of particles in the longest dimension of particles is 10 micrometers or less, and (B) the active ingredient is present in the form of granules in combination with a pharmaceutically acceptable vehicle, with the proviso that the granules have a particle size distribution in which D10 of particles is 50 micrometers or more and D90 of particles is 400-500 micrometers.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition in which the particle size of granules containing the active ingredient and the particle size of the active ingredient is controlled double. [0002]

The present invention relates to a pharmaceutical composition wherein the particle size of the active ingredient and the particle size of the granules containing the active ingredient are double controlled. More particularly, the present invention relates to a pharmaceutical composition comprising a pharmacologically active active ingredient, wherein the particle size of the active ingredient is adjusted to a predetermined range and the particle size of the granule containing the active ingredient is also controlled within a specific category, The present invention relates to a pharmaceutical composition which enables the preparation of a unit dosage form in which the mass deviation and the degree of grinding are minimized in a mass production process.

Among the oral dosage unit formulations of medicines, tablets are most widely used because they are convenient to formulate, have an accurate ingredient content in the formulation, are easy to mask, such as bitter taste, and are capable of mass production.

In designing the tablet formulation, it is required that the flowability, bonding property, lubricity, and the like of the raw material powder are required, and that refining after production requires strengthening of resistance to mass loss. The resistance to mass loss is used as an index for evaluating the ability to handle tablets or withstand breakage during packaging and shipping, which is not solved by simply increasing the mechanical strength of the tablet. This is because, when the mechanical strength of tablets is increased by using a large amount of binder or the like in order to enhance the resistance to mass loss, the disintegrability tends to be lowered, which is not appropriate from the viewpoint of pharmaceutical and therapeutic point of view.

On the other hand, in the production of tablets, the mass deviation leads to a variation in the content of the active ingredient, so it is necessary to reduce the mass deviation as much as possible. When a large amount of fine powder is mixed with the granules for compression or when the particle size distribution is wide, there is a problem in the uniformity of the contents, and when the particles are large, there is a possibility that the mass deviation becomes large. The resistance to mass loss of the tablet can be evaluated by measuring the degree of fatigue, and the mass deviation is evaluated by the mass deviation test method.

With respect to the malfunction of the tablet, the following conventional techniques exist.

Korean Patent Laid-Open Publication No. 10-2013-0076015 discloses a low-wet granule containing spray-dried mannitol and white sugar binder and having a dry weight loss value of 1.05 times or more and 5 times or less the dry weight loss of dried granules, It begins to increase the hardness and fatigue of tablets when tabletting with chewing gum using low wet granulation.

Korean Patent Laid-Open Publication No. 10-2014-0015361 discloses a binder capable of improving the hardness of a tablet without delaying the disintegration time of the tablet using a novel binder having high binding and fluidity.

Korean Patent Laid-Open Publication No. 10-2009-0103810 discloses a process for producing tablets having good disintegrability and excellent mechanical strength, characterized by containing Carmelose or a salt thereof and silicon dioxide.

In any of the above documents, however, there is no correlation between the particle size of the active ingredient and the granularity of the granule containing the active ingredient, and the degree of malodour and mass deviation. The particle size and the degree of grinding of the active ingredient and the granules disclosed in the present invention It is thought that the correlation between mass deviations can not be perceived without a deep reflection on the production process that mass-produced the actual tablets.

Usually, when a formulation is designed for a solid preparation, a variety of excipients will be studied together with the active ingredient, and an additive or the like for imparting a specific function is used. When a certain level of prescription is established through such a process, the tablet is tested and produced by using a laboratory tablet machine or a charger, and the final prescription is confirmed by testing various physicochemical properties. However, it is impossible to recognize all of the problems that arise when mass production of actual tablets is made solely by such a laboratory process. Because the process of mass-producing the actual tablets may have different factors from the laboratory environment, such as using a large amount of raw materials and excipients and increasing the process speed, It is difficult to say that the physicochemical properties appear directly in the production process.

Particularly, the fact that the particle size of the active ingredient and the granules containing the same affect the degree of malleability and the mass deviation, which occurs in the actual mass production process, Is clearly distinguished.

That is, according to the present invention, as a result of examining a means capable of reducing the marginalness and the mass deviation in the mass production process, the particle size of the active ingredient and the particle size of the granule containing the active ingredient are double controlled, And that it has been found to have a new knowledge that it reduces it.

Korean Patent Publication No. 10-2013-0076015 Korean Patent Publication No. 10-2014-0015361 Korean Patent Laid-Open No. 10-2009-0103810

Disclosure of the Invention The present invention provides a pharmaceutical composition which is capable of minimizing fatigue and minimizing the degree of fatigue when a final tablet is prepared in a pharmaceutical composition containing the active ingredient

Means for solving the above problems are disclosed as means for solving the above problems.

(I)

[Chemical Formula]

(A) a particle size distribution in which the D ₉₀ of the particles at the longest dimension of the particles is not more than 10 탆, and (B) a compound represented by the formula ) The active ingredient is present in the form of a granule together with a pharmaceutically acceptable excipient, wherein the granule has a particle size distribution of D ₁₀ of 50 탆 or more and D ₉₀ of 400 or more and 500 탆 or less ≪ / RTI > are disclosed.

In the pharmaceutical composition, the pharmaceutical composition is characterized in that, in the longest dimension of the particles, the D ₉₀ of the drug particle is 7 탆 or less.

In the above pharmaceutical composition, a pharmaceutical composition is characterized in that, in the longest dimension of the particles, the D ₉₀ of the drug particle is 5 탆 or less.

In the pharmaceutical composition, the pharmaceutical composition is characterized in that the D ₉₀ of the granule is 400 to 450 μm.

In the pharmaceutical composition, the pharmaceutical composition has a unit dose capsule or tablet form, wherein the excipient is selected from pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants.

In the pharmaceutical composition, a pharmaceutical composition is provided which has the following prescription.

Purpose of blending  Ingredients

chief ingredient Gefitinib

Excipient Lactose baggage

Excipient Microcrystalline cellulose

Binder Povidone

Disintegration Croscarmellose sodium

Dissolution aid Sodium lauryl sulfate

Lubricant Magnesium stearate

Lubricant Sodium stearyl fumarate

Zephyrate Opa Dry II Brown

When the pharmaceutical composition of the present invention is prepared in the form of tablets, it is possible to produce a tablets having excellent dissolution rate, minimization of the degree of grind, and further having a small mass deviation.

The pharmaceutical composition of the present invention is a pharmaceutical composition which can produce tablets having excellent elution, minimization of the degree of fibrillation and further having small mass deviation by controlling the particle size of the active ingredient having a specific particle size and the granules containing the active ingredient And a composition for compression.

The pharmaceutical composition of the present invention may be prepared by tableting by mixing with other pharmaceutically acceptable excipients.

The active ingredient of the present invention may be any ingredient that exhibits pharmacological activity by oral administration and is not particularly limited,

(I)

Or a pharmaceutically acceptable salt thereof may be used as the quinazoline compound. The quinazoline compound inhibits receptor tyrosine kinase associated with epidermal growth factor receptor (EGFR) and thus has antiproliferative activity such as anticancer activity.

The present inventors have found that the correlation between the particle size of the active ingredient and the particle size of the granule containing the active ingredient to be described later may affect the dissolution rate, malodility and mass deviation of the active ingredient, It has been found that an optimized effect can be obtained when D ₉₀ is 10 or less with respect to the particle size of the component. When D ₉₀ exceeds 10, it is not only disadvantageous in terms of dissolution rate, but also in terms of the degree of wastage and mass deviation of the finally produced tablets.

In general, the particle size of the active ingredient is known to affect the solubility or bioavailability of the active ingredient. However, in the present invention, in order to increase the solubility and increase the dissolution rate, It should be noted that the purpose of the present invention is to limit the particle size of the active ingredient.

In the present invention, the particle size was measured by using QICPIC-OASIS / L (manufactured by Sympatec, Germany), measurement range 2 to 1705 μm, dispersing machine RODOS, dry dispersion system, dispersion pressure 0.5 bar, Volume average) method. As used herein, the terms D ₁₀ , D ₅₀ and D ₉₀ (or X ₁₀ , X ₅₀ , X ₉₀ ) correspond to 10%, 50%, and 90%, respectively, Quot; size " Particle size distribution devices are also commercially available from a variety of suppliers, such as Sympatec or Malvern Instruments Ltd.

The present invention discloses granules comprising an active ingredient having a controlled particle size as described above. The granules can be prepared using a wet or dry granulation method or by using a fluidized bed granulation method with the active ingredient and other excipients or additives which are pharmaceutically acceptable.

Such excipients or additives may include, but are not limited to, diluents, disintegrants, surfactants, binders, lubricants, and lubricants. Examples of such excipients are described in Handbook of Pharmaceutical Excipients, 7th Ed. Pharmaceutical Press, Can be referred to. Examples of the diluent include lactose, pre-classified, crystalline cellulose, sucrose, mannitol and the like. Examples of the disintegrant include crospovidone, corn starch and low-substituted hydroxypropylcellulose, and binders such as hydroxypropylmethylcellulose , Hydroxypropylcellulose, gelatin, alpha starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan and the like. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate talc, and hardened oils. As the surfactant, sodium lauryl sulfate and the like can be used.

The granule of the present invention may be prepared by mixing the active ingredient with a pharmaceutically acceptable excipient and then separately using a wet granulation method in which a binding agent in which a binder is dissolved in an appropriate solvent is used, Fluid bed assembly can be used.

One aspect of the present invention is that the particle size of the granules containing the active ingredient is such that D ₉₀ has a particle size distribution of 400 탆 or more and 500 탆 or less. As can be seen from the examples which will be described later, when the particle size of the granules is less than 400 mu m or exceeds 500 mu m, there is a disadvantage in marringness and mass deviation in the production process of producing a large amount of tablets.

In the case of tableting using granules having a specific particle size as described above, the produced tablets have a reduced degree of malleability and mass deviation. However, the relationship between the particle size, the degree of malleability and the mass deviation of the granules for compression has not been reported , And such knowledge of the present invention is novel.

It is presumed that, in the present invention, the degree of grindability and mass deviation is influenced by the particle size distribution of the granules, it is presumed to be a physical interaction between the physical properties of the specific active ingredient and the particle size distribution of granules under the environment of a mass production process, But is not limited to.

Another aspect of the present invention is that the relationship between grain size, graininess and mass deviation of granules as described above is a problem that occurs in actual production sites, and it is difficult to recognize such a problem in a simple experimental facility. That is, in the experimental results, it is possible to control various kinds of specific additives, moisture content, or pressure to increase the degree of grinding, but there is a causal relationship between the specific grain size range of granules, Can not be recognized.

The granules may be tableted as such or may be mixed with a lubricant to be tableted.

The granule of the present invention having the controlled particle size has another advantage that it is superior in terms of fluidity since the angle of repose is small as compared with granules which do not satisfy the particle size range of the present invention. It is generally known that the smaller the angle of repose is, the better the fluidity. However, according to the conventional knowledge, it is known that the larger the particle size, the greater the angle of repose, and when the particle size of the granule is within a specific numerical range, It is not known.

The present invention provides a solid preparation in which the granules are tableted. As described above, the tablets prepared by tableting the granules of the present invention are excellent in elution of the active ingredient, and have low degree of margins and mass deviations. Specifically, tablets satisfying the conditions of the present invention exhibit excellent effects as compared with tablets that do not have such properties, in the abrasion test and the content test according to the Korean Pharmacopoeia. The tablets thus obtained may be formed into film coating tablets or dragee tablets by a conventional method, as desired, and specific coating materials are not limited, but Opadry II Brown can be used.

Hereinafter, the technical idea of the present invention will be described by way of examples. The following examples are intended to illustrate the technical spirit of the present invention and should not be construed as limiting the scope of the invention in any way.

Preparation Example 1: Preparation of gefitinib granules

The gefitinib granule mixture is prepared by the following production method with the composition shown in Table 1 below.

Classification (Unit: mg) Manufacturing example Gefitinib 250.00 Lactose baggage 153.00 Microcrystalline cellulose 50.00 Cross Carmelose sodium 20.00 Povidone K-30 15.00 Sodium lauryl sulfate 2.00 Magnesium stearate 5.00 Sodium stearyl fumarate 5.00 Total amount 515.00

1) Preparation of binding solution or spray solution

Povidone K-30 and sodium lauryl sulfate are completely dissolved in the water by stirring.

2) mixing

The mixture of goethitipine and lactose hydrate, microcrystalline cellulose, and croscarmellose sodium is put into a mixer and mixing of the main ingredient and excipient is carried out.

3) Union and Drying

2) is put into a coalescing machine and the coalescing solution of 1) is sprayed to coalesce and then dried in a fluidized bed dryer. This is established as a co-miller.

4) Final mixing and tableting

3) is put into a mixer, and croscarmellose sodium is put into the mixer, followed by primary mixing. After completion of the primary mixing, magnesium stearate was added in a 30 mesh sieve, followed by secondary mixing to prepare a final mixture, which was then tableted using an automatic tablet machine (XP1, Korsch, Germany).

Examples 1 to 5: Effect of gefitinib raw material particle size

The gefitinib compositions of Examples 1 to 5 were prepared according to Preparation Example 1 in order to examine the physical properties of the composition and the effect on the biological activity of the composition according to the particle size of the gefitinib raw material. Each final mixture was tableted to give a total weight of 515 mg tablets. The resulting tablet contains 250 mg of gefitinib. The characteristics of the raw material particles in each of the examples are shown in Table 2 below.

Raw particle size Example 1 Example 2 Example 3 Example 4 Example 5 D ₉₀ (占 퐉) 5 7 10 15 20

Experimental Example 1: Elution experiment of composition according to raw particle size

The preparations obtained in Examples 1 to 5 according to the present invention were subjected to a dissolution test according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia 10th edition, and the analysis was carried out according to the following method.

1) Experimental method

[Dissolution Test Method]

- Elution test apparatus: Hanson SR 8 (Hanson Research, USA)

- eluent: pH 1.2 medium 900 mL

- Temperature of eluent: 37 ± 0.5

- Rotation speed: 50 rpm

- Test time: 30 minutes

[Assay: HPLC Liquid Chromatography Method]

- Detector: UV absorptiometer (measuring wavelength: 247 nm)

Column: Inertsil ODS 3 (3.0 占 100 mm, 5 占 퐉) or equivalent column

- mobile phase: a mixture of ammonium acetate TS and acetonitrile (4: 6)

- Injection volume: 5 μl

- Flow rate: 1.0 mL / min

- Column temperature: 50 ° C

- Sample temperature: 4 ℃

2) Experimental results

When the elution of the gefitinib composition with different particle sizes of raw materials was measured, the results are shown in Table 3 below.

pH 1.2 Elution rate by time (%) Specimen One 2 3 4 5 6 Average Example 1 96 88 94 94 96 88 93 Example 2 86 91 87 90 94 92 90 Example 3 91 88 83 85 89 92 88 Example 4 68 75 78 85 73 88 78 Example 5 65 66 68 73 69 78 70

The results of elution in the pH 1.2 medium of Examples 1 to 5 show that the results of Examples 1 to 3 are all appropriate to the standards. The smaller the particle size, the higher the average dissolution rate (%). In the case of Examples 4 to 5, the average dissolution rate was inadequate for the standard. Since elution is a representative index of in vitro experiments exhibiting biological equivalence, the raw material used to prepare the composition should have a particle size characteristic of D ₉₀ of less than 10 μm.

Examples 6 to 8: Preparation of continuous three batch granule composition

In order to compare the granular properties and the qualities, three batches were prepared by the same composition and manufacturing method. The gefitinib compositions of Examples 6 to 8 were prepared according to Preparation Example 1. The tablet was then tableted to obtain a tablet having a total weight of 515 mg. The resulting tablet contains 250 mg of gefitinib.

Experimental Example 2: Properties of continuous three batch granule composition

The formulations obtained in Examples 6 to 8 according to the present invention were subjected to various physical property investigations according to the following methods, and the results are shown in [Table 4] and [Table 5].

1) Experimental method

Perform the physical property investigation using the following equipment.

[Cost Measurement]

- Equipment used: PT-TDI (Pharmatest Apparate, Germany)

- Measurement method: Measured by tapping 1250 times

[Measurement of Repose Angle]

- Equipment: PTG-S4 + PTG-NIR ((Pharmatest Apparatebau, Germany)

- Measuring method: Measured using a measuring instrument with prepared sample

[Dry weight loss measuring instrument]

- Equipment used: MB45 ((OHAUS, USA)

- Measuring method: Measurement of drying loss at 105 ℃, 30 minutes

[Particle Size Meter]

- Equipment used: QICPIC-OASIS / L (Sympatec, Germany)

- Measuring method: Measured using a particle size analyzer as a prepared sample

[Measuring the degree of wear]

- Equipment used: SVM-102 ((Pharmatest Apparatebau, GmbH, Germany)

- Measuring method: Measuring 20 marks, 100 marks after measuring the degree of wear

[Content Test Method: HPLC Liquid Chromatography Condition]

- Detector: UV absorptiometer (measuring wavelength: 247 nm)

Column: Inertsil ODS 3 (3.0 占 100 mm, 5 占 퐉) or equivalent column

- mobile phase: a mixture of ammonium acetate TS and acetonitrile (62:38)

- Injection volume: 5 μl

- Flow rate: 1.0 mL / min

- Column temperature: 50 ° C

- Sample temperature: 4 ℃

2) Test result

Item Example 6 Example 7 Example 8 Cost-effective (ml / g) bulk 2.00 1.90 2.22 tapped 1.40 1.30 1.45 Hausner Ratio 1.43 1.46 1.53 Angle of repose 39 44 38 moisture L.O.D 0.78 0.80 0.80 Granularity X ₁₀ 44.97 45.84 49.41 X ₅₀ 86.10 105.41 113.91 X ₉₀ 353.92 500.86 536.41 content 97.9 101.3 98.9

In all three batches, the angle of repose is greater than 38, which corresponds to fairness in the flow criterion. In the case of particle size, X ₉₀ has a large deviation. When the granules were tableted, the mass deviation and the degree of grinding were both large as shown in [Table 5].

Item Example 6 Example 7 Example 8 Mass deviation (%) 1.8 2.0 1.9 Marson (%) 0.41 0.45 0.46

Preparation Example 2: Preparation of gefitinib granules

The gefitinib granule mixture is prepared in the composition of the above Table 1 through the following production process.

1) Preparation of binding solution or spray solution

Povidone K-30 and sodium lauryl sulfate are completely dissolved in the water by stirring.

2) mixing

The mixture of goethitipine and lactose hydrate, microcrystalline cellulose, and croscarmellose sodium is put into a mixer and mixing of the main ingredient and excipient is carried out.

3) Union and Drying

2) is placed in a fluidized bed granulator and the combined liquid of 1) is sprayed to proceed with granulation and drying. It is formed by a co-mitt sizing machine.

4) Final mixing and tableting

3) is put into a mixer, and croscarmellose sodium is put into the mixer, followed by primary mixing. After completion of the primary mixing, magnesium stearate was added in a 30 mesh sieve, followed by secondary mixing to prepare a final mixture, which was then tableted using an automatic tablet machine (XP1, Korsch, Germany).

Examples 9 to 11: Preparation of continuous three batch granule composition

The gefitinib compositions of the series of three batches of Examples 9 to 11 were prepared according to Production Example 2. Each final mixture was tableted to give tablets of a total weight of 515 mg (including 250 mg of gefitinib). The granular properties of each of the examples were as shown in Table 6.

Experimental Example 3: Properties of continuous three batch granule composition

The formulations obtained in Examples 9 to 11 according to the present invention were subjected to various physical property tests according to the following methods, and the results are shown in [Table 6] and [Table 7].

1) Experimental method

Perform the physical property investigation using the following equipment.

[Cost Measurement]

- Equipment used: PT-TDI (Pharmatest Apparate, Germany)

- Measurement method: Measured by tapping 1250 times

[Measurement of Repose Angle]

- Equipment: PTG-S4 + PTG-NIR ((Pharmatest Apparatebau, Germany)

- Measuring method: Measured using a measuring instrument with prepared sample

[Dry weight loss measuring instrument]

- Equipment used: MB45 ((OHAUS, USA)

- Measuring method: Measurement of drying loss at 105 ℃, 30 minutes

[Particle Size Meter]

- Equipment used: QICPIC-OASIS / L (Sympatec, Germany)

- Measuring method: Measured using a particle size analyzer as a prepared sample

[Measuring the degree of wear]

- Equipment used: SVM-102 ((Pharmatest Apparatebau, GmbH, Germany)

- Measuring method: Measuring 20 marks, 100 marks after measuring the degree of wear

[Content Test Method: HPLC Liquid Chromatography Condition]

- Detector: UV absorptiometer (measuring wavelength: 247 nm)

Column: Inertsil ODS 3 (3.0 占 100 mm, 5 占 퐉) or equivalent column

- mobile phase: a mixture of ammonium acetate TS and acetonitrile (62:38)

- Injection volume: 5 μl

- Flow rate: 1.0 mL / min

- Column temperature: 50 ° C

- Sample temperature: 4 ℃

2) Test result

Item Example 9 Example 10 Example 11 Cost-effective (ml / g) bulk 2.50 2.45 2.30 tapped 2.05 1.90 1.65 Hausner Ratio 1.22 1.29 1.39 Angle of repose 34 35 33 moisture L.O.D 1.03 1.15 1.04 Granularity X ₁₀ 77.62 62.84 74.73 X ₅₀ 185.87 243.90 191.46 X ₉₀ 410.45 423.73 422.41 content 99.8 99.7 99.2

The angle of repose of continuous three batch granules is 33 ~ 35, which corresponds to Good in flow standard. In case of particle size, 10%, 50% and 90% of cumulative particles showed similar results.

Item  standard Example 9 Example 10 Example 11 Mass deviation (%) 2.0% or less 1.2 1.1 0.9 Marson (%) 0.5% or less 0.10 0.08 0.11

The values of the mass deviation and the degree of abrasion were also significantly lower than those of Examples 6 to 8. This is because the particle size of 10% of the cumulative particles is 60 or more, which is a result of the reduction of the fine particles. In addition, the reproducibility was secured because the value of 90% of the cumulative particles was uniformly formed to 400. It is considered that the granular size of such granules is the optimal granular size in which the mass deviation value decreases.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to produce tablets having a good dissolution rate, minimizing the degree of abrasion and having a small mass deviation in the mass production process of tablets.

Claims (6)

(I)
(I)

(A) a particle size distribution in which the D ₉₀ of the particles at the longest dimension of the particles is not more than 10 탆, and (B) a compound represented by the formula ) The active ingredient is present in the form of granules together with a pharmaceutically acceptable excipient, wherein the granules have a particle size distribution of D ₁₀ of 50 탆 or more and D ₉₀ of 400 탆 or more and 500 탆 or less ≪ / RTI > The pharmaceutical composition according to claim 1, wherein the D ₉₀ of the drug particles is 7 탆 or less at the longest dimension of the particles. The pharmaceutical composition according to claim 1, wherein, in the longest dimension of the particles, the D ₉₀ of the drug particle is 5 탆 or less. The pharmaceutical composition according to claim 1, wherein D ₉₀ of the granule is 400 μm or more and 450 μm or less. 6. The pharmaceutical composition according to any one of claims 1 to 5, having a unit dose capsule or tablet form, wherein the excipient is selected from pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. Composition. 6. The pharmaceutical composition according to any one of claims 1 to 5, having the following prescription.
(Blending objective ingredient name
The main component, gefitinib
Excipient lactose hydrate
Excipient microcrystalline cellulose
Binder povidone
Disintegrating croscarmellose sodium
Dissolution aid sodium lauryl sulfate
Magnesium stearate lubricant
Sodium lauryl stearyl fumarate
Jeffrey's Opa Dry II Brown)