WO2016052945A1

WO2016052945A1 - Granules containing oseltamivir, capsules comprising the granules, and method of preparing the capsules

Info

Publication number: WO2016052945A1
Application number: PCT/KR2015/010184
Authority: WO
Inventors: Seung Jun Lee; Jung Hyun Cho; Kyeong Soo Kim; Yong Il Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharmaceutical Co Ltd; Hanmi Pharmaceutical Industries Co Ltd
Current assignee: Hanmi Pharmaceutical Co Ltd; Hanmi Pharmaceutical Industries Co Ltd
Priority date: 2014-09-30
Filing date: 2015-09-25
Publication date: 2016-04-07
Anticipated expiration: 2017-03-30
Also published as: KR20160038837A

Abstract

Oseltamivir granules, capsules including the oseltamivir granules, and a method of preparing the capsules are provided. The oseltamivir granules include: oseltamivir or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable additive, wherein the oseltamivir granules have a mean diameter of about 150 ㎛ to about 400 ㎛ and include about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛.

Description

GRANULES CONTAINING OSELTAMIVIR, CAPSULES COMPRISING THE GRANULES, AND METHOD OF PREPARING THE CAPSULES

The present disclosure relates to granules containing oseltamivir or a pharmaceutically acceptable salt thereof, and capsules including the granules, and more particularly, to oseltamivir-containing granules having good stability and bioavailability, as well as improved productivity with a reduced defect rate when formulated into capsules due to good flowability compared to conventional oseltamivir granules.

Tamiflu^®(available from Roche), used as a therapeutic agent for Influenza A (H1N1) generally called "novel flu" or "novel influenza", includes oseltamivir phosphate as an active ingredient, and is formulated into suspensions or capsules.

However, formulating oseltamivir into capsules requires a large amount of the active ingredient per capsule, and the source material of the active ingredient is in the form of micronized powder, which lowers the flowability of the active ingredient and consequentially, leads to a high defect rate, and thus poor productivity when formulated into capsules by filling capsules with the active ingredient.

Oseltamivir phosphate is known to have high stability, compared to oseltamivir free base, but it is hard to reach a satisfactory dissolution rate even by reducing the particle size of oseltamivir phosphate. Furthermore, a high deviation in dissolution rate of oseltamivir phosphate may make quality control difficult.

According to an aspect of the present disclosure, there are provided oseltamivir granules having good flowability compared to conventional oseltamivir granules used in oseltamivir capsules, and consequentially, improved productivity of capsules, and that may improve the stability of oseltamivir free base, as well as may provide similar bioavailability to conventional oseltamivir capsules when formulated into capsules.

According to another aspect of the present disclosure, there are provided oseltamivir capsules with high productivity, including the above-described oseltamivir granules.

According to another aspect of the present disclosure, there is provided a method of preparing the oseltamivir capsules.

According to an aspect of the present invention, there are provided oseltamivir granules including: oseltamivir or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable additive, wherein the oseltamivir granules have a mean diameter of about 150 ㎛ to about 400 ㎛ and comprise about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛.

According to another aspect of the present invention, there is provided an oseltamivir capsule including the above-described oseltamivir granules.

According to another aspect of the present invention, there is provided a method of preparing the above-described oseltamivir capsule, the method including: preparing granules comprising oseltamivir or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, and a hydrophilic binder; sieving the granules to obtain granules having a mean diameter of about 150 ㎛ to about 400 ㎛ and comprising about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛; mixing the sieved granules with a disintegrant and a lubricant to obtain a mixture; and filling a capsule with the mixture.

As described above, the oseltamivir granules according to the present disclosure may have a larger size than granules in conventional oseltamivir capsules, and thus improved flowability, which may reduce a defect rate in filling capsule with the oseltamivir granules, and consequentially, improve the productivity in preparing capsules. The oseltamivir granules according to the present disclosure may improve the productivity of capsules compared to conventional oseltamivir capsules and have similar bioavailability to conventional oseltamivir capsules. In general, the larger the size of granules, the lower the dissolution rate and the lower the bioavailability. Contrary to this general phenomenon, the oseltamivir granules according to the present disclosure may both increase productivity and maintain bioavailability, which are unexpected effects to one or ordinary skill in the art.

Due to the use of a hydrophilic binder, the oseltamivir granules according to the present disclosure may have satisfactory stability of oseltamivir that meets a stability level required in a related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the U.S. Pharmacopeia (USP), which may be measured by analyzing an amount of related compounds in the oseltamivir capsules using the method of the USP. Even with oseltamivir free base, the oseltamivir granules according to the present disclosure may obtain a level of stability equivalent to with oseltamivir phosphate.

Due to the above-described effects, the oseltamivir capsules according to the present disclosure, including the above-described oseltamivir granules, may have good productivity compared to conventional oseltamivir capsules, similar bioavailability to conventional oseltamivir capsules, and improved stability even with oseltamivir free base that is equivalent to the stability with oseltamivir phosphate.

The oseltamivir capsules according to the present disclosure may reduce generation of related compounds by using capsule having a low moisture content of about 3% to about 7%, and thus further improve the stability of oseltamivir.

FIG. 1 is a graph of drug concentration in blood with respect to time in beagle dogs after 0.5, 1, 2, 4, 6, 8, 10, and 24 hours from the time of administration of oseltamivir capsules according to an embodiment of the present disclosure and Tamiflu^® capsules to 12 beagle dogs.

The present disclosure will be described with reference to exemplary embodiments.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although exemplary methods or materials are listed herein, other similar or equivalent ones are also within the scope of the present invention. All publications disclosed as references herein are incorporated in their entirety by reference.

According to an aspect of the present disclosure, oseltamivir granules include: oseltamivir or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable additive, wherein the oseltamivir granules have a mean diameter of about 150 ㎛ to about 400 ㎛ and comprise about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛.

The oseltamivir granules may have a mean diameter of about 200 ㎛ to about 350 ㎛ and comprise about 20wt% to about 30 wt% of the granules having a granule size of about 500 ㎛ to about 850 ㎛.

The pharmaceutically acceptable additive may be selected from the group consisting of a diluent, a disintegrant, a binder, and any combinations thereof. For example, the pharmaceutically acceptable additive may include all of a diluent, a disintegrant, and a binder.

The term "mean diameter" used herein refers to a "volume mean diameter (VMD)", which means a mean diameter of particles having different shapes with the assumption that the particles are in spherical form having the same area as in the original shape. The volume mean diameter of the oseltamivir granules may be measured using, for example, a HELOS (available from Sympatec GmbH, Germany).

Due to having a mean diameter of about 150 ㎛ to about 400 ㎛ and including about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛, the oseltamivir granules may have improved flowability compared to oseltamivir granules of conventional oseltamivir capsules, and thus have a reduced defect rate when filling capsules, and high productivity with easier quality control (see Test Example 1 and Test Example 2). In some embodiments, the oseltamivir granules may have a mean diameter of about 200 ㎛ to about 350 ㎛, and include about 20wt% to about 30wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛.

To achieve these granule size ranges of the oseltamivir granules according to embodiments, any pharmaceutical means may be used. For example, the oseltamivir granules may be prepared using a hydrophilic binder, followed by sieving with a 20 mesh sieve.

The binder may be any binder available for granule preparation and not affecting the function of the active ingredient. For example, the binder may be a hydrophilic binder. The hydrophilic binder may be selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, silicate derivatives such as hard anhydrous silicate, aluminum silicate, or calcium silicate, carbonates such as calcium carbonate, and any combinations thereof, but is not limited thereto.

In some embodiments, the hydrophilic binder may be povidone, hydroxypropyl cellulose, or any combinations thereof.

According to embodiments, when the oseltamivir granules were prepared using a hydrophilic binder, the granule diameter range of the oseltamivir granules were within the above-described ranges (Test Examples 1 and 2), and the amount of generated related compound C, as analyzed according to a related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the U.S. Pharmacopeia (USP), was remarkably reduced, compared to when using a nonhydrophilic binder (Test Example 3). Therefore, using a hydrophilic binder in preparing oseltamivir granules according to embodiments may result in the above-described granule size ranges of the oseltamivir granules, and may also improve the stability of the active ingredient.

In some embodiments, the oseltamivir granules may include about 0.3% or less of related compound C after storage in a high-density polyethylene (HDPE) bottle under accelerated conditions of a temperature of about 40℃ and a relative humidity (RH) of about 75% for about 6 months, as analyzed according to a related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the USP.

In some embodiments, the oseltamivir or a pharmaceutically acceptable salt thereof in the oseltamivir granules may include oseltamivir free base or oseltamivir phosphate, or any other pharmaceutically acceptable salts thereof.

In general, oseltamivir phosphate is known to be more stable than oseltamivir free base. However, oseltamivir free base has pharmacological advantages that oseltamivir free base may have a high initial dissolution rate through granule size control and have not so large deviation in dissolution rate (KR 2014-0081137). In some embodiments, the oseltamivir granules may also sufficiently stabilize oseltamivir free base due to the use of a hydrophilic binder, as described above. Accordingly, the oseltamivir granules according to embodiments may include oseltamivir free base as an active ingredient, with similar stability as when including oseltamivir phosphate as an active ingredient. The oseltamivir granules according to embodiments may use oseltamivir free base having pharmaceutical advantages over oseltamivir phosphate, as an active ingredient.

The diluent may be any diluents available in preparing granules, not affecting the function of the active ingredient. For example, the diluent may be selected from the group consisting of pregelatinized starch, mannitol, lactose, microcrystalline cellulose, calcium hydrogen phosphate, and any combinations thereof, but is not limited thereto.

The disintegrant may be any disintegrants available in preparing granules, not affecting the function of the active ingredient. For example, the disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and any combinations thereof, but is not limited thereto.

According to another aspect of the present disclosure, there is provided an oseltamivir capsule including the oseltamivir granules according to any of the above-described embodiments.

The oseltamivir capsule may have a reduced defect rate, due to good flowability of the oseltamivir granules, and consequentially remarkably improved productivity compared to conventional oseltamivir capsules.

In some embodiments, an empty capsule of the oseltamivir capsule may be a capsule having a moisture content of about 3wt% to about 7wt%. For example, the empty capsule of the oseltamivir capsule may be a hydroxypropyl methylcellulose (HPMC) capsule, but is not limited thereto. An HPMC capsule refers to a capsule including HPMC as a major ingredient. For example, the HPMC capsule may include about 79.6% to about 98.7% of HPMC. HPMC capsules are known to contain about 3% to about 7% of moisture that is remarkably lower than the moisture content of gelatin or gelatin-polyethylene glycol (PEG) capsule that are conventionally in wide use.

As a test result, an oseltamivir capsule prepared by filling an HPMC capsule having about 3% to about 7% of moisture content with oseltamivir granules according to an embodiment of the present disclosure was found to include a remarkably reduced amount of a related compound of oseltamivir after a test under accelerated conditions and to have a similar 20-min dissolution rate, i.e., initial dissolution rate, compared to oseltamivir capsules prepared by filling gelatin or gelatin-PEG capsule having about 10% to about 15% of moisture content with the oseltamivir granules (see Test Example 4). Therefore, in the oseltamivir capsules according to embodiments, the stability of the active ingredient may be remarkably improved without influencing the initial dissolution rate, due to the use of HPMC capsule having about 3% to about 7% of moisture content.

In some embodiments, the oseltamivir capsule may include about 0.2% or less of related compound C after storage in an HDPE bottle under accelerated conditions of a temperature of about 40℃ and an RH of about 75% for about 6 months, as analyzed according to a related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the USP.

In some embodiments, the oseltamivir capsule may have a dissolution rate of about 90% or greater in about 20 minutes, as measured in an about 0.1N aqueous hydrochloric acid (HCl) solution at a paddle rotation speed of about 50 rpm according to Dissolution method II in the Korean Pharmacopoeia.

As a result of a test of pharmacokinetic (PK) profile comparison between oseltamivir capsules according to an embodiment and currently commercially available Tamiflu^® capsules used as a control group after administration to beagle dogs, the oseltamivir capsules according to an embodiment had a similar body absorption rate, the area under the concentration-time curve (AUC), and a maximum concentration of drug in blood (Cmax) to those of Tamiflu^® capsules that are currently available on the market (Test Example 5). Accordingly, the oseltamivir capsules according to an embodiment may have higher productivity than the currently commercially available Tamiflu^® capsules, due to high flowability of oseltamivir granules included in the oseltamivir capsules according to an embodiment, and have a similar bioavailability to Tamiflu^® capsules. In general, the larger the size of granules, the lower the dissolution rate, and consequentially, the lower the bioavailability. However, unlike this general phenomenon, the oseltamivir capsules according to an embodiment may both increase productivity and maintain bioavailability, which are unexpected effects to one or ordinary skill in the art.

According to another aspect of the present disclosure, there is provided a method of preparing oseltamivir capsule including: preparing granules comprising oseltamivir or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, and a hydrophilic binder; sieving the granules to obtain granules having a mean diameter of about 150 ㎛ to about 400 ㎛ and comprising about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛; mixing the sieved granules with a disintegrant and a lubricant to obtain a mixture; and filling a capsule with the mixture.

The above-described descriptions of oseltamivir granules and oseltamivir capsules according to the above-described embodiments may apply to the method of preparing oseltamivir capsules.

The preparing of the granules may be performed using any granule preparation method known in the art, for example, using a wet granulation method or a dry granulation method.

The wet granulation method may include blending a mixture of oseltamivir or a pharmaceutically acceptable salt thereof, a diluent, and a disintegrant with a binder solution, forming granules, and drying the granules. A solvent for the binder solution may be water, ethanol, isopropanol, acetone, or a combination thereof. The binder solution may be prepared by adding a binder and any additive available in the pharmaceutical field, for example, a surfactant, a buffer, or a combination thereof, to a solvent. For example, the binder solution may be prepared by dissolving a hydrophilic binder in ethanol.

The drying may be performed at a temperature not exceeding about 60℃, and in some embodiments, a temperature not exceeding about 50℃, and in some other embodiments, not exceeding about 40℃, and in still other embodiments, at a temperature of about 20 ℃ to about 40 ℃, by taking into account the stability of the active ingredient, by air drying, fluid bed drying, oven drying, or microwave drying.

The sieving of the granules may be performed using any methods available to obtain granules having a mean diameter of about 150 ㎛ to about 400 ㎛ and including about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛. For example, the sieving may be performed using a 20 mesh sieve to obtain the granules within the above granule size range.

As a test result, the size of the oseltamivir granules may be determined by use of a hydrophilic binder, the mesh size of a sieve used in sieving, or the like (Test Examples 1 and 2). For example, when the granules are prepared using a hydrophilic binder and then sieved with a 20 mesh sieve, granules having a mean diameter of about 150 ㎛ to about 400 ㎛ and including about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛ may be obtained.

In the mixing of the sieved granules with a disintegrant and a lubricant, the disintegrant may be any disintegrants available for granule-containing capsule preparation. In some embodiments, the disintegrant may be selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and any combinations thereof. For example, the disintegrant may be croscarmellose sodium. The lubricant may be selected from the group consisting of magnesium stearate, talc, sodium stearyl fumarate, and any combinations thereof. For example, the lubricant may be a combination of talc and sodium stearyl fumarate.

One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. However, these examples are only for illustrative purposes and are not intended to limit the scope of the one or more embodiments of the present disclosure.

Example 1: Preparation of oseltamivir granules 1

Oseltamivir (InistST, Korea), pregelatinized starch, and croscarmellose sodium were mixed together according to the composition of Table 1, followed by blending with a binder solution of povidone dissolved in 70% ethanol, drying, and sieving with a 20 mesh sieve to form wet granules.

Next, croscarmellose sodium, talc, and sodium stearyl fumarate were added to the formed granules, and mixed together, thereby preparing oseltamivir granules.

Example 2: Preparation of oseltamivir granules 2

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that mannitol instead of pregelatinized starch was used as a diluent, as shown in Table 1.

Example 3: Preparation of oseltamivir granules 3

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that lactose instead of pregelatinized starch was used as a diluent, as shown in Table 1.

Example 4: Preparation of oseltamivir granules 4

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that microcrystalline cellulose instead of pregelatinized starch was used as a diluent, as shown in Table 1.

Example 5: Preparation of oseltamivir granules 5

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that calcium hydrogen phosphate instead of pregelatinized starch was used as a diluent, as shown in Table 1.

Example 6: Preparation of oseltamivir granules 6

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that hydroxypropyl cellulose L-type (HPC-L) instead of povidone was used as a binder, as shown in Table 1.

Example 7: Preparation of oseltamivir granules 7 (dry granulation)

Oseltamivir (InistST, Korea), pregelatinized starch, croscarmellose sodium, and povidone were mixed together according to the composition of Table 1, followed by granulation with a roller compactor and sieving with a 20 mesh sieve to prepare dry granules.

Next, croscarmellose sodium, talc, and sodium stearyl fumarate were added to the prepared granules, and mixed together, thereby preparing oseltamivir granules.

Comparative Example 1: Preparation of oseltamivir granules 8

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that acacia gum as a nonhydrophilic binder, instead of povidone, was used, as shown in Table 2.

Comparative Example 2: Preparation of oseltamivir granules 9

Oseltamivir granules were prepared by the same composition and the same manner as in Example 1, except that ethyl cellulose as a nonhydrophilic binder, instead of povidone, was used, as shown in Table 2.

Comparative Example 3: Preparation of oseltamivir granules 10

Oseltamivir granules were prepared by the same composition as shown in Table 2 and the same manner as in Example 1, except that a 35-mesh sieve, instead of a 20 mesh sieve, was used in sieving.

Comparative Example 4: Preparation of oseltamivir granules 11

Oseltamivir granules were prepared by the same composition as shown in Table 2 and the same manner as in Example 1, except that a Fitz mill, instead of a 20 mesh sieve, was used in sieving under the conditions of 20 mesh/2400 rpm.

Comparative Example 5: Preparation of oseltamivir mixture 1 (simple mixing)

An oseltamivir mixture as a simple mixture having the same composition as in Example 7 was prepared.

The ingredients, amounts thereof, and processes used to prepare oseltamivir granules in Examples 1 to 7 and Comparative Examples 1 to 5 are shown in Tables 1 and 2.

Table 1

Table 2

Comparative Example 6: Preparation of oseltamivir mixture 2 (granules from Tamiflu capsules)

4.95 g of granules were separated from 30 Tamiflu^® capsules that are currently available on the market.

Test Example 1: Granule size evaluation

Granule sizes of the oseltamivir granules of Examples 1 to 7 and Comparative Examples 1 to 6 were measured using sieves. The percentages of granules having a granule size of about 500 ㎛ to about 850 ㎛ and granules having a granule size of about 75 ㎛ to about 150 ㎛, and mean diameters of the granules were evaluated. The results are shown in Table 3.

Table 3

According to the results of Table 3, the oseltamivir granules of Examples 1 to 7, prepared using a hydrophilic binder via wet granulation or dry granulation and sieving with a 20 mesh sieve, were found to include about 20 wt% to about 30wt% of the granules having a granule size of about 500 ㎛ to about 850 ㎛ and to have a mean diameter of about 200 ㎛ to about 350 ㎛, and thus they were shown to have a similar granule size distribution. On the other hand, the oseltamivir granules of Comparative Examples 1 and 2, prepared using a nonhydrophilic binder, were found to have a mean diameter of about 130 ㎛ to about 150 ㎛, which is less than the granule size of the oseltamivir granules of Examples 1 to 7. The oseltamivir granules of Comparative Examples 3 and 4, prepared using a 35-mesh sieve and a Fitz mill, respectively, and the oseltamivir mixture 1 of Comparative Example 5 were found to include 2wt% or less of the granules having a granule size of about 500 ㎛ to about 850 ㎛ and to have a mean diameter of about 140 ㎛ or less, which is less than the granule size of the oseltamivir granules of Examples 1 to 7.

The oseltamivir granules from conventional Tamiflu^® capsules (Comparative Example 6), were found to have a mean diameter of less than 150 ㎛, and include about less than 10wt% of the granules having a granule size of about 500 ㎛ to about 850 ㎛, which is significantly less than the oseltamivir granules of Examples 1 to 7.

Test Example 2: Productivity test (Evaluation of filling defect rate)

Oseltamivir capsules including about 75 mg of oseltamivir per capsule were prepared from the oseltamivir granules of Examples 1 to 7 and Comparative Examples 1 to 7 with a capsule filler (Sejong Pharmatech, Korea). Defect rates T₁ and T₂ of the capsules are shown in Table 4. The defect rate T1 indicates the percentage of capsules having a reference weight with 3% to 7%, and the defect rate T₂ indicates the percentage of capsules having a reference weight with more than 7%.

Table 4

According to the results in Table 4, the capsules of the oseltamivir granules of Examples 1 to 6, prepared using diluents and the hydrophilic binder in wet granulation, had good productivity, with no detectable defect rate T₂. No defect rate T₂ was detected in the capsules of oseltamivir granules of Example 7 prepared via dry granulation using a roller compactor. On the other hands, a defect rate T₂ was detected in the capsules including the oseltamivir granules of Comparative Example 1 and Comparative Example 2 having a remarkably small mean diameter of granules due to the use of nonhydrophilic binders. The capsules including the oseltamivir granules of Comparative Examples 3 and 4 having a remarkably small granule size, prepared via sieving with a 35-mesh sieve and a Fitz mill, respectively, and the capsules including the oseltamivir simple mixture of Comparative Example 5 having a remarkably small particle size had a defect rate T₂ of about 3.0% or greater.

Summing up the results of Test Example 1 and Test Example 2, it is found that oseltamivir granules according to an embodiment of the present disclosure having a mean diameter of about 200 ㎛ to about 350 ㎛ and including about 20wt% to about 30wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛ may be obtained using a hydrophilic binder via sieving with a 20 mesh sieve. Capsules including the oseltamivir granules having a mean diameter within this range may have good productivity with no defect rate T₂, compared to capsules including oseltamivir granules having a mean diameter less than the above-described range.

Test Example 3: Granule stability test

An appropriate amount of oseltamivir granules prepared in Examples 1 to 7 and Comparative Examples 1 to 5 were taken and stored in HDPE bottles under accelerated conditions of a temperature of about 40℃ and an RH of about 75% for about 6 months, to analyze related compounds, followed by calculating the amount of related compound C therefrom according to a related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the USP. A reference level of related compound C according to the related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the USP is about 0.50% or less. The results are shown in Table 5.

Table 5

According to the results of Table 5, the oseltamivir granules of Examples 1 to 7 and Comparative Examples 3 to 5, prepared using hydrophilic binders, were found to have good stability, with about 0.35% or less of related compound C. Meanwhile, the oseltamivir granules of Comparative Examples 1 and 2, prepared using nonhydrophilic binders, were found to have poor stability with more than about 0.60% of related compound C. Therefore, it is found that oseltamivir granules, prepared using a hydrophilic binder, may have high stability of oseltamivir.

In view of the results of Tests Examples 1 to 3, when oseltamivir granules are prepared using a hydrophilic binder and have a mean diameter of about 200 ㎛ to about 350 ㎛, including about 20wt% to about 30wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛, the oseltamivir granules may have high productivity in capsule preparation and high stability of oseltamivir.

Test Example 4: Stability and dissolution test with different capsule

Oseltamivir capsules were prepared by filling different capsule of a size No. 2 with an amount of the oseltamivir granules of Example 1 by using a Polycap filler (Sejong Pharmatech, Korea) to contain about 75 mg of oseltamivir per capsule. The used capsule were HPMC capsules having a moisture content of about 3 to about 7%, gelatin capsules having a moisture content of about 13% to about 16%, and gelatin-polyethylene glycol (PEG) capsules having a moisture content of about 10% to about 14%.

The prepared oseltamivir capsules were stored in HDPE bottles under accelerated conditions of a temperature of about 40℃ and an RH of about 75% for about 6 months, to analyze related compounds, followed by calculating the amount of related compound C therefrom according to a related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the USP.

Separately, a dissolution test was performed on the prepared oseltamivir capsules under the following test conditions to calculate an average 20-min dissolution rate.

The amounts of related compound C and the dissolution rates as the test results are shown in Table 6.

Dissolution test method: Dissolution method II in the Korean Pharmacopoeia (Paddle method)

Dissolution medium: 0.1N-HCl solution

Amount of dissolution medium: 900 mL

Temperature of dissolution medium: 37.5 ℃

Paddle speed: 50 rpm

Number of test samples in each experimental group: 6

Sampling time: 20 min

Table 6

According to the results in Table 6, the oseltamivir capsules prepared using low-moisture HPMC capsule (Examples 8 to 10) had high stability with less than 0.2% of related compound C, while the oseltamivir capsules using gelatin or gelatin-PEG capsule having more than 10% moisture content (Examples 11 to 16) were found to have poor stability with more than 0.50% of a related compound (For reference, a reference level of related compound C according to the related compound analysis method described in the "Oseltamivir phosphate Capsule" section of the USP is about 0.50% or less).

As a result of the dissolution test under the above-described conditions, though gelatin and gelatin-PEG capsule are in general known to have a good dissolution rate, compared to HPMC capsule (Ku MS et al., Performance qualification of a new hypromellose capsule Int J Pharm. 2011 Sep 15; 416(1):16-24)), the average 20-min dissolution rates of the oseltamivir capsules made of HPMC capsule were also good, similar to those of the oseltamivir capsules made of gelatin or gelatin-PEG capsule. Therefore, the effects of oseltamivir capsules according to embodiments prepared using HPMC capsule, i.e., higher stability of the active ingredient) and similar dissolution rate, compared to those using gelatin or gelatin-PEG capsule, are unexpected to one of ordinary skill in the art.

Test Example 5: PK parameter comparison in animal test

After each group of oseltamivir capsules of Example 8, and Tamiflu^® capsules (75 mg) as a control group were administered to 12 beagle dogs, blood samples were taken from the dogs after 0.5, 1, 2, 4, 6, 8, 10, and 24 hours. A graph of drug oseltamivir concentration in blood with respect to time, as shown in FIG. 1, was obtained using the blood sample. PK parameters, including the area under the curve (AUC), maximum concentration of drug in blood (Cmax), and time to maximum drug concentration (Tmax) were obtained based on the PK profile (FIG. 1). The results are shown in Table 7.

Table 7

Referring to Table 7 and FIG. 1, the oseltamivir capsules of Example 8 had a similar body absorption rate, AUC, and Cmax to those of Tamiflu^®capsules (75 mg) that are currently available on the market. Therefore, the oseltamivir capsules according to an embodiment may have better flowability, and thus better productivity than Tamiflu^®, and similar bioavailability to Tamiflu^®.

While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. The disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the invention is defined not by the detailed description of the invention but by the appended claims, and all differences within the scope will be construed as being included in the present invention.

Claims

Oseltamivir granules comprising:

oseltamivir or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable additive,

wherein the oseltamivir granules have a mean diameter of about 150 ㎛ to about 400 ㎛ and comprise about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛.
The oseltamivir granules of claim 1, wherein the oseltamivir granules have a mean diameter of about 200 ㎛ to about 350 ㎛ and comprise about 20wt% to about 30 wt% of the granules having a granule size of about 500 ㎛ to about 850 ㎛.
The oseltamivir granules of claim 1, wherein the oseltamivir or pharmaceutically acceptable salt thereof includes an oseltamivir free base or oseltamivir phosphate.
The oseltamivir granules of claim 1, wherein the pharmaceutically acceptable additive is selected from the group consisting of a diluent, a disintegrant, a binder, and any combinations thereof.
The oseltamivir granules of claim 4, wherein the diluent is selected from the group consisting of pregelatinized starch, mannitol, lactose, microcrystalline cellulose, calcium hydrogen phosphate, and any combinations thereof.
The oseltamivir granules of claim 4, wherein the binder includes a hydrophilic binder.
The oseltamivir granules of claim 6, wherein the hydrophilic binder is selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hard anhydrous silicate, aluminum silicate, calcium silicate, calcium carbonate, and any combinations thereof.
The oseltamivir granules of claim 6, wherein the oseltamivir granules comprise about 0.3% or less of related compound C after storage in a high-density polyethylene (HDPE) bottle under accelerated conditions of a temperature of about 40℃ and a relative humidity (RH) of about 75% for about 6 months, as analyzed according to a related compound analysis method described in the Oseltamivir phosphate Capsule section of the U.S. Pharmacopeia (USP).
An oseltamivir capsule comprising the oseltamivir granules of any one of claims 1 to 8.
The oseltamivir capsule of claim 9, wherein an empty capsule of the oseltamivir capsule has a moisture content of about 3wt% to about 7wt%.
The oseltamivir capsule of claim 10, wherein the empty capsule of the oseltamivir capsule is a hydroxypropyl methylcellulose (HPMC) capsule.
The oseltamivir capsule of claim 10, wherein the oseltamivir capsule comprises about 0.2% or less of related compound C after storage in a high-density polyethylene (HDPE) bottle under accelerated conditions of a temperature of about 40℃ and a relative humidity (RH) of about 75% for about 6 months, as analyzed according to a related compound analysis method described in the Oseltamivir phosphate Capsule section of the U.S. Pharmacopeia (USP).
The oseltamivir capsule of claim 10, wherein the oseltamivir capsule has a dissolution rate of about 90% or greater in about 20 minutes, as measured in an about 0.1N aqueous hydrochloric acid (HCl) solution at a paddle rotation speed of about 50 rpm according to Dissolution method II in the Korean Pharmacopoeia.
A method of preparing the oseltamivir capsule of claim 9, comprising:

preparing granules comprising oseltamivir or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, and a hydrophilic binder;

sieving the granules to obtain granules having a mean diameter of about 150 ㎛ to about 400 ㎛ and comprising about 15wt% to about 35wt% of granules having a granule size of about 500 ㎛ to about 850 ㎛;

mixing the sieved granules with a disintegrant and a lubricant to obtain a mixture; and

filling a capsule with the mixture.
The method of claim 14, wherein the sieving of the granules is performed using a 20 mesh sieve.