KR20160140567A - Pharmaceutical composition comprising oseltamivir free base - Google Patents

Abstract

Provided are a pharmaceutical composition comprising oseltamivir free base of which 90% of the particles preferably have particle size less than or equal to 200 m for oral administration, a medicine comprising the same, and a preparation method thereof. The pharmaceutical composition of the present invention may be in a capsule form, a tablet form, a dried syrup form, a chew tablet form, or a powder form.

Description

A pharmaceutical composition comprising oseltamivir free base,

The present invention relates to a pharmaceutical composition for oral administration comprising oseltamivir free base which minimizes the deviation and also provides a high initial dissolution rate, a medicament containing the same, and a process for producing the same.

Influenza A (H1N1) is referred to as [Influenza A ((H1N1)] is usually from influenza or influenza, has been used as a therapeutic agent Tamiflu ^TM (Tamiflu ^TM, Roche). Tamiflu ^TM is a main component superior stability compared to the free base Containing oseltamivir phosphate, which is known to have the form of a suspension or capsule.

H1N1 influenza is an acute respiratory disease and may be associated with symptoms such as initial acute respiratory failure. Therefore, the United States Centers for Disease Control recommends starting Tamiflu ^TM treatment within 48 hours of the onset of symptoms early in the infection. Therefore, the initial rate of absorption immediately after administration of Tamiflu ^TM may have a significant effect on the therapeutic effect. However, the initial dissolution rate of oseltamivir phosphate-containing capsules (Tamiflu ^TM ), which is currently used, is only about 57.8 ± 20.9% within 5 minutes in the gastric juice environment, and the deviation of the dissolution rate is also very large have. Therefore, in order to achieve the desired therapeutic effect, it is necessary not only to improve the low initial dissolution rate, but also to minimize the dissolution rate deviation.

One of the various factors that may be considered for the improvement of the initial dissolution rate includes the control of the particle size of the active ingredient. That is, it may be considered to increase the initial dissolution rate by increasing the surface area by reducing the particle size of the active ingredient oseltamivir phosphate. However, it has been found that it is difficult to increase the initial dissolution rate to a desired level (for example, about 85% or more), even though the particle size of oseltamivir phosphate is significantly reduced using a conventional mill (see Examples below) ). Moreover, when the particle size of oseltamivir phosphate is reduced from about 250 [mu] m to about 5 [mu] m, the solubility in the pH 1.2 gastric juice environment will vary from a wide range (e.g., 0.654 g / ml to 1.627 g / ml) (See Examples below). Therefore, when the formulation is carried out using the pulverized product obtained by pulverizing oseltamivir phosphate using a conventional pulverizer at the production site, the dissolution rate, particularly the initial dissolution rate, from the resulting preparation shows a large deviation, .

The present inventors have conducted various studies to improve the initial dissolution rate of solid preparations such as capsules containing oseltamivir phosphate. Surprisingly, the inventors have found that the oseltamivir free base has a significantly higher solubility than the oseltamivir phosphate; Also, by reducing the particle size of the oseltamivir free base to a certain range, a high initial dissolution rate of a desired level can be achieved; Particularly, when the particle size of the oseltamivir free base is in the above range, the solubility change is minimized, thereby minimizing the dissolution rate deviation, and it is possible to facilitate the quality control at the production site.

Accordingly, it is an object of the present invention to provide a solid formulation comprising an oseltamivir free base having a particle size within a certain range.

According to one aspect of the present invention, there is provided a pharmaceutical composition for oral administration containing oseltamivir free base.

In the pharmaceutical composition of the present invention, 90% of the oseltamivir free base particles may have a particle size of preferably 200 μm or less, more preferably 10 μm to 200 μm.

The pharmaceutical compositions of this invention may have the form of capsules, tablets, dry syrups, powders, or creams. In one embodiment, the pharmaceutical compositions of the present invention may have the form of a dry syrup comprising granules and pharmaceutically acceptable additives obtained through a granulation process of the oseltamivir free base. In another embodiment, the pharmaceutical composition of the present invention may have the form of a capsule obtained by filling the capsules with the granules obtained through the granulation process of the oseltamivir free base with a pharmaceutically acceptable additive. In another embodiment, the pharmaceutical composition of the present invention may have a tablet form obtained by tableting the granules obtained through the granulation process of the oseltamivir free base with a pharmaceutically acceptable additive.

The pharmaceutical compositions of the present invention may include one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low-substituted hydroxypropylcellulose. In addition, the pharmaceutical compositions of the present invention may comprise at least one lubricant selected from the group consisting of magnesium stearate, talc, and sodium stearyl fumarate. In one embodiment, the pharmaceutical composition of the present invention in the form of a capsule or tablet, when subjected to a dissolution test at a paddle rotation speed of 50 rpm according to the dissolution method 2 of the Korean Pharmacopoeia in a 0.1 N aqueous hydrochloric acid solution, % Dissolution rate.

According to another aspect of the present invention, there is provided a pharmaceutical product obtained by packing the pharmaceutical composition with a packaging material having a moisture permeability of 4.0 g / m ² / d or less. The packaging material having a moisture permeability of 4.0 g / m ² / d or less may be a high density polyethylene (HDPE), a polyvinyl chloride-aluminum blister, a PVDC-Alu blister, , A polychlorotrifluoroethylene-aluminum blister (PCTFE-Alu blister), a cyclic olefin copolymer-COC-Alu blister, and an aluminum-aluminum blister (Alu-Alu blister) More than species can be selected. In one embodiment, when the drug is left for 6 months under accelerated conditions at 40 DEG C and 75% relative humidity, the sum of the total soft substances is 2.0% or less.

According to still another aspect of the present invention, there is provided a method for preparing an oseltamivir free base, comprising: (a) performing wet granulation by adding a binding liquid to a mixture of oseltamivir free base and disintegrant; (b) drying the wet granules obtained in step (a) to obtain granules; And (c) filling or tableting the granules obtained in step (b) with a pharmaceutically acceptable additive in a capsule, wherein the oseltamivir free base is provided for the manufacture of a pharmaceutical composition for oral administration do.

According to still another aspect of the present invention, there is provided a method for preparing a granule comprising: (a ') performing a dry granulation using a roller compactor to obtain a mixture of oseltamivir free base and disintegrant to obtain granules; And (b ') filling or tableting the granules obtained in step (a ') with a pharmaceutically acceptable additive in a capsule, or a method for producing a pharmaceutical composition for oral administration containing free base oseltamivir / RTI >

It has been found by the present invention that the oseltamivir free base has a significantly higher solubility than oseltamivir phosphate. In addition, when the particle size of the oseltamivir free base is within a certain range, that is, when 90% of oseltamivir free base particles have a particle size of 200 mu m or less, preferably 10 mu m to 200 mu m, It has been found by the present invention that the dissolution rate can be achieved. Particularly, when the particle size of the oseltamivir free base is in the above range, the solubility change is minimized, so that the dissolution rate deviation can be minimized and quality control in the production site can be facilitated. Therefore, the solid preparation according to the present invention can achieve an initial dissolution rate with a high initial dissolution rate and a minimized deviation, thereby effectively solving the drawbacks of conventional oseltamivir phosphate-containing solid preparations.

The present invention provides a pharmaceutical composition for oral administration containing oseltamivir free base. 90% of the oseltamivir free base particles may have a particle size of preferably 200 μm or less.

When the particle size of the oseltamivir free base is reduced to a specific range, that is, when 90% of the oseltamivir free base particles [i.e., d _(0.9) ] are finely divided to have a particle size of 200 μm or less, ≪ / RTI > and also the increased variation in solubility is minimized by the present invention. That is, if the 90% of the oseltamivir free base particles ₍ i.e., d _(0.9)) is finely divided to have a particle size of 200 μm to 5 μm, for example, the solubility in a gastric environment of pH 1.2 is about 2.429 to 2.571 lt; / RTI > g / ml, as well as minimized variation in increased solubility. On the other hand, if the 90% of the particles of oseltamivir phosphate ₍ i.e., d _(0.9) ) are micronized to have the same particle size, that is, a particle size of 200 μm to 5 μm, for example, The solubility was only about 0.885 to 1.627 g / ml, and the increased solubility variation was also found to be very large. In general, in view of the fact that, compared with a suitable salt-type material used as a medicine, a free base material is low in solubility, has poor physical properties and is difficult to formulate and has a low initial dissolution rate. It's amazing.

In the pharmaceutical composition of the present invention, more preferably, 90% of the oseltamivir free base particles may have a particle size of 10 탆 to 200 탆. When 90% of the oseltamivir free base particles are less than 10 탆 (for example, about 5 탆), the flowability of the granules may be deteriorated and the capsule filling or tableting may become difficult. If 90% of the oseltamivir free base particles exceed 200 탆, a desired initial dissolution rate may not be obtained.

The pharmaceutical compositions of this invention may have the form of capsules, tablets, dry syrups, powders, or creams.

In one embodiment, the pharmaceutical compositions of the present invention comprise granules and pharmaceutically acceptable additives (e.g., talc, xanthan gum, D-sorbitol, saccharin, anhydrous citric acid, etc.) obtained through the granulation process of oseltamivir free base ). ≪ / RTI > In another embodiment, the pharmaceutical composition of the present invention may have the form of a capsule obtained by filling the capsules with the granules obtained through the granulation process of the oseltamivir free base with a pharmaceutically acceptable additive. In another embodiment, the pharmaceutical composition of the present invention may have a tablet form obtained by tableting the granules obtained through the granulation process of the oseltamivir free base with a pharmaceutically acceptable additive.

The granulation process may be performed by wet granulation or dry granulation. For example, the wet granulation process may be carried out by a conventional method using a binding liquid obtained by dissolving a binder such as povidone, hydroxypropylcellulose, and hypromellose in a suitable solvent such as 70% ethanol and the like have. The dry granulation process may be carried out using conventional equipment such as roller compactors. Preferably by wet granulation.

The oseltamivir free base shows a tendency that the stability is lowered when it is mixed with a conventional additive to be used pharmaceutically. It has been found by the present invention that this problem can be overcome through the use of certain disintegrants. That is, it has been found by the present invention that the stability of the oseltamivir free base in a preparation can be ensured by preparing granules using a particular disintegrant in the granulation process. The specific disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low-substituted hydroxypropylcellulose. The disintegrant may preferably be present in an amount of 1 to 20% by weight based on the total weight of the composition. When the content of the disintegrant is in the above range, for example, disintegration of the capsules and tablets upon wetting is accelerated, problems such as sticking during tablets and tableting can be eliminated, and the density of granules becomes suitable for tableting and filling It is possible to prevent a change in properties of the preparation due to moisture. If the content of the disintegrant is less than 1% by weight, elution may be slowed, and if it is more than 20% by weight, the stability may be lowered.

In the pharmaceutical compositions of this invention in the form of capsules or tablets, the pharmaceutically acceptable excipients include various lubricants and the like. It has been found that the stability of the formulation may be poor and it may be difficult to ensure sufficient uniformity depending on the type of the lubricant, and it has been found that this problem can be overcome by using a specific lubricant. That is, the lubricant may be at least one selected from the group consisting of magnesium stearate, talc, and sodium stearyl fumarate. If desired, the pharmaceutically acceptable additive may be selected from the group consisting of disintegrants such as croscarmellose sodium, crospovidone, sodium starch glycolate, and low-substituted hydroxypropylcellulose. As shown in FIG. The glidant may preferably be present in an amount of from 0.25% to 10% by weight based on the total weight of the composition. When the lubricant is in the above range, for example, it is possible to easily discharge the tablet from the compression die, to eliminate the problems such as sticking during tablets tableting, and to eliminate the possibility of tablet breakage or tablet layer separation can do. The lubricant is highly water repellent and can cause unintended problems such as delayed disintegration and deterioration of dissolution when used in excessive amounts. That is, when the content of the lubricant is less than 0.25% by weight, the efficiency of the capsule filling and tableting may be inferior and productivity may be problematic. If the content of the lubricant is more than 10% by weight, the elution and disintegration may be deteriorated and the stability may be deteriorated .

In one embodiment, when the elution test is conducted at a paddle rotation speed of 50 rpm according to Method 2 of the Korean Pharmacopoeia in 0.1 N hydrochloric acid aqueous solution, the dissolution rate is 85% or more within 5 minutes. A pharmaceutical composition is provided.

In another embodiment, when the dissolution test is carried out in a 0.1 N aqueous hydrochloric acid solution at a paddle rotation speed of 50 rpm according to the dissolution method 2 of the Korean Pharmacopoeia, the dissolution rate is 85% or more within 5 minutes A composition is provided.

The present invention also provides a medicament obtained by packaging the pharmaceutical composition with a packaging material having a water vapor transmission rate (WVTR) value of 4.0 g / m ² / d or less. In this specification, the term "water vapor permeability (WVTR) value" refers to a value measured under conditions of 38 ° C. and 90% relative humidity.

The packaging material having a moisture permeability of 4.0 g / m ² / d or less may be a high-density polyethylene (HDPE), a polyvinyl chloride-aluminum blister (PVC-Alu) blister, Polyvinylidene chloride-aluminum (PVDC-Alu) blister, polychlorotrifluoroethylene-aluminum (PCTFE-Alu) blister, cyclic olefin copolymer, aluminum blister, cyclic olefin copolymer-aluminum (COC-Alu) blister, and aluminum-aluminum blister (Alu-Alu blister). In one embodiment, when the drug is left for 6 months under accelerated conditions at 40 DEG C and 75% relative humidity, the sum of the total soft substances is 2.0% or less. The suppository can be analyzed through a flexible substance analysis method described in USP 'Oseltamivir phosphate Capsule'.

The present invention also provides a method for producing the above pharmaceutical composition.

In one embodiment, the present invention is directed to a method of making a composition comprising: (a) performing wet granulation by adding a binding liquid to a mixture of oseltamivir free base and disintegrant; (b) drying the wet granules obtained in step (a) to obtain granules; And (c) filling or tableting the granules obtained in step (b) with a pharmaceutically acceptable additive in capsules, comprising the steps of: (a) providing an oseltamivir free base; do. The disintegrant and binding solution used in step (a) are as described above. The wet granulation can be carried out according to a conventional method used in the pharmaceutical industry. The drying process may also be performed according to a conventional method used in the pharmaceutical industry, and may further include a step of forming the obtained granules, if necessary. The pharmaceutically acceptable additives used in step (c) are also as described above.

In another embodiment, the present invention provides a process for preparing granules comprising: (a ') performing a dry granulation using a roller compactor to obtain a mixture of oseltamivir free base and disintegrant to obtain granules; And (b ') filling or tableting the granules obtained in step (a ') with a pharmaceutically acceptable additive in a capsule, or a method for producing a pharmaceutical composition for oral administration containing free base oseltamivir . The disintegrant used in step (a ') and the pharmaceutically acceptable additives used in step (b') are as described above. The dry granulation may be carried out according to a conventional method used in the pharmaceutical industry, and if necessary, may further include a step of granulating the obtained granules.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are for the purpose of illustrating the present invention and the present invention is not limited by the following examples.

Example  One: By size  Saturation solubility test

Solubility tests were performed on various types of test solutions for oseltamivir free base and oseltamivir phosphate having various particle sizes as shown in Table 1 below. The raw material of each particle size was prepared by pulverizing the raw material having the maximum particle size of 300 mu m supplied from the manufacturer and using an air jet mill pulverizer under the condition that a desired particle size could be obtained. The solubility test was performed by adding 5 g of raw material per 1 ml of each test solution, saturating the mixture, stirring the mixture at room temperature for 2 hours, centrifuging the supernatant, and analyzing by HPLC.

Principal component type d _(0.9)
(탆) Solubility (g / ml) pH 1.2 solution pH 4.0 solution pH 6.8 solution Distilled water Oseltamivir free base 5 2.571 2.494 2.315 2.448 10 2.559 2.299 2.343 2.485 50 2.501 2.318 2.208 2.420 100 2.543 2.343 2.213 2.319 200 2.429 2.204 2.198 2.308 250 1.928 2.087 1.859 1.951 Oseltamivir phosphate 5 1.627 1.550 1.570 1.432 10 1.454 1.311 1.338 1.259 50 1.209 1.189 1.085 1.135 100 1.076 0.996 1.044 1.095 200 0.885 0.805 0.927 0.923 250 0.654 0.679 0.786 0.714

As can be seen from the results shown in Table 1, the oseltamivir free base was remarkably increased in solubility as compared with oseltamivir phosphate by decreasing the particle size, and in addition, There was little difference in solubility. On the other hand, in the case of oseltamivir phosphate, the solubility of all test solutions is lower than that of the free base, and the solubility variation varies with the particle size throughout the entire particle size region.

Example  2: Preparation of granules and obtained from them Capsule  And evaluation of tablets

Granules were prepared according to the ingredients and contents in Table 2 below. Povidone dissolved in 70% ethanol was used as a binding solution, and a high-speed mixer chamber was charged with oseltamivir free base or oseltamivir hydrochloride, pregelatinized starch, croscarmellose sodium And the mixture was stirred for 3 minutes. Then, wet granulation was carried out under the conditions of agitator 100 rpm, chopper 3000 rpm, and co-ordination time 2 minutes while adding the binding solution. The obtained wet granules were dried in a fluidized bed drier for 15 minutes to prepare granules.

75 mg of oseltamivir was taken from the granules obtained above and mixed with talc, sodium stearyl fumarate and sodium croscarmellose sodium (30% of the amount used in the following Table 2), and the resulting mixture was applied to a No. 2 gelatin capsule Capsule) to prepare a capsule. Further, 75 mg of oseltamivir was taken from the granules thus obtained and mixed with talc, sodium stearyl fumarate and sodium croscarmellose sodium (30% of the amount shown in Table 2 below), and the resulting mixture was applied to a rotary tablet machine (Sejong, MRC-18) at a hardness of about 10 to prepare tablets.

d _(0.9)
(탆) Type and amount of oseltamivir (mg) Type and amount of additive (mg) Formulation Example 1 5 Oseltamivir free base 75 mg Pre-gelatinized starch 45 mg
Croscarmellose sodium 10 mg
Povidone 2 mg
Talc 9 mg
Sodium stearyl fumarate 2 mg Formulation Example 2 10 Formulation Example 3 50 Formulation Example 4 100 Formulation Example 5 200 Formulation Example 6 250 Formulation Example 7 5 Oseltamivir phosphate 98.5 mg
(75 mg as oseltamivir) Formulation Example 8 10 Formulation Example 9 50 Formulation Example 10 100 Formulation Example 11 200 Formulation Example 12 250

The capsules and tablets obtained above were subjected to a dissolution test under the following test conditions. The results are shown in Table 3 below.

≪ Dissolution test conditions >

Dissolution test method: Dissolution method 2 of Korea Pharmacopoeia (paddle method)

Eluent: 0.1N-hydrochloric acid solution

Amount of eluate: 900 mL

Effluent temperature: 37.5 DEG C

Paddle speed: 50 rpm

Number of test specimens: 6

Sample collection time: 5 minutes

Capsule 5 minutes Leaching rate (%) Tablet 5 minutes Elution rate (%) Average Standard Deviation Average Standard Deviation Formulation Example 1 90.9 2.2 93.9 3.1 Formulation Example 2 91.9 3.9 92.3 2.1 Formulation Example 3 90.7 2.9 94.4 3.6 Formulation Example 4 89.7 5.1 93.3 4.2 Formulation Example 5 90.0 3.6 91.8 2.9 Formulation Example 6 81.7 5.5 84.3 3.2 Formulation Example 7 63.9 11.4 75.1 5.7 Formulation Example 8 59.5 18.9 69.4 7.1 Formulation Example 9 55.7 15.4 66.8 6.9 Formulation Example 10 49.0 21.1 63.4 7.7 Formulation Example 11 44.5 19.3 58.1 11.5 Formulation Example 12 40.8 17.7 56.3 9.8

As can be seen from the results in Table 3, when oseltamivir free base was used, 85% in 5 minutes in the range of particle size [d _(0.9) ] of 200 쨉 m or less (i.e., formulations 1 to 5) And the change of the dissolution rate according to the particle size is hardly observed. However, in the case of formulation example 1, the dissolution rate was excellent, but the flowability of the granules was poor and it was not suitable for filling the capsule or tablet, and there was a great difficulty in production. Therefore, it is understood that the particle size of oseltamivir phosphate ₍ i.e., d _(0.9)) is preferably in the range of 10 탆 to 200 탆. Formulation examples 7 to 12 using oseltamivir phosphate had a significantly lower dissolution rate in the initial 5 minutes and had difficulty in producing a product of uniform quality with a wide range of dissolution rate depending on the particle size. The results were similar in both capsules and tablets.

Example  3: Disintegration star  Stability test

As shown in the following Table 4, the stability test was carried out on the mixture of oseltamivir free base with various disintegrants and adding an appropriate amount of purified water. Each mixture was allowed to stand at 50 ° C and 75% relative humidity for 2 weeks, and then the content of the total of the flexible substances was calculated by measuring the contents of the flexible substances according to the method of analysis of the contents of the USP's Oseltamivir phosphate Capsule . The results are shown in Table 4 below.

Amount of active ingredient Disintegration type Disintegration
amount Total Flexible Substance (%) Oseltamivir free base 75 mg Croscarmellose sodium 10 mg 0.46 Crospovidone 0.34 Glycolic acid starch sodium 0.48 Low-substituted hydroxypropylcellulose 0.65 Calcium alginate 4.27 Magnesium aluminum silicate 2.90 Oseltamivir phosphate 98.5 mg
(75 mg as oseltamivir) Croscarmellose sodium 0.44 Crospovidone 0.19 Glycolic acid starch powder 0.55 Low-substituted hydroxypropylcellulose 0.59 Calcium alginate 0.37 Magnesium aluminum silicate 0.20

It is generally known that the free base form is often less stable than the salt form. As can be seen from the results in Table 4 above, the oseltamivir free base was found to be more effective when using croscarmellose sodium, crospovidone, glycolic acid starch sodium, or low-substituted hydroxypropylcellulose as the disintegrant, oseltamivir phosphate And a similar level of stability.

Example  4: Stability test by live contact

As shown in the following Table 5, the stability test was carried out on the mixture of oseltamivir free base with various lubricants and adding an appropriate amount of purified water. Each mixture was allowed to stand at 50 ° C and 75% relative humidity for 2 weeks, and then the content of the total of the flexible substances was calculated by measuring the contents of the flexible substances according to the method of analysis of the contents of the USP's Oseltamivir phosphate Capsule . The results are shown in Table 5 below.

Amount of active ingredient Type of lubricant Lubricant
amount Total Flexible Substance (%) Oseltamivir free base 75 mg Magnesium stearate 10 mg 0.49 Talc 0.27 Sodium stearyl fumarate 0.18 Light anhydrous silicic acid 2.71 Sucrose fatty acid 2.93 Glyceryl behenate 3.15 Oseltamivir phosphate 98.5 mg
(75 mg as oseltamivir) Magnesium stearate 0.48 Talc 0.31 Sodium stearyl fumarate 0.25 Light anhydrous silicic acid 0.76 Sucrose fatty acid 0.41 Glyceryl behenate 0.59

As can be seen from the results in Table 5 above, the oseltamivir free base exhibits a similar level of stability to oseltamivir phosphate when magnesium stearate, talc, and / or sodium stearyl fumarate is used as a lubricant.

Example  5: Stability test by packaging materials

600 mg of oseltamivir was taken from the capsules and tablets prepared in Example 2 and the granules obtained in Example 2, and the amounts of talc (10 mg), xanthan gum (5 mg), D-sorbitol (30 mg) (10 mg) and anhydrous citric acid (10 mg) were packed in the respective packaging materials shown in Table 6, and the stability test was conducted. Each package was allowed to stand for 6 months under the conditions of 40 ° C and 75% relative humidity, and then the content of the total flexible material was calculated by measuring the flexible material according to the flexible material analysis method described in USP 'Oseltamivir phosphate Capsule' . The results are shown in Table 6 below.

From the results shown in Table 6, it can be confirmed that the stability of the oseltamivir free base capsules and tablets is poor in a packaging material having a water vapor transmission rate (WVTR) value exceeding 4.0 g / m ² / d. On the other hand, it can be confirmed that when the porcelain having WVTR value of 4.0 or less is used, the total content of the flexible material is very good, which is less than 2%.

Claims (14)

A pharmaceutical composition for oral administration containing granules obtained by granulating the oseltamivir free base, wherein 90% [d _(0.9) ] of the oseltamivir free base particles has a particle size of 200 μm or less . The pharmaceutical composition according to claim 1, wherein 90% [d _(0.9) ] of the oseltamivir free base particles has a particle size of 10 μm to 200 μm. The pharmaceutical composition according to claim 1 having the form of a capsule, a tablet, a dry syrup, a powder or a chewable tablet. The pharmaceutical composition according to claim 1 having a dry syrupy form comprising granules and pharmaceutically acceptable additives obtained through a granulation process of oseltamivir free base. The pharmaceutical composition according to claim 1, wherein the granule obtained through the granulation process of oseltamivir free base is filled in capsules together with a pharmaceutically acceptable additive. The pharmaceutical composition according to claim 1, wherein the granule obtained through the granulation process of oseltamivir free base is tableted together with a pharmaceutically acceptable additive. The pharmaceutical composition according to claim 1, further comprising at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low-substituted hydroxypropylcellulose. The pharmaceutical composition according to claim 1, further comprising at least one lubricant selected from the group consisting of magnesium stearate, talc, and sodium stearyl fumarate. The pharmaceutical composition according to claim 1, wherein the dissolution test is carried out at a paddle rotation speed of 50 rpm according to the dissolution method 2 of the Korean Pharmacopoeia in 0.1 N hydrochloric acid aqueous solution, and the dissolution rate is 85% or more within 5 minutes. A medicament obtained by packing the pharmaceutical composition according to any one of claims 1 to 9 with a packaging material having a moisture permeability of 4.0 g / m ² / d or less. The packaging material according to claim 10, wherein the packaging material having the moisture permeability value of 4.0 g / m ² / d or less is a high density polyethylene (HDPE), a polyvinyl chloride-aluminum blister, a polyvinylidene chloride- (PVDC-Alu blister), polychlorotrifluoroethylene-aluminum blister (PCTFE-Alu blister), cyclic olefin copolymer-COC-Alu blister, and Alu-Alu blister ). ≪ / RTI > The medicament according to claim 10, wherein the total amount of the flexible substances measured according to the flexible substance analysis method described in the United States Pharmacopoeia is 2.0% or less when allowed to stand for 6 months under an acceleration condition of 40 DEG C and 75% relative humidity. (a) performing a wet granulation by adding a binding liquid to a mixture of oseltamivir free base and disintegrant having a particle size of 90% [d _(0.9) ] of particles of 200 mu m or less;
(b) drying the wet granules obtained in step (a) to obtain granules; And
(c) filling or granulating the granules obtained in step (b) with a pharmaceutically acceptable additive in a capsule
≪ / RTI > wherein the oseltamivir free base is selected from the group consisting < RTI ID = 0.0 > of: < / RTI > (a ') 90% of the particles [d _(0.9) ] have a particle size of 200 μm or less, and a mixture of the disintegrant is subjected to dry granulation using a roller compactor to obtain granules ; And
(b ') filling or granulating the granules obtained in step (a') with a pharmaceutically acceptable additive into the capsule
≪ / RTI > wherein the oseltamivir free base is selected from the group consisting < RTI ID = 0.0 > of: < / RTI >