WO2016003194A1

WO2016003194A1 - Tenofovir disoproxil phosphate, and pharmaceutical composition thereof comprising non-metallic salt disintegrant and non-metallic salt lubricant

Info

Publication number: WO2016003194A1
Application number: PCT/KR2015/006766
Authority: WO
Inventors: Jung Hyun Cho; Young Keun Choi; Hyung Seo Kim; Kyeong Soo Kim; Yong Il Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2014-07-01
Filing date: 2015-07-01
Publication date: 2016-01-07
Also published as: EP3154975A1; KR20160003532A; EP3154975A4

Abstract

A tenofovir disoproxil phosphate, and a pharmaceutical composition including tenofovir disoproxil phosphate or a pharmaceutically acceptable salt thereof, a non-metallic salt disintegrant, and a non-metallic salt lubricant are provided.

Description

TENOFOVIR DISOPROXIL PHOSPHATE, AND PHARMACEUTICAL COMPOSITION THEREOF COMPRISING NON-METALLIC SALT DISINTEGRANT AND NON-METALLIC SALT LUBRICANT

The present disclosure relates to a tenofovir disoproxil phosphate (hereinafter, also referred to as "TDP"), a pharmaceutical composition thereof comprising tenofovir disoproxil or pharmaceutically acceptable salt thereof, a non-metallic salt disintegrant and a non-metallic salt lubricant, and more particularly, to a tenofovir disoproxil phosphate with high bioavailability and stability, and a pharmaceutical composition thereof comprising a non-metallic salt disintegrant and a non-metallic salt lubricant.

Tenofovir (Systematic (IUPAC) name; ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid) represented by Formula A as a nucleotide analog is known to suppress the proliferation of viruses such as HIV and HBV and thus is effectively used in treatment of HIV-1 infection and chronic hepatitis B.

[Formula A]

However, tenofovir has low bioavailability (Antimacrobial Agents and Chemotherapy, July 1998, p.1568-1573). To address this drawback, using tenofovir disoproxil (compound represented by Formula 1) as a prodrug of tenofovir with high bioavailability has been suggested, but it is still difficult to formulate tenofovir disoproxil due to its poor stability. For this reason, various efforts have been made to develop a salt form of tenofovir disoproxil and prepare a formulation therefrom. For example, tenofovir disoproxil fumarate (WO 1999-005150), tenofovir disoproxil succinate (WO 2010-142761), and tenofovir disoproxil aspartate (WO 2014-035064) have been disclosed.

[Formula 1]

In particular, WO 1999-005150 discloses preparing a tablet including tenofovir disoproxil fumarate by wet granulation. However, according to a published article (Pharmaceutical Research., 2001, Vol. 18, p. 234-237), such wet granulation method may lower the stability of tenofovir disoproxil due to the influence of moisture, which has been experimentally confirmed by the inventors of the present application.

Accordingly, there is a need for a novel salt of tenofovir disoproxil with higher bioavailability and stability than tenofovir disoproxil fumarate and a pharmaceutical composition with improved stability of tenofovir disoproxil.

The present invention provides a novel salt of tenofovir disoproxil that has pharmacokinetic advantages, higher bioavailability than tenofovir disoproxil fumarate, and that has lower generation of related compounds, and a pharmaceutical composition with higher stability of tenofovir disoproxil.

According to an aspect of the present invention, there is provided a phosphate of a compound represented by Formula 1:

[Formula 1]

According to another aspect of the present invention, there is provided a pharmaceutical composition including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; a non-metallic salt disintegrant; and a non-metallic salt lubricant.

According to another aspect of the present invention, a method of preparing the above-described pharmaceutical composition includes: (a) preparing a granule by granulating a mixture of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; (b) preparing a mixed granule by mixing the granule prepared in (a) with a non-metallic salt disintegrant and adding a non-metallic salt lubricant thereto; and (c) formulating the mixed granule prepared in (b).

According to the one or more embodiments of the present invention, tenofovir disoproxil phosphate may have higher bioavailability and lower generation of related compounds than conventional tenofovir disoproxil fumarate. According to any of the embodiments, a pharmaceutical composition including tenofovir disoproxil or a pharmaceutically acceptable salt thereof, a non-metallic salt disintegrant, and a non-metallic salt lubricant may remarkably improve the stability of tenofovir disoproxil compared to conventional drug formulations. Therefore, the pharmaceutical composition may have high bioavailability and stability.

FIG. 1 illustrates graphs of the amounts of generated unknown related compounds A and B as a result of a stability test at 60℃ with regard to a compound of Formula 1 and various pharmaceutically acceptable salts thereof, wherein TD denotes tenofovir disoproxil, TDF denotes tenofovir disoproxil fumarate, TDO denotes tenofovir disoproxil orotate, and TDP denotes tenofovir disoproxil phosphate.

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, there is provided a phosphate of a compound represented by Formula 1.

[Formula 1]

The phosphate of the compound of Formula 1 may be a tenofovir disoproxil phosphate, which is a salt resulting from about 1:1 ionic bonding of phosphoric acid and tenofovir disoproxil free base.

In some embodiments, the tenofovir disoproxil phosphate may be prepared by a method that includes:

dissolving tenofovir disoproxil free base in water;

adding phosphoric acid to a resulting aqueous solution of tenofovir disoproxil free base and heating a resulting mixture while stirring; and

cooling a resulting heated and stirred reaction solution down to room temperature or lower while stirring to crystallize the same, thereby obtaining the tenofovir disoproxil phosphate.

The tenofovir disoproxil free base may be purchased or prepared using a known method.

The amount of phosphoric acid relative to tenofovir disoproxil free base may be in the range of about 1 to 3 equivalents, and in some embodiments, about 1.1 to about 1.5 equivalents.

The amount of water used as a reaction solvent may be in the range of about 5 mL to about 100 mL, and in some embodiments, about 10 mL to about 50 mL, based on 1 g of the tenofovir disoproxil free base.

In the preparation method of the tenofovir disoproxil phosphate, a reaction temperature in the heating and stirring may be room temperature or a temperature less than or approximately equal to a boiling point temperature of the reaction solvent, i.e., 100℃ or lower, and in some embodiments, may be in the range of about 40℃ to about 60℃.

In the preparation method of the tenofovir disoproxil phosphate, the reaction time in the heating and stirring may vary depending on the reaction temperature and may be, for example, in the range of about 10 hours to about 15 hours.

The tenofovir disoproxil phosphate may have remarkably high bioavailability and high stability compared to conventional other salts of tenofovir disoproxil. Accordingly, a pharmaceutical composition including the tenofovir disoproxil phosphate may be provided as a pharmaceutical product with ensured efficacy and stability.

According to another aspect of the present disclosure, there is provided a pharmaceutical composition including: the compound of Formula 1 or a pharmaceutically acceptable salt thereof; a non-metallic salt disintegrant; and a non-metallic salt lubricant.

Hereinafter, types and characteristics of each ingredient of the pharmaceutical composition will be described in greater detail.

(1) Pharmacologically active ingredient

Pharmacologically active ingredients of the pharmaceutical composition may include a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The compound of Formula 1 is known to be effective in treatment or prevention of a viral infection, caused by a retrovirus, HIV, SIV, GALV, hepadnavirus, HBV, etc. in a human or animal (WO 1999-005150).

The pharmaceutically acceptable salt of the compound of Formula 1 may be an acid addition salt, including an inorganic acid salt and an organic acid salt. In some embodiments, the acid addition salt may be phosphate, fumarate, succinate, or orotate. For example, the acid addition salt may be phosphate or orotate. However, embodiments are not limited thereto.

In some embodiments, the amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be in the range of about 1.0 wt% to about 80 wt%, and in some embodiments, about 1.0 wt% to about 50wt%, based on a total weight of the pharmaceutical composition. However, embodiments are not limited thereto.

(2) Non-metallic salt disintegrant

A disintegrant, which is an ingredient added to facilitate swelling of a solid, compressed drug formulation, is an essential excipient for the preparation of general solid, compressed formulations. Disintegrants may facilitate absorption of pharmacological active ingredients of a drug formulation in the body by disintegrating the drug formulation into smaller particles when the drug formulation is administered into the body.

Disintegrants available in the field of pharmaceutics include metallic salt disintegrants and non-metallic salt disintegrants. As a result of research, the inventors of the present disclosure found that a metallic salt in a metallic-salt ingredient may facilitate the generation of unknown related compounds A and B as major decomposition products of the compound of Formula 1, whereas a non-metallic salt disintegrant does not facilitate generation of the unknown related compounds A and B. Based on this research result, the pharmaceutical composition according to an embodiment of the present disclosure may include a non-metallic salt disintegrant.

The term "non-metallic salt disintegrant" refers to a disintegrant not including a metallic component, i.e., excluding a metallic salt disintegrant such as sodium alginate, sodium carboxymethyl cellulose, sodium croscarmellose, and sodium starch glycolate. Non-limiting available examples of the non-metallic salt disintegrant are crospovidone, low-substituted hydroxypropyl cellulose, alginic acid, or pregelatinized starch. Use of the non-metallic salt disintegrant may enable preparation of a tenofovir disoproxil or a salt thereof-containing pharmaceutical composition with improved storage stability.

In some embodiments, the non-metallic salt disintegrant may be crospovidone, low-substituted hydroxypropyl cellulose, alginic acid, pregelatinized starch, or any combinations thereof. For example, the non-metallic salt disintegrant may be crospovidone, low-substituted hydroxypropyl cellulose, or any combinations thereof. However, embodiments are not limited thereto.

The above-listed non-metallic salt disintegrants may be used alone or in a combination of at least two.

For example, the amount of the non-metallic salt disintegrant may be in the range of about 0.001 parts to about 10 parts by weight, and in some embodiments, about 0.005 parts to about 5 parts by weight, and in some other embodiments, about 0.01 parts to about 1 part by weight, based on 1 part by weight of the pharmacologically active ingredient. However, embodiments are not limited thereto.

When the amount of the non-metallic salt disintegrant is about 0.01 parts by weight or more, disintegration of a tablet may be improved when a tablet gets wet and a drawback such as sticking may occur less likely during a tableting process. On the other hand, when the amount of the non-metallic salt disintegrant is about 1 part by weight or less, the pharmaceutical composition may have advantages such as a granule density appropriate for tableting, maintenance of an appropriate hardness and a standard friability, and prevention of state change caused by moisture.

(3) Non-metallic salt lubricant

A lubricant, which is an ingredient added to facilitate the process of compressing granules, is an essential excipient for the preparation of general solid compressed formulations. Lubricants may facilitate flowability of a granule and powder to easily fill in a die, may reduce friction between granules and powder themselves and friction among a die, punch, granules and powder, and may facilitate tablet compressing and discharge from a die.

Lubricants that are available in the field of pharmaceutics include metallic salt lubricants and non-metallic salt lubricants. As a result of research, the inventors of the present disclosure found that a metallic salt in a metallic salt lubricant may facilitate generation of unknown related compounds A and B which are major decomposition products of the compound of Formula 1, whereas a non-metallic salt lubricant does not facilitate generation of the unknown related compounds A and B. Based on this research result, the pharmaceutical composition according to an embodiment of the present disclosure may include a non-metallic salt lubricant.

The term "non-metallic salt lubricant" refers to a lubricant not including a metallic component, i.e., which excludes a metallic salt lubricant such as calcium stearate, magnesium stearate, sodium stearyl fumarate, and zinc stearate. Non-limiting available examples of the non-metallic salt lubricant are fatty acid esters, fatty acids, alcohols, oils, fumaric acid, polyethylene glycol, polytetrafluoroethylene, talc, or a mixture thereof. Use of the non-metallic salt lubricant may enable preparation of a tenofovir disoproxil or a salt thereof-containing pharmaceutical composition with improved storage stability.

In some embodiments, the non-metallic salt lubricant may be fatty acid esters (for example, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl trimyristearate, glyceryl tristearate, or sucrose fatty acid ester); fatty acids and alcohols thereof (for example, palmitic acid, palmitoyl alcohol, stearic acid, or stearyl alcohol); oils (for example, hydrogenated castor oil, mineral oil, or hydrogenated vegetable oil); fumaric acid; polyethylene glycol (for example, PEG 4000 or PEG 6000); polytetrafluoroethylene; talc; or any combinations thereof. In some other embodiments, the non-metallic salt lubricant may be sucrose fatty acid ester, stearic acid, hydrogenated vegetable oil, talc, glyceryl behenate, glyceryl palmitostearate, starch, PEG 6000, or any combinations thereof. In another embodiment, the non-metallic salt lubricant may be sucrose fatty acid ester, stearic acid, or any combinations thereof. However, embodiments are not limited thereto.

The above-listed non-metallic salt lubricants may be used alone or in a combination of at least two.

For example, the amount of the non-metallic salt lubricant may be in the range of about 0.0005 parts to about 5 parts by weight, and in some embodiments, about 0.001 parts to about 1 parts by weight, and in some other embodiments, about 0.005 parts to about 0.5 parts by weight, based on 1 part by weight of the pharmacologically active ingredient. However, embodiments are not limited thereto.

When the amount of the non-metallic salt lubricant is about 0.005 parts by weight or more, discharging tablets from a compression die may be facilitated, and a drawback such as sticking may less likely occur during a tabeting process. In addition, when the amount of the non-metallic salt lubricant is less than about 0.5 parts by weight or less, tablet capping or laminating may less likely occur during a tabeting process. In general, a lubricant may have high water repellency, and thus, when used in excess, may lead to unexpected results such as a disintegration delay or a dissolution reduction of pharmacologically active ingredients.

(4) Pharmaceutically acceptable additive

According to an embodiment of the present disclosure, the pharmaceutical composition may further include a pharmaceutically acceptable additive and may be obtained in a variety of forms. In some embodiments, the pharmaceutical composition may be, but is not limited to, an oral drug formulation.

In some embodiments, the oral drug formulation may be a powder, a tablet, a pill, a capsule, liquid, a suspension, an emulsion, syrup, or a granule. For example, the oral drug formulation may be in the form of a tablet or capsule. However, embodiments are not limited thereto.

In some embodiments, the oral drug formulation may further include, a diluent, a binder, or the like as a pharmaceutically acceptable additive.

Non-limiting examples of the diluents are microcrystalline cellulose, lactose, mannitol, and calcium phosphate. Non-limiting examples of the binder are pregelatinized starch, povidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and sodium carboxymethyl cellulose.

For example, the amount of the diluent may be in the range of about 0.1 parts to about 100 parts by weight based on 1 part by weight of the pharmacologically active ingredient. For example, the amount of the binder may be in the range of about 0.01 part to about 10 parts by weight based on 1 part by weight of the pharmacologically active ingredient.

According to another aspect of the present disclosure, a method of preparing a pharmaceutical composition according to any of the above-described embodiments includes: (a) granulating a mixture of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to prepare a granule; (b) mixing the granule prepared in step (a) with a non-metallic salt disintegrant and adding a non-metallic salt lubricant thereto to prepare a mixed granule; and (c) formulating the mixed granule prepared in step (b).

In some embodiments, the pharmaceutical composition may be prepared as granules by i) dry granulation using compaction granulation or ii) wet granulation using water added as a binding solution. In addition, the pharmaceutical composition may be prepared as tablets by adding a non-metallic salt disintegrant to the resulting granules and mixing together, adding a non-metallic salt lubricant to the resulting mixture and finally mixing together, and then tableting the final mixture using a tablet press.

Various processes involved in the preparation of a pharmaceutical composition according to any of the above-described embodiments may be performed through common pharmaceutical formulation manufacturing processes that are known in the pharmaceutical industry.

The pharmaceutical composition according to any of the embodiments may be effectively used in treatment of HIV-1 infection and chronic hepatitis B due to the inclusion of a compound of Formula 1 that is known to be effective in treatment or prevention of at least one viral infection caused by a retrovirus, HIV, SIV, GALV, hepadnavirus, HBV, etc. in a human or animal. Due to the inclusion of a non-metallic salt disintegrant and a non-metallic salt lubricant, the pharmaceutical composition according to any of the embodiments may also suppress generation of impurities (unknown related compounds A and B) to be within about 0.2% when stored in an airtight container such as a high-density polyethylene (HDPE) bottle under the stressed condition at about 60℃ for about 4 weeks or under the accelerated condition at about 40℃ and a a relative humidity (RH) of about 75% for about 3 months, satisfying a requirement of the Guidelines of the International Conference on Harmonization (ICH) that unknown related compounds is about 0.2wt% or less in the case of 3-month storage under the ICH accelerated condition. Therefore, the pharmaceutical composition according to any of the embodiments may be manufactured as a pharmaceutical product with ensured high stability of the compound of Formula 1.

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.

Examples 1 to 4: Preparation of tablets including non-metallic salt disintegrant

Tablets were prepared using tenofovir disoproxil phosphate (TDP, available from HANMI FINE CHEMICAL CO., LTD, Korea), microcrystalline cellulose (available from MINGTAI), lactose (WON POONG PHARM CO. LTD, Korea), pregelatinized starch (available from Roquette), sucrose fatty acid ester (available from STEARINERIEDUBOIS), and a non-metallic salt disintegrant selected from alginic acid (available from FMC), low-substituted hydroxypropyl cellulose (available from SHIN-ETSU), crospovidone (available from BASF), and pregelatinized starch (available from Roquette), according to the compositions in Table 1, in which the amounts of ingredients are represented in milligram (mg).

In particular, TDP, microcrystalline cellulose, lactose, and pregelatinized starch were each sieved, mixed together, dry-granulated using a roller compactor, and then were established in an oscillator to obtain granules. The resulting granules were mixed with a disintegrant and then finally with sucrose fatty acid ester that was sieved through a sieve having a mesh size of 30. The resulting final mixture was pressed using a tablet press (available from Sejong Pharmatech Co., Ltd., Korea) according to a common method to form tablets having a hardness of about 10 kp to about 15 kp.

[Table 1]

Comparative Examples 1 to 4: Preparation of tablets including metallic salt disintegrant

Tablets including a metallic salt disintegrant were prepared in the same manner as in Examples 1 to 4, according to the compositions in Table 2, in which the amounts of ingredients are represented in milligram (mg).

[Table 2]

Examples 5 to 19: Preparation of tablets including non-metallic salt lubricant

Tablets were prepared using TDP (available from HANMI FINE CHEMICAL CO., LTD, Korea), and microcrystalline cellulose (available from MINGTAI), lactose (WON POONG PHARM CO. LTD, Korea), pregelatinized starch (available from Roquette), crospovidone (available from BASF), and a non-metallic salt lubricant selected from sucrose fatty acid ester (available from DAI-ICHI KOGYO SEIYAKU, Japan), stearic acid (available from Emeryoleochemicals) hydrogenated vegetable oil (Lubritab, available from JRS Pharma), and talc (available from Nippon talc corp.) , according to the compositions in Table 3, in which the amounts of ingredients are represented in milligram (mg).

In particular, TDP, microcrystalline cellulose, lactose, and pregelatinized starch were each sieved, mixed together, dry-granulated using a roller compactor, and then were established in an oscillator to obtain granules. The resulting granules were mixed with crospovidone and then finally with a lubricant that was sieved through a sieve having a mesh size of 30. The resulting final mixture was pressed using a tablet press (available from Sejong Pharmatech Co., Ltd., Korea) according to a common method to form tablets having a hardness of about 10 kp to about 15 kp.

[Table 3]

Tablets were prepared in the same manner as described above using TDP (available from HANMI FINE CHEMICAL CO., LTD, Korea), and microcrystalline cellulose (available from MINGTAI), lactose (WON POONG PHARM CO. LTD, Korea), pregelatinized starch (available from Roquette), crospovidone (available from BASF), and a non-metallic salt lubricant selected from glyceryl behenate (Compritol 888 ATO, available from Gattefosse), glyceryl palmitostearate (Compritol HD5, available from Gatefosse), starch (available from Roquette), and PEG 6000 (available from Sanyo chemical), according to the compositions in Table 4, in which the amounts of ingredients are represented in milligram (mg).

[Table 4]

Tablets were prepared in the same manner as described above using TDP (available from HANMI FINE CHEMICAL CO., LTD, Korea), microcrystalline cellulose (available from MINGTAI), lactose (WON POONG PHARM CO. LTD, Korea), pregelatinized starch (available from Roquette), crospovidone (available from BASF), and a non-metallic salt lubricant selected from glyceryl monostearate (Capmul GMS-50), palmitoyl alcohol (Landzinternational Company, China), stearyl alcohol (available from Lubrizol Advanced Materials, U.S.A.), hydrogenated castor oil (available from BASF), mineral oil (Alfa Aesar, U.S.A.), fumaric acid (available from Merck), and silicon dioxide (Grace Davison, U.S.A.), according to the compositions in Table 5, in which the amounts of ingredients are represented in milligram (mg).

[Table 5]

Comparative Examples 5 to 8: Preparation of tablets including metallic salt lubricant

Tablets including a metallic salt lubricant were prepared in the same manner as in Examples 5 to 19, according to the compositions in Table 6, in which the amounts of ingredients are represented in milligram (mg).

[Table 6]

Comparative Examples 9 to 12: Preparation of tablets by wet granulation

Tablets were prepared using TDP (available from HANMI FINE CHEMICAL CO., LTD, Korea), microcrystalline cellulose (available from MINGTAI), lactose (WON POONG PHARM CO. LTD, Korea), pregelatinized starch (available from Roquette), sucrose fatty acid ester (available from STEARINERIEDUBOIS), and a non-metallic salt disintegrant selected from alginic acid (available from FMC), low-substituted hydroxypropyl cellulose (available from SHIN-ETSU), crospovidone (available from BASF), and pregelatinized starch (available from Roquette), according to the compositions in Table 7, in which the amounts of ingredients are represented in milligram (mg).

In particular, TDP, microcrystalline cellulose, lactose, and pregelatinized starch were each sieved, mixed together, wet-granulated according to a common method with purified water, and then dried to obtain granules. The resulting granules were mixed with a disintegrant and then finally with sucrose fatty acid ester that was sieved through a sieve having a mesh size of 30. The resulting final mixture was pressed using a tablet press (available from Sejong Pharmatech Co., Ltd., Korea) according to a common method to form tablets having a hardness of about 10 kp to about 15 kp.

[Table 7]

Examples 20 to 23: Preparation of tablets including TDO and non-metallic salt disintegrant

Tablets including tenofovir disoproxil orotate (hereinafter, also referred to as "TDO") and a non-metallic salt disintegrant were prepared in the same manner as in Example 1, according to the compositions in Table 8, in which the amounts of ingredients are represented in milligram (mg).

[Table 8]

Comparative Examples 13 to 16: Preparation of tablets including TDO and metallic salt disintegrant

Tablets including TDO and a metallic salt disintegrant were prepared in the same manner as in Comparative Example 1, according to the compositions in Table 9, in which the amounts of ingredients are represented in milligram (mg).

[Table 9]

Examples 24 to 27: Preparation of tablets including TDO and non-metallic salt lubricant

Tablets including TDO and a non-metallic salt lubricant were prepared in the same manner as in Example 5, according to the compositions in Table 10, in which the amounts of ingredients are represented in milligram (mg).

[Table 10]

Comparative Examples 17 to 20: Preparation of tablets including TDO and metallic salt lubricant

Tablets including TDO and a metallic salt lubricant were prepared in the same manner as in Example 24, according to the compositions in Table 11, in which the amounts of ingredients are represented in milligram (mg).

[Table 11]

Experimental Example 1: Measurement of amount of related compound generated in the pharmaceutical composition

To observe time changes for predicting the storage stability of the tablets of Examples 1 to 12, Examples 20 to 27, and Comparative Examples 1 to 20, tablets of each example were put in a high-density polyethylene (HDPE) bottle together with about 1 g of silica gel and stored in a 60℃ chamber. Unknown related compounds A and B, as major decomposition products of the compound of Formula 1, were extracted after 2 weeks and 4 weeks from each sample with an extraction solution (including a pH 5.5 phosphate buffer solution, methanol, and butyl alcohol in a ratio of about 28:11:1), and the amounts thereof were analyzed by high-performance liquid chromatography (HPLC). The results are shown in Tables 12 to 21, in which the amounts of unknown related compounds A and B are represented in w/v%. In particular, Table 12 shows the results with regard to Examples 1 to 4, Table 13 shows the results with regard to Examples 5 to 8, Table 14 shows the results with regard to Examples 9 to 12, Table 15 shows the results with regard to Examples 20 to 23, Table 16 shows the results with regard to Examples 24 to 27, Table 17 shows the results with regard to Comparative Examples 1 to 4, Table 18 shows the results with regard to Comparative Examples 5 to 8, Table 19 shows the results with regard to Comparative Examples 9 to 12, Table 20 shows the results with regard to Comparative Examples 13 to 16, and Table 21 shows the results with regard to Comparative Examples 17 to 20.

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

To observe changes in stability caused by moisture and temperature in the tablets of Examples 1, 2, 5, and 6, Comparative Examples 1, 2, 5, and 6, after the tablets of each example put in a HDPE bottle were stored at a temperature of about 40℃ and a relative humidity (RH) of about 75% for 1 months and 3 months, unknown related compounds A and B as major decomposition products of the compound of Formula 1 were extracted from each sample with an extraction solution (including a pH 5.5 phosphate buffer solution, methanol, and butyl alcohol in a ratio of about 28:11:1), and the amounts thereof were analyzed by HPLC. The results are shown in Tables 22 and 23.

[Table 22]

[Table 23]

Referring to Tables 12 to 23, in the tablets including TDP or TDO as an active ingredient, the amounts of generated unknown related compounds A and B were about 5 times to about 50 times less when a non-metallic salt disintegrant and a non-metallic salt lubricant were used compared to the case when a metallic disintegrant was used alone or together with a metallic salt lubricant, which indicates that the tablets including a non-metallic salt disintegrant and a non-metallic salt lubricant had remarkably improved storage stability. Also, in the tablets prepared by dry granulation, the amounts of generated unknown related compounds A and B were less about 2 times up to about 20 times compared to the tablets prepared by wet granulation.

According to the Guidelines of the International Conference on Harmonization (ICH), an allowable level of an unknown impurity with an unidentified structure is 0.2% and an allowable level of an impurity with an identified structure is 0.5%. When stored at about 40℃ under the accelerated condition according to the ICH Guidelines, the tablets of Examples 1, 2, 5, and 6 including a non-metallic salt disintegrant and lubricant as excipients satisfied a 0.2% allowable level of the unknown impurity, while the tablets of Comparative Example 1, 2, 5, and 6 including metallic salt disintegrant or lubricant exceeded the allowable level.

These results indicate that the compatibility stability of a pharmaceutical composition including the tenofovir disoproxil phosphate (TDP) of the current embodiments may vary with the types of excipients. In other words, specific types of selected excipients, even when they have the same function, may significantly lower the stability of pharmaceutical compositions. This fact may be useful in developing similar drug formulations.

Experimental Example 2: Bioavailability evaluation of compound of Formula 1 and salts thereof

Bioavailabilities of a compound represented by Formula A (tenofovir, also referred to as T), a compound of Formula 1 (tenofovir disoproxil, also referred to as TD), and salts of the compound of Formula 1, i.e., tenofovir disoproxil fumarate (TDF), tenofovir disoproxil orotate (TDO), and tenofovir disoproxil phosphate (TDP) were evaluated according to the following method.

Twenty-four Sprague-Dawley (SD) rats as subjects were divided into 6 groups, each group including four rats. Each of the test compounds in an amount equivalent to 4.3 mg of tenofovir was completely dissolved in purified water, and then orally administered into the rats using a 1-mL syringe. After the administration, about 0.3 mL of blood was taken from the jugular vein of each rat at each hour to obtain blood samples, followed by centrifugation to collect only plasma. To evaluate bioavailability, the concentration of blood tenofovir in each blood sample was measured at each hour after the administration, and pharmacokinetic parameters of tenofovir (T) were analyzed. The results are shown in Table 24.

[Table 24]

According to Table 24, tenofovir (T) has a low bioavailability (BA) of about 9.90%, while tenofovir disoproxil (TD) developed to improve the low bioavailability of T has an improved bioavailability. Although the salts of the compound of Formula 1 have a lower bioavailability than the compound of Formula 1, tenofovir disoproxil phosphate (TDP) has highest bioavailability among the salts.

Experimental Example 3: Stability evaluation of compound of Formula 1 and salts thereof

To observe time changes for predicting stability of TD, TDF, TDO, and TDP, each raw material was put in HDPE bottles together with 1 g of silica gel, and stored in a 60℃-chamber. Unknown related compounds A and B as major decomposition products of the compound of Formula 1 were extracted after 2 weeks and 4 weeks from each sample with an extraction solution (including a pH 5.5 phosphate buffer solution, methanol, and butyl alcohol in a ratio of about 28:11:1), and the amounts thereof were analyzed by HPLC. The results are shown in FIG. 1 and Table 25.

[Table 25]

According to Table 25 and FIG. 1, upon comparing the amount of unknown related compounds A and B, generated in the tablets including the compound of Formula 1 or a pharmaceutical acceptable salt thereof, it was found that the pharmaceutically acceptable salts have improved stability compared to the compound of Formula 1, and more particularly, the TDP has highest stability among the salts.

Claims

A phosphate of a compound represented by Formula 1:

[Formula 1]
A pharmaceutical composition comprising:

a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof;

a non-metallic salt disintegrant; and

a non-metallic salt lubricant:

[Formula 1]
The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt thereof is a phosphate or an orotate.
The pharmaceutical composition of claim 2, wherein the amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is in the range of about 1.0 wt% to about 80 wt% based on the total weight of the pharmaceutical composition.
The pharmaceutical composition of claim 2, wherein the non-metallic salt disintegrant is selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, alginic acid, pregelatinized starch, and any combinations thereof.
The pharmaceutical composition of claim 2, wherein the non-metallic salt disintegrant is comprised in an amount of about 0.001 parts to about 10 parts by weight based on 1 part by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of claim 2, wherein the non-metallic salt lubricant is selected from the group consisting of fatty acid esters, fatty acids, alcohols, oils, fumaric acid, polyethylene glycol, polytetrafluoroethylene, talc, and any combinations thereof.
The pharmaceutical composition of claim 2, wherein the non-metallic salt lubricant is selected from the group consisting of sucrose fatty acid ester, stearic acid, hydrogenated vegetable oil, talc, glyceryl behenate, glyceryl palmitostearate, starch, PEG 6000, and any combinations thereof.
The pharmaceutical composition of claim 2, wherein the non-metallic salt lubricant is comprised in the range of about 0.0005 parts to about 5 parts by weight based on 1 part by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in the form of a tablet.
The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises about 0.2wt% or less of unknown related compounds when stored for about 3 months under an accelerated condition according to the Guidelines of the International Conference on Harmonization (ICH).
The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is antiviral.
A method of preparing the pharmaceutical composition of claim 2, the method comprising:

(a) preparing a granule by granulating a mixture comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive;

(b) preparing a mixed granule by mixing the granule prepared in (a) with a non-metallic salt disintegrant and adding a non-metallic salt lubricant thereto; and

(c) formulating the mixed granule prepared in (b):

[Formula 1]
The method of claim 13, wherein the granulating in step (a) is dry granulation.