KR20160003532A - Tenofovir disoproxil phosphate, and pharmaceutical composition comprising non-metalic salt disintegrant and non-metalic salt lubricant - Google Patents

Abstract

Provided in the present invention are: a phosphate of a chemical compound represented by chemical formula 1; and a pharmaceutical composition including the chemical compound represented by chemical formula 1 or a pharmaceutically permitted salt thereof, a non-metallic salt disintegrant, and a non-metallic salt lubricant. A tenofovir disoproxil phosphate of the present invention shows higher bioavailability than an existing tenofovir disoproxil fumarate, while also showing significantly reduced amount of related compound. A pharmaceutical composition including a non-metallic salt disintegrant or a non-metallic salt lubricant has a significantly improved stability of the tenofovir disoproxil, compared with an existing pharmaceutical agent, thereby ensuring a compatible stability of the tenofovir disoproxil depending on diluting agents used for manufacturing medicine.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a pharmaceutical composition comprising tenofovir disoproxil phosphate, a nonmetallic salt disintegrating agent and a nonmetallic salt lubricant. [0002] TENOFOVIR DISPROXIL PHOSPHATE, AND PHARMACEUTICAL COMPOSITION COMPRISING NON-METALIC SALT DISINTEGRANT AND NON-METALIC SALT LUBRICANT [

The present invention relates to a pharmaceutical composition comprising tenofovir disoproxil phosphate (terfenoviride soaproxylphosphate, hereinafter referred to as "TDP"), a non-metallic salt disintegrating agent and a non-metallic salt lubricant, Relates to a pharmaceutical composition comprising tenofovir disoproxil phosphate exhibiting excellent bioavailability and stability and a non-metallic salt disintegrating and non-metallic salt lubricant.

(6-amino-9H-puri-9-yl) prop-2-yl] oxy} methyl) phosphonic Is a nucleotide analogue that is useful for the treatment of HIV-1 infection and chronic hepatitis B by inhibiting the proliferative process of viruses such as HIV and HBV.

(A)

However, Tenofovir has a disadvantage of low bioavailability. (Antimicrobial agents and chemotherapy July 1998, p.1568-1573). An attempt to solve this problem is a tenofovir disoproxyl (a compound of the following formula [1]), which is a prodrug of Tenofovir, but it has a high bioavailability and poor stability, which makes it difficult to formulate it. Therefore, various attempts have been made to develop and formulate the salt form of tenofovir disoproxil. Typically, domestic patent 10-0661153 discloses that tenofovir disoproxil fumarate is disclosed in WO 2010-142761 Disclose tenofovir disoproxil succinate, and domestic patent publication 10-2014-0028790 describe tenofovir disoproxil aspartate.

[Chemical Formula 1]

Among them, the tablet composition comprising the tenofovir disoproxil fumaric acid salt described in Korean Patent No. 10-0661153 is the product prepared by the wet granule production method. However, according to the published literature (Pharmaceutical Research, 2001, 18, 234-237), it has been reported that tenofovir disoproxil has a problem in stability due to the influence of water, and the inventors of the present invention And that there is a need for another method of preparation for the preparation of compositions with good stability and stability.

In other words, the present inventors have recognized that another type of terfenoviridisoproxyl salt exhibiting superior bioavailability and less generation of a flexible substance than terfenoviride soaproxyl fumarate is required, and that the stability of tenofovir disoproxil fumarate itself Lt; RTI ID = 0.0 > a < / RTI >

Korean Patent No. 10-0661153 International Patent Publication No. WO 2010-142761 Korean Patent Publication No. 10-2014-0028790

It is an object of the present invention to provide a pharmaceutical composition which has pharmacokinetic merits that show better bioavailability than that of terfenoviride soaproxyl fumarate, and that the stability of the tenofovir disoproxylin novel salt and the tenofovir disoproxil itself, And to provide an improved pharmaceutical composition.

In order to accomplish the above object, the present invention provides a phosphate of the compound of the following formula (1).

[Chemical Formula 1]

Also, the present invention provides a compound of the above formula (1), or a pharmaceutically acceptable salt thereof; Nonmetallic salt disintegration; And a non-metallic salt gliding agent.

The present invention also provides a method for preparing granules comprising the steps of: (a) granulating a mixture comprising the compound of the formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, to prepare granules; (b) adding a non-metallic salt disintegrant to the granule produced in the step (a), mixing the non-metallic salt disintegrant, and adding a non-metallic salt lubricant to the mixed granule; And (c) formulating the mixed granules prepared in the step (b).

The inventors of the present invention have found that the tenofovir disoproxil phosphate exhibits excellent bioavailability as compared with the existing tenofovir disoproxil fumarate and exhibits a small effect on the production of a flexible substance and exhibits a low toxicity of the tenofovir disoproxil phosphate and the non- When the pharmaceutical composition is formulated using a lubricant, the stability of the tenofovir disoproxil is remarkably improved as compared with the conventional formulation, and the compatibility of the tablet of tenofovir disoproxyl with the compatibility of the excipient used in the formulation Compatibility Stability), thereby completing the present invention.

1 is a graph comparing the amounts of the unknown softening substances A and B produced according to the 60 ° C stability test performed on the compound of Formula 1 and various salts thereof (TD: tenofovir disoproxil; TDO: tenofovir disoproxil orophosphate; TDP: tenofovir disulfoproxylphosphate).

The present invention provides phosphates of the compound of the formula (1).

[Chemical Formula 1]

Also, the present invention provides a compound of the above formula (1), or a pharmaceutically acceptable salt thereof; Nonmetallic salt disintegration; And a non-metallic salt gliding agent.

The characteristics and kinds of each component constituting the pharmaceutical composition of the present invention will be described in more detail as follows.

(1) a pharmacologically active ingredient

The pharmaceutical composition according to the present invention comprises a compound of the above formula (1) or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient.

The compound of the above formula 1 may be used for the treatment or prevention of one or more viral infections in a human or animal including retrovirus, HIV, SIV and GALV, hepadnavirus, HBV, or the like, as described in Korean Patent No. 10-0661153 ≪ / RTI >

The pharmaceutically acceptable salts of the compounds of formula (I) above may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Preferably, it may be a salt with phosphoric acid, fumaric acid, succinic acid, aspartic acid, orotic acid, and more preferably, it may be a salt with phosphoric acid or orotic acid, but is not limited thereto.

The compound of Formula 1, or a pharmaceutically acceptable salt thereof, may be contained in an amount of 1.0 to 80% by weight, preferably 1.0 to 50% by weight, based on the total weight of the composition, but is not limited thereto.

(2) Non-metallic salt disintegration

Disintegrants are ingredients that are added to the solid compression formulation for swelling during wetting and are essential excipients in the manufacture of common solid compression preparations. The disintegrant serves to assist in the absorption of pharmacological ingredients by making the preparation into small particles when the preparation is administered in vivo.

In the present invention, in the preparation of a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the compound of the metal salt contained in the disintegrant is a major decomposition product of the compound of the formula Characterized in that a non-metallic salt disintegrant is used in order to prevent the promotion of the production of the flexible substances A and B.

&Quot; Non-metallic salt disintegration "according to the present invention means a disintegrant which does not contain a metallic substance and does not include metal salt disintegrants such as sodium alginate, sodium carboxymethyl cellulose, croscarmellose sodium, starch glycolate sodium . Examples of usable non-metallic defoliants according to the invention are crospovidone, low substituted hydroxypropylcellulose, alginic acid, or pregelatinized starch, and the use of such non-metallic salt disintegrants, The improved pharmaceutical composition of the present invention can be produced.

In one aspect of the invention, the non-metallic defoliant is preferably selected from crospovidone, low substituted hydroxypropylcellulose, alginic acid, or pregelatinized starch, most preferably crospovidone or low substituted hydroxypropylcellulose , But is not limited thereto.

The non-metallic salt decomposing may be used alone or in combination of two or more.

In one aspect of the present invention, the non-metallic salt disintegrant can be used in an amount of 0.001 to 10 parts by weight, preferably 0.005 to 5 parts by weight, more preferably 0.01 to 1 part by weight, based on 1 part by weight of the pharmacologically active ingredient , But is not limited thereto.

When the amount of the non-metallic decarboxylation salt is 0.01 part by weight or more, the disintegration of the tablets when wetted is the fastest, and the possibility of problems such as sticking during tablets and tableting is minimized. In addition, when the amount of the non-metallic decarboxylator is 1 part by weight or less, the density of the granules becomes most suitable for tableting, and advantages such as maintenance of proper hardness, maintenance of standard flaws, have.

(3) non-metallic salt lubricants

The lubricant is an ingredient added for smoothly advancing the compression operation of the granule, and is an essential excipient for manufacturing a general solid compression preparation. The lubricant improves the flowability of the powder and improves the filling of the die, reduces frictions between the granules and the friction between the die and the punch, and facilitates discharging the tablet from the die by compressing the tablet .

In the present invention, in the preparation of a pharmaceutical composition comprising a compound of the formula (1) or a pharmaceutically acceptable salt thereof, the component of the metal salt contained in the lubricant is a major decomposition product of the compound of the formula A non-metallic salt lubricant is used in order to prevent the promotion of the production of the unknown soft materials A and B.

"Nonmetallic salt glidant" according to the present invention means a glidant containing no metallic substance, and does not include metal salt glidants such as calcium stearate, magnesium stearate, sodium stearyl fumarate, and zinc stearate. Examples of usable non-metallic salt lubricants according to the present invention include fatty acid esters, fatty acids, alcohols, oils, fumaric acid, polyethylene glycol, polytetrafluoroethylene, talc or mixtures thereof. It is not.

Specifically, in one aspect of the present invention, the non-metallic salt lubricant is preferably selected from the group consisting of fatty acid esters (e.g., glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, Glyceryl tristearate, or sucrose fatty acid ester); Fatty acids and alcohols (e.g., palmitic acid, palmitoyl alcohol, stearic acid or stearyl alcohol); Oils (for example, hydrogenated castor oil, mineral oil or hydrogenated vegetable oil, etc.); Fumaric acid; Polyethylene glycol (e.g., PEG 4000 or PEG 6000), polytetrafluoroethylene; Or talc, more preferably sucrose fatty acid ester, stearic acid, hydrogenated vegetable oil, talc, glyceryl behenate, glyceryl palmitostearate, starch, or PEG 6000, and most preferably sucrose fatty acid Ester or stearic acid.

The non-metallic salt lubricant may be used alone or in combination of two or more.

In one embodiment of the present invention, the non-metallic salt lubricant may be used in an amount of 0.0005 to 5 parts by weight, preferably 0.001 to 1 part by weight, more preferably 0.005 to 0.5 part by weight, based on 1 part by weight of the pharmacologically active ingredient .

If the amount of the nonmetallic salt glidant is 0.005 part by weight or more, the tablet can be easily discharged from the compression die, and there is no possibility of problems such as sticking or the like when tablets are tableted. In addition, when the amount of the non-metallic salt lubricant is less than 0.5 part by weight, the possibility of tablet capping or laminating is least likely to occur. Generally, lubricating agents are highly water repellent, and when used in excessive amounts, unintentional problems such as delayed disintegration and deterioration of dissolution may occur.

(4) Pharmaceutically acceptable additives

The pharmaceutical composition according to the present invention may be formulated into various preparations by additionally containing pharmaceutically acceptable additives, and the pharmaceutical composition according to the present invention is preferably an agent for oral administration, but the present invention is not limited thereto.

The formulations for oral administration may be in the form of powders, tablets, pills, capsules, solutions, suspensions, emulsions, syrups, granules and the like, preferably tablets or capsules, no.

The pharmaceutical preparations for oral administration of the present invention may include diluents, binders and the like as pharmaceutically acceptable additives.

Examples of the diluent include microcrystalline cellulose, lactose, mannitol, calcium phosphate and the like. Examples of the binder include pregelatinized starch, povidone, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) Polyvinyl alcohol (PVA), carboxymethylcellulose sodium and the like can be used.

The diluent may be used in an amount of 0.1 to 100 parts by weight based on 1 part by weight of the pharmacologically active ingredient and the binder may be used in an amount of 0.01 to 10 parts by weight based on 1 part by weight of the pharmacologically active ingredient.

The present invention also provides a method for preparing a granule, comprising the steps of: (a) granulating a mixture comprising the compound of the formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, (b) adding a non-metallic salt disintegrant to the granule produced in the step (a), mixing the non-metallic salt disintegrant, and adding a non-metallic salt lubricant to the mixed granule; And (c) formulating the mixed granules prepared in the step (b).

In one aspect of the present invention, the pharmaceutical composition of the present invention comprises 1) a compound of the above formula (1), or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose, pregelatinized starch, Or 2) wet granulation in which water is added as a binding liquid. The non-metallic salt disintegrant is added to the granules, mixed with the non-metallic salt gliding agent, and finally mixed. The resulting final granulate can be purified using a purifier.

The various processes involved in the production of the pharmaceutical composition according to the present invention can be carried out based on a conventional process for producing a pharmaceutical preparation.

The thus prepared pharmaceutical composition of the present invention can be used for the treatment or prevention of one or more viral infections in human or animal including retrovirus, HIV, SIV and GALV, hepadnavirus, HBV, In addition to being able to effectively treat HIV-1 infection and chronic hepatitis B, including non-metallic decongestants and non-metallic salt lubricants, Or the generation of impurities (unknown substances A and B) can be suppressed to within 0.2% even under accelerated condition of 3 months in a sealed container storage state such as 40 ° C., 75% relative humidity and packaging of HDPE bottles, Harmonization) When stored for 3 months under accelerated conditions, it is possible to satisfy the condition that the amount of unknown softening material is 0.2% by weight or less, so that the stability of the compound of formula (1) , So that it is possible to increase the pharmacological effect in the body of the [formula a].

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

EXAMPLES 1 to 4 Preparation of Tablets Containing Non-metal Dehydrochloride

(FMC) as a non-metallic salt disintegrant, low-substituted hydrolyzate as a non-metallic salt disintegrant, TDP (Hanmi Precision, Korea) and microcrystalline cellulose (MINGTAI), lactose Tablets were prepared according to the composition and the content (unit: mg) shown in Table 1 below, using Roxypropylcellulose (SHIN-ETSU), Crospovidone (BASF) and Pregelatinized Starch (Roquette).

Specifically, TDP and microcrystalline cellulose, lactose and pregelatinized starch are sieved, dry granulated using a Roller compactor after mixing, and then granulated with an oscillator to prepare granules Respectively. The disintegrant was mixed with the granules prepared above, and the sucrose fatty acid ester sieved with 30 mesh was added and finally mixed. The final mixture thus prepared was made into tablets having a hardness of about 10 to 15 kp by a conventional method using a purifier (Sejong, Korea).

Example 1 Example 2 Example 3 Example 4 deflation
Granule TDP 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 - - - Low substituted hydroxypropyl cellulose - 5.0 - - Alginic acid - - 5.0 - Pregelatinized starch - - - 5.0 Final mixing Sucrose fatty acid ester 2.0 2.0 2.0 2.0 Total weight 100 100 100 100

≪ Comparative Examples 1 to 4 > Preparation of a tablet containing a metal salt disintegrant

Using the composition and the content (unit: mg) shown in the following Table 2, the tablets containing the disintegrant of metal salt were prepared in the same manner as above.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 deflation
Granule TDP 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Croscarmellose sodium 5.0 - - - Starch glycolate sodium - 5.0 - - Sodium alginate - - 5.0 - Carboxymethylcellulose sodium - - - 5.0 Final mixing Sucrose fatty acid ester 2.0 2.0 2.0 2.0 Total weight 100 100 100 100

≪ Examples 5 to 19 > Preparation of Tablets Containing Nonmetallic Salt Glidants

(DAI-ICHI KOGYO SEIYAKU, Japan) as a surfactant for TDP (Hanmi Precision, Korea) and microcrystalline cellulose (MINGTAI), lactose (original blowing agent), pregelatinized starch (roquette), crospovidone (BASF) JBS Pharma) or talc (Nippon talc corp.) With the composition and the content (unit: mg) shown in Table 3 below.

Specifically, TDP and microcrystalline cellulose, lactose, and pregelatinized starch were sieved, dry granulated using a roller compactor, and granulated with an oscillator to prepare granules. The granules thus prepared were mixed using crospovidone, and then the lubricant sieved with 30 mesh was added and finally mixed. The final mixture thus prepared was made into tablets having a hardness of about 10 to 15 kp by a conventional method using a purifier (Sejong, Korea).

Example 5 Example 6 Example 7 Example 8 deflation
Granule TDP 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 5.0 5.0 5.0 Final mixing Sucrose fatty acid ester 2.0 - - - Stearic acid - 2.0 - - Hydrogenated vegetable oil - - 2.0 - talc - - - 2.0 Total weight 100 100 100 100

In addition, a mixture of TDP (Hanmi Precision, Korea) and microcrystalline cellulose (MINGTAI), lactose (Nippon Poultry), pregelatinized starch (Roquette), crospovidone (BASF) and glyceryl behenate (Compritol 888 ATO , Gattefosse glyceryl palmitostearate (Compritol HD5, Gatefosse), starch (Roquette) or PEG 6000 (Sanyo chemical) were prepared in the same manner as above with the composition and the content (unit: mg) Respectively.

Example 9 Example 10 Example 11 Example 12 deflation
Granule TDP 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 5.0 5.0 5.0 Final mixing Glyceryl behenate 2.0 - - - Glyceryl palmitostearate - 2.0 - - Starch - - 2.0 - PEG 6000 - - - 2.0 Total weight 100 100 100 100

In addition, glyceryl monostearate (Capmul GMS) as a TDP (Hanmi Precision, Korea) and microcrystalline cellulose (MINGTAI), lactose (Nippon Poultry), pregelatinized starch (Roquette), crospovidone -50), landz international company (China), stearyl alcohol (Lubrizol advanced materials, USA), hydrogenated castor oil (BASF), mineral oil (Alfa aesar, USA), fumaric acid (Merck) Grace davison, USA) was prepared in the same manner as above with the composition and the content (unit: mg) shown in Table 5 below.

Example
13 Example
14 Example
15 Example
16 Example
17 Example
18 Example
19 deflation
Granule TDP 44.5 44.5 44.5 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Final mixing Glyceryl monostearate 2.0 - - - - - - Palmitoyl alcohol - 2.0 - - - - - Stearyl alcohol - - 2.0 - - - - Hydrogenated castor oil - - - 2.0 - - - Mineral oil - - - - 2.0 - - Fumaric acid - - - - - 2.0 - Silicon dioxide - - - - - - 2.0 Total weight 100 100 100 100 100 100 100

≪ Comparative Examples 5 to 8 > Preparation of Tablets Containing Metal Salt Glue Agent

Using the composition and the content (unit: mg) shown in Table 6 below, the tablets containing the metal salt glue were prepared in the same manner as above.

Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 deflation
Granule TDP 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 5.0 5.0 5.0 Final mixing Magnesium stearate 2.0 - - - Sodium stearyl fumarate - 2.0 - - Calcium stearate - - 2.0 - Zinc stearate - - - 2.0 Total weight 100 100 100 100

≪ Comparative Examples 9 to 12 > Preparation of tablet using wet granulation method

(FMC) as a non-metallic salt disintegrant, low-substituted hydrolyzate as a non-metallic salt disintegrant, TDP (Hanmi Precision, Korea) and microcrystalline cellulose (MINGTAI), lactose Tablets were prepared according to the composition and the content (unit: mg) shown in Table 7 below. TABLE-US-00007 TABLE 7 Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets

Specifically, TDP and microcrystalline cellulose, lactose, and pregelatinized starch were sieved, mixed, and then subjected to wet granulation using purified water according to a conventional method, followed by drying to prepare granules. The disintegrant was mixed with the granules prepared above, and the sucrose fatty acid ester sieved with 30 mesh was added and finally mixed. The final mixture thus prepared was made into tablets having a hardness of about 10 to 15 kp by a conventional method using a purifier (Sejong, Korea).

Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Wet
Granule mix TDP 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 Union <Purified water> <20> <20> <20> <20> mix Crospovidone 5.0 - - - Low substitution
Hydroxypropylcellulose - 5.0 - - Alginic acid - - 5.0 - Pregelatinized starch - - - 5.0 Final mixing Sucrose fatty acid ester 2.0 2.0 2.0 2.0 Total weight 100 100 100 100

Examples 20 to 23 Preparation of tablets containing TDO and non-metallic salt disintegrants

(Hereinafter referred to as "TDO") and a non-metallic salt disintegrant were carried out in the same manner as in Example 1 using the composition and the content (unit: mg) shown in Table 8 below &Lt; / RTI &gt;

Example 20 Example 21 Example 22 Example 23 deflation
Granule TDO 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 - - - Low substituted hydroxypropyl cellulose - 5.0 - - Alginic acid - - 5.0 - Pregelatinized starch - - - 5.0 Final mixing Sucrose fatty acid ester 2.0 2.0 2.0 2.0 Total weight 100 100 100 100

&Lt; Comparative Examples 13 to 16 > Preparation of tablets containing TDO and metal salt disintegrant

Tablets containing TDO and a metal salt disintegrant were prepared in the same manner as in Comparative Example 1 using the composition and the content (unit: mg) shown in Table 9 below.

Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 deflation
Granule TDO 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Croscarmellose sodium 5.0 - - - Starch glycolate sodium - 5.0 - - Sodium alginate - - 5.0 - Carboxymethylcellulose sodium - - - 5.0 Final mixing Sucrose fatty acid ester 2.0 2.0 2.0 2.0 Total weight 100 100 100 100

Examples 24-27 Preparation of tablets containing TDO and non-metallic salt lubricants

Tablets containing TDO and a non-metallic salt lubricant were prepared by performing the same procedure as in Example 5 using the composition and the content (unit: mg) shown in Table 10 below.

Example 24 Example 25 Example 26 Example 27 deflation
Granule TDO 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 5.0 5.0 5.0 Final mixing Sucrose fatty acid ester 2.0 - - - Stearic acid - 2.0 - - Hydrogenated vegetable oil - - 2.0 - talc - - - 2.0 Total weight 100 100 100 100

&Lt; Comparative Examples 17 to 20 > Preparation of tablets containing TDO and a metal salt lubricant

Using the composition and the content (unit: mg) shown in Table 11 below, the same procedure as above was carried out to prepare tablets containing TDO and a metal salt lubricant.

Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 deflation
Granule TDO 44.5 44.5 44.5 44.5 Microcrystalline cellulose 18.5 18.5 18.5 18.5 Lactose 25.0 25.0 25.0 25.0 Pregelatinized starch 5.0 5.0 5.0 5.0 mix Crospovidone 5.0 5.0 5.0 5.0 Final mixing Magnesium stearate 2.0 - - - Sodium stearyl fumarate - 2.0 - - Calcium stearate - - 2.0 - Zinc stearate - - - 2.0 Total weight 100 100 100 100

&Lt; Test Example 1 >

The tablets prepared in Examples 1 to 12, 20 to 27 and Comparative Examples 1 to 20 were examined for changes with time in order to predict storage stability. The tablets were individually packed in HDPE bottles containing 1 g silica gel And stored in a 60 ° C chamber. After 2 weeks and 4 weeks, the amount of the unknown products A and B, which are major degradation products of the compound of formula (1), was extracted with an extract (pH 5.5 phosphate buffer: methanol: butyl alcohol = 28: 11: 1) Lt; / RTI &gt; The results of Examples 1 to 4 are shown in Table 12, the results of Examples 5 to 8 are shown in Table 13, the results of Examples 9 to 12 are shown in Table 14, and the results of Examples 20 to 23 are shown in Table 15 , The results of Examples 24 to 27 are shown in Table 16, the results of Comparative Examples 1 to 4 are shown in Table 17, the results of Comparative Examples 5 to 8 are shown in Table 18, the results of Comparative Examples 9 to 12 are shown in Table 19, The results of Comparative Examples 13 to 16 are shown in Table 20, and the results of Comparative Examples 17 to 20 are shown in Table 21.

Example One 2 3 4 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.00 0.01 0.00 0.02 0.00 0.01 0.00 0.01 60 ℃ 4 weeks 0.00 0.03 0.00 0.03 0.02 0.05 0.01 0.02

Example 5 6 7 8 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.01 0.03 0.01 0.03 0.02 0.03 0.02 0.04 60 ℃ 4 weeks 0.01 0.04 0.00 0.05 0.05 0.08 0.01 0.03

Example 9 10 11 12 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.00 0.01 0.02 0.04 0.03 0.01 0.00 0.03 60 ℃ 4 weeks 0.03 0.04 0.05 0.09 0.05 0.05 0.01 0.04

Example 20 21 22 23 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.01 0.02 0.00 0.02 0.01 0.03 0.01 0.01 60 ℃ 4 weeks 0.03 0.02 0.01 0.04 0.01 0.06 0.02 0.03

Example 24 25 26 27 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.03 0.05 0.02 0.01 0.01 0.04 0.03 0.02 60 ℃ 4 weeks 0.06 0.08 0.02 0.07 0.03 0.09 0.03 0.05

Comparative Example One 2 3 4 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.15 0.24 0.10 0.18 0.09 0.25 0.11 0.25 60 ℃ 4 weeks 0.28 0.38 0.21 0.34 0.21 0.34 0.30 0.45

Comparative Example 5 6 7 8 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.31 0.38 0.15 0.20 0.21 0.33 0.32 0.40 60 ℃ 4 weeks 0.54 0.69 0.24 0.34 0.38 0.57 0.51 0.71

Comparative Example 9 10 11 12 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.07 0.08 0.06 0.06 0.11 0.16 0.12 0.10 60 ℃ 4 weeks 0.13 0.17 0.11 0.19 0.23 0.30 0.18 0.26

Comparative Example 13 14 15 16 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.24 0.19 0.15 0.21 0.12 0.26 0.14 0.28 60 ℃ 4 weeks 0.32 0.39 0.28 0.33 0.25 0.42 0.32 0.42

Comparative Example 17 18 19 20 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.34 0.34 0.18 0.23 0.25 0.28 0.31 0.48 60 ℃ 4 weeks 0.60 0.61 0.30 0.40 0.39 0.63 0.62 0.92

The tablets prepared in Examples 1, 2, 5, and 6 and Comparative Examples 1, 2, 5, and 6 were examined for changes in stability with respect to moisture and temperature. HDPE After the mixture was stored for 1 month and 3 months in a packed state, the amount of the produced flexible substances A and B, which are major degradation products of the compound of formula (1), was measured using an extract (pH 5.5 phosphate buffer: methanol: butyl alcohol = 1), followed by HPLC analysis. The results are shown in Tables 22 and 23 below.

Example 1 Example 2 Example 5 Example 6 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 40 ℃, 1 month acceleration 0.00 0.01 0.00 0.01 0.01 0.01 0.00 0.02 40 ℃, accelerated 3 months 0.00 0.01 0.00 0.02 0.02 0.03 0.00 0.04

Comparative Example 1 Comparative Example 2 Comparative Example 5 Comparative Example 6 Unknown unknown substance type A B A B A B A B first 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 40 ℃, 1 month acceleration 0.10 0.11 0.08 0.11 0.15 0.20 0.12 0.15 40 ℃, accelerated 3 months 0.18 0.24 0.12 0.21 0.33 0.42 0.20 0.28

As shown in Tables 12 to 23, when a non-metallic salt disintegrant and a lubricant were used in place of the metallic disintegrant and the lubricant in the formulation containing TDP or TDO as a main component, the production of the unknown softening substances A and B was about 5 It was found that the tablets of the present invention using the non-metallic salt disintegrating agent and the glidant improved the stability in storage of the preparation remarkably. In addition, when the composition was prepared by a dry granulation method other than the wet granulation method, the production of the unknown softening materials A and B was reduced from about 2 times to at least 20 times.

Also, according to the International Conference on Harmonization (ICH) standards, the permit standard for unknown impurity is set at 0.2% and the standard for known impurities is set at 0.5%. In the present invention, the tablets of Examples 1, 2, 5 and 6 satisfy the ICH standard of 0.2% under the condition of 40 ° C, which is presented as an accelerated condition in ICH. However, it was found that the tablets of Comparative Examples 1, 2, 5 and 6 using metal salt excipients exceeded the allowance standards.

From the above results, it can be confirmed that tenofovir disoproxil phosphate exhibits other compatibility stability depending on the excipient used in the formulation. This means that even an excipient having the same role in the formulation can have a serious effect on the stability of the formulation depending on the selection, and will be of great help in the development of the similar formulation in the future.

&Lt; Test Example 2 > Determination of bioavailability of the compound of formula (I) and its salt

(Hereinafter referred to as 'T') and a compound of the formula (1) (terfenoviridisoproxyl, hereinafter referred to as 'TD') and a salt thereof such as tenofovir disoproxil In order to predict the bioavailability of fumarate (hereinafter referred to as "TDF"), tenofovir disoproxylolate (hereinafter referred to as "TDO") and TDP, the following experiment was conducted.

The test subjects were SD rats (Sprague-Dawley Rat) and 24 rats were used for each group. Each test substance was completely dissolved in purified water by 4.3 mg of Tenofovir, and then orally administered with 1 ml of syringe. After the administration, 0.3 ml of blood was collected from the jugular vein by time, and blood samples were centrifuged and plasma was taken and analyzed. The method of evaluating the bioavailability was carried out by measuring the concentration of Tenofovir in blood after the administration and analyzing the pharmacokinetic parameters of Tenofovir. The results are shown in Table 24.

IV Oral T T TD TDF TDO TDP AUC (ng · hr / ml) 3961.1
± 565.3 393.2
± 179.9 1287.8
± 556.8 867.2
± 112.1 852.5
± 93.5 985.4
± 120.8 Cmax (ng / ml) 24451.3
± 4489.2 52.9
± 21.1 210.9
± 70.3 195.4
± 67.5 150.0
± 22.4 204.0
± 56.4 Tmax (hour) 0.017
± 0.00 1.56
± 0.77 0.33
± 0.00 0.46
± 0.30 0.44
± 0.10 0.40
± 0.85 BA (%) - 9.90 32.50 21.90 21.50 24.90

As shown in Table 24, the bioavailability of T was as low as 9.90%, and it was confirmed that the developed TD to improve the bioavailability showed a higher bioavailability. On the other hand, the salts of the compound of the formula (1) showed a somewhat lower bioavailability, but among them, the phosphate showed the highest bioavailability.

Test Example 3 Confirmation of the stability of the compound of formula (I) and its salt

In order to observe the change with time in order to predict the stability of TD, TDF, TDO, and TDP, tablets containing the compound were packed in HDPE bottles containing 1 g silica gel, respectively, and stored in a chamber at 60 ° C. After 2 weeks and 4 weeks, the amount of the unknown products A and B, which are major degradation products of the compound of formula (a), was extracted with an extract (pH 5.5 phosphate buffer: methanol: butyl alcohol = 28: 11: 1) Lt; / RTI &gt; The results are shown in FIG. 1 and Table 25.

Example TD TDF TDO TDP Unknown unknown substance type A B A B A B A B first 0.04 0.14 0.00 0.08 0.00 0.00 0.00 0.00 60 ℃ 2 weeks 0.33 1.31 0.07 0.21 0.01 0.00 0.00 0.00 60 ℃ 4 weeks 0.58 2.02 0.12 0.28 0.08 0.10 0.00 0.00

As shown in Table 25 and FIG. 1, the stability of the salts of the compound of the formula (1) and the permissible salts thereof was superior to that of the compound of the formula (1) Was found to have the best stability.

Claims (13)

The phosphate of the compound of the following formula:
[Chemical Formula 1]

. Claims 1. A compound of the following formula (1), or a pharmaceutically acceptable salt thereof; Nonmetallic salt disintegration; And a non-metallic salt lubricant.
[Chemical Formula 1]

3. The method of claim 2,
Wherein said pharmaceutically acceptable salt is a phosphate or orotic salt. 3. The method of claim 2,
The pharmaceutical composition according to claim 1, wherein the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is contained in an amount of 1.0 to 80% by weight based on the total weight of the composition. 3. The method of claim 2,
Wherein said non-metallic salt disintegrant is any one selected from the group consisting of crospovidone, low substituted hydroxypropyl cellulose, alginic acid, pregelatinized starch, and mixtures thereof. 3. The method of claim 2,
Wherein the non-metallic salt disintegrant is contained in an amount of 0.001 to 10 parts by weight based on 1 part by weight of the compound of the formula (1), or a pharmaceutically acceptable salt thereof. 3. The method of claim 2,
Wherein the nonmetallic salt glidant is any one selected from the group consisting of fatty acid esters, fatty acids, alcohols, oils, fumaric acid, polyethylene glycol, polytetrafluoroethylene, talc, &Lt; / RTI &gt; 3. The method of claim 2,
Wherein the non-metallic salt lubricant is any one selected from the group consisting of sucrose fatty acid ester, stearic acid, hydrogenated vegetable oil, talc, glyceryl behenate, glyceryl palmitostearate, starch, PEG 6000, Lt; / RTI &gt; 3. The method of claim 2,
Wherein the non-metallic salt glidant is contained in an amount of 0.0005 to 5 parts by weight based on 1 part by weight of the compound of the formula (1) or a pharmaceutically acceptable salt thereof. 3. The method of claim 2,
Wherein the antiviral pharmaceutical composition is a tablet. 3. The method of claim 2,
Wherein the antiviral pharmaceutical composition has an unknown microcrystalline content of 0.2% by weight or less when stored for 3 months under an accelerated condition of ICH (International Conference on Harmonization). (a) granulating a mixture comprising a compound of the following formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to prepare a granule;
(b) adding a non-metallic salt disintegrant to the granule produced in the step (a), mixing the non-metallic salt disintegrant, and adding a non-metallic salt lubricant to the mixed granule; And
(c) Formulating the mixed granules prepared in the step (b)
2. The method for producing a pharmaceutical composition for an antiviral according to claim 2,
[Chemical Formula 1]

13. The method of claim 12,
The method according to claim 2, wherein the granulation in step (a) is dry granulation.

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