KR102077060B1 - Pharmaceutical composition comprising Tenofovir Disoproxil Aspartate salt - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising tenofovir disoproxyl aspartic acid salt and a method for preparing the same. The composition of the present invention is superior in dissolution rate and friability than tablets containing conventional tenofovir disoproxyl fumarate.

Description

Pharmaceutical composition comprising Tenofovir Disoproxil Aspartate salt

The present invention relates to a pharmaceutical composition comprising tenofovir disoproxyl and a pharmaceutically acceptable salt thereof having excellent dissolution rate and improved friability when prepared as a tablet.

Tenofovir (Compound name: ([(2R) -1- (6-amino-9H-purin-9-yl) propan-2-yl] oxymethyl) phosphonic acid) represented by the following Chemical Formula 1 is a nucleotide analogue. It is useful for the treatment of HIV-1 infection and chronic hepatitis B by inhibiting the proliferation of viruses such as HIV and HBV.

Tenofovir not only has potent hepatitis B virus DNA suppression ability in lamivudine (zepix) resistant patients, but also tenofovir is classified by the US Food and Drug Administration (FDA) as the fetal risk classification B (non-fetal risk in animal studies). It is an antiviral agent belonging to.

However, tenofovir has the disadvantage of low bioavailability (Antimacrobial agents and chemotherapy July 1998, p. 1568-1573). In an attempt to develop and formulate a salt form of tenofovir disoproxyl to solve this problem, Korean Patent No. 66153 discloses tenofovir disofoxyl fumarate, and International Patent Publication No. WO 2010-142761 discloses Salts and the like, and among these, tenofovir disoproxyl fumarate is used.

Tenofovir disopoxyl fumarate (hereinafter TDF) has the chemical name 9- [2- (R)-[[bis [[((isopropoxycarbonyl) oxy] methoxy] phosphinoyl] methoxy] propyl ] Adenine fumaric acid (1: 1), a prodrug that hydrolyzes upon absorption.

The development of other salts of tenofovir disoproxyl having an excellent effect is in progress, and in particular, the development of a formulation useful for mass production with an excellent dissolution rate is required. In addition, in order to develop a formulation that is excellent in formulation according to the type of salt of tenofovir disoproxyl, the use of additives according to the characteristics of the salt and the preparation method should be found.

The present inventors have therefore developed a pharmaceutical composition comprising an additive comprising tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as an active ingredient and having pharmaceutically superior properties.

It is intended to provide a pharmaceutical composition comprising tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as an active ingredient and an additive which has pharmaceutically superior properties. In particular, it is to provide a pharmaceutical composition comprising tenofovir disoproxyl aspartic acid salt as an active ingredient and a specific pregelatinized starch as a binder.

The present invention relates to a pharmaceutical composition comprising tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising Starch 1500 and Prejel PA5 PH.

Starch 1500 and Prejel PA5 PH are trade names for pre-gelatinized starch, and pregelatinized starch is mainly used as disintegrants, excipients, etc. in the preparation of preparations and as a binder to improve fluidity and compressibility in dry tablets. It can also be used for wet granules.

Starch 1500 is a pregelatinized corn starch that acts as a disintegrant, binder, etc. in solid oral dosage forms such as direct tableting, wet and dry granulation. Hydrate to make slurry. In addition, by inhibiting the water activity in the formulation, when used in water-sensitive drugs, it helps to improve the stability, and has an easy feature to ensure content uniformity.

Prejel PA5 PH (PA5) is potato starch and is mainly used in oral solid preparations such as tablets. PA5 has high solubility and high fluidity compared to natural starch, and is suitable as a binder, and can be used in tablets to increase hardness and reduce wear.

The present inventors have found that when preparing a pharmaceutical formulation comprising tenofovir disoproxyl or a pharmaceutically acceptable salt thereof, when further comprising Starch 1500 and PA5, the friability is reduced and the dissolution rate is improved. And the present invention was completed.

In addition, the inventors have found that the formulation properties are superior when used together with Starch 1500 and PA5 alone as binders, respectively.

In addition, the present invention may be a pharmaceutical composition comprising Starch 1500 and PA5 in a ratio of 1: 0.5 to 1: 2 as a binder, but is not limited thereto. Preferably, the ratio of Starch 1500 and PA5 is 1: 0.7 to 1. 1: 1.5, more preferably, the ratio of starch 1500 and PA5 is 1: 1.

Starch 1500 and PA5 in the present invention may be included in 5 to 10% by weight relative to the total weight.

Starch 1500 and PA5 in the present invention may be included in 5 to 30% by weight based on the weight of the active ingredient.

Pharmaceutically acceptable salts of tenofovir disoproxyl for use in the present invention include acid addition salts, which include inorganic or organic acid salts.

The inorganic acid salts include, but are not limited to, hydrochloride, phosphate, sulfate or disulfate. The organic acid salt is acetate, dichloroacetate, adipate, alginate, ascorbate, camphorate, caprate, caproate, caprylate, cyclate, galactate, gluceptate, glucuronate , Glutamate, oxoglutarate, lactobionate, thiocyanate, malonate, uronate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propionol Laterate, malonate, succinate, suverate, sebacate, maleate, orotate, myristate, butyne-1,4-dioate, hexine-1,6-dioate, citrate, lactate, betahydroxy Butyrate, glycorate, malate, tartrate; Aliphatic sulfone organic acid salts such as methanesulfonate, propanesulfonate, camphor sulfonate, camsylate, edisilate, esyrate and isethionate; Aromatic organic acid salts, benzoate, chloro benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, phenylacetate, phenylpropionate, phenylbutyrate, mandelate, salicylate , Para-aminosalicylate, tannate, cinnamate; Salts such as benzenesulfonate, toluenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, or naphthalenesulfonate, which are aromatic sulfone organic acid salts.

Preferably the pharmaceutically acceptable salt of tenofovir disoproxyl may be phosphate, orotate, fumarate, succinate or aspartate. More preferably it may be tenofovir disoproxyl aspartate.

The chemical name of the tenofovir disoproxyl aspartate of the present invention is 9- [2 [(R)-[[bis [(isopropoxycarbonyl) oxy] methoxy] phosphinoyl] methoxy] propyl] adenine aspart An acid, represented by the following formula (2).

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive, which includes at least one excipient selected from the group consisting of microcrystalline cellulose, anhydrous lactose or any lactose hydrate; At least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, and sodium starch glyconate; At least one lubricant selected from the group consisting of calcium stearate, magnesium stearate, sodium stearyl fumarate and zinc stearate; Ethyl cellulose, shellac, ammonio methacrylate copolymer, polyvinylacetate, polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl One or more coating agents selected from the group consisting of cellulose, hydroxypropylmethyl cellulose, hydroxypropylbutyl cellulose, hydroxypropylpentyl cellulose, and Opadry Blue may be used, but is not limited thereto.

The pharmaceutical composition of the present invention contains tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as an active ingredient, and is a conventional agent in the pharmaceutical field, such as tablets, capsules, beads, beadlets, granules, It may be formulated as a preparation for oral administration such as pills, troches, solutions, suspensions, or parenteral administration.

In addition, the pharmaceutical formulation of the present invention may further include a pH adjuster, suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like as necessary. The content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.

If the pharmaceutical formulation comprising tenofovir disoproxyl or a salt thereof of the present invention is a tablet, the tablet comprises the steps of admixing disoproxyl or a salt thereof and a pharmaceutically acceptable additive to form granules and the granule It may be prepared by a manufacturing method comprising the step of tableting.

In this case, the granules may be prepared by conventional wet granulation or dry granulation methods known in the art. In addition, the tablet may be prepared by a direct tableting method, it may be tableted using a tableting machine that is commonly used for tableting.

For example, the tablet may be prepared by mixing tenofovir disoproxyl salt, Starch 1500, PA5, and the like to prepare primary granules; Preparing a final mixture by mixing an excipient and a lubricant with the primary granules; And it may be prepared by a manufacturing method comprising the step of tableting the final mixture into a tablet.

At this time, the wear degree of the prepared tablet is preferably 0.5 or less, more preferably 0.3 or less.

The composition according to the present invention comprises tenofovir disoproxyl or salts thereof, binders and the like, and when prepared as a preparation, the dissolution rate is improved to have an excellent bioavailability, and the friability is improved.

1 is a graph showing the dissolution rate of the preparation prepared in Examples 1 to 4 and the reference drug.

Through the following examples will be described in more detail the present invention. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

[Examples 1 to 5]

(1) Preparation of Granules

Tenofovir disoproxyl aspartate, lactose hydrate, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch (Starch 1500 and Prejel PA5), purified water in a high speed mixer (LFS-GS-2J, Fukae Powtec, Japan) The granules were put together and granulated and then dried in a fluidized bed dryer (FBCG-1, Chongjin Industrial Technology, Korea). After drying it was established as Co-mil (U3, Quadro, Canada).

(2) Final mixing and tableting

The dried granules of (1) were placed in a mixer, and croscarmellose sodium was added thereto to carry out the first mixing. After completion of the primary mixing, stearyl fumarate sodium was added through a 30mesh sieve, followed by secondary mixing to prepare a final mixture.

Here, the addition amount of the main component and the binder (mg) is shown in Table 1 below.

*% By weight of binder = binder content / tablet content (620.00 mg)

* Binder weight relative to main component = content of binder / main component content

[Test Example 1]

Wear and tear measurement

[Wearness Measurement Method]

Wear and tear meter: SVM-102 (Pharmatest Apparatebau, GmbH, Germany)

-Measurement method: 20 tablets, wear and tear measurement after 100 rotations

Table 2 shows the measurement results of the wear and tear of the tablets prepared in Examples 1 to 5.

* Standard: 0.5% or less

Looking at Table 2, it can be seen that when added and mixed Starch 1500 and PA5 in a ratio of 1: 0.5 to 1: 2, wear and tear is significantly improved than when using only Starch 1500.

[Test Example 2]

Dissolution Rate Measurement

As a reference drug, the solution of ^{Gualid Viriard®} and the preparations prepared according to Examples 1 to 4 were subjected to a dissolution test under the following conditions by the Flow through cell method.

Dissolution test method

 -Dissolution test equipment: Sotax CE 7smart_off-line (Sotax, Switzerland)

 Eluent: pH 1.2 medium

 Eluent temperature: 37 ± 0.5 ° C

 Flow rate: 4 mL / min

 Sample volume: 1 tablet per vessel

 Assay HPLC Liquid Chromatography Conditions

 -Detector: UV-visible spectrophotometer (wavelength: 260mm)

 Column: Inertsil ODS 4 (4.6 × 150 mm, 5 μm) or equivalent column

Mobile phase: acetonitrile and pH 6.0 buffer * Mixed solution of (45: 55)

 Injection volume: 10 μl

 Flow rate: 1.5 mL / min

 -Column temperature: constant temperature around 30 ℃

 * pH 6.0 buffer solution: 1 mL of triethylamine in a 1 L volumetric flask, labeled with purified water and adjusted to pH 6.0 with phosphoric acid.

Dissolution rate (µg / ml) with time at pH 1.2 is shown in Table 3 below.

As shown in the experimental results of Table 3 and Figure 1, it can be seen that the formulations prepared in Examples 1 and 2 show a similar or better dissolution rate than the reference drug. That is, it can be seen that Starch 1500 and PA5 have an excellent dissolution rate when the mixture is added in a ratio of 1: 0.5 to 1: 1.

[Test Example 3]

Dissolution Rate Measurement

As a reference drug, the solution prepared according to the ^{viridum ® of} Gilliard and the preparation prepared according to Example 2 was subjected to dissolution test in pH 1.2, 4.0, 6.8 and water by paddle method. Dissolution rate (µg / ml) with time at each pH is shown in Table 4.

As shown in the experimental results of Table 4, it can be seen that the formulation prepared in Example 2 shows a better dissolution rate than the control in pH 1.2, 4.0, 6.8 and water. That is, it can be seen that Starch 1500 and PA5 have an excellent dissolution rate when mixed and added at a ratio of 1: 1.

As a result, when mixed with Starch 1500 or PA5, the wear and tear rate is improved, especially when mixing Starch 1500 and PA5 in a ratio of 1: 1, both the wear and dissolution rate is very excellent.

Claims (14)

A pharmaceutical composition comprising tenofovir disoproxyl as an active ingredient and a pharmaceutically acceptable salt thereof, and further comprising Starch 1500 and PA5 in a weight ratio of 1: 0.5 to 1: 2. The pharmaceutical composition of claim 1, wherein the active ingredient is tenofovir disoproxyl aspartic acid salt. delete The pharmaceutical composition of claim 1 comprising Starch 1500 and PA5 in a weight ratio of 1: 0.7 to 1: 1.5. The pharmaceutical composition of claim 4 comprising Starch 1500 and PA5 in a weight ratio of 1: 1. The pharmaceutical composition of claim 1 or 2 comprising Starch 1500 and PA5 in an amount of 5 to 10% by weight, based on the total weight. The pharmaceutical composition according to claim 1 or 2, comprising Starch 1500 and PA5 in an amount of 5 to 30% by weight based on the weight of the active ingredient. The pharmaceutical composition of claim 1 or 2 further comprising an excipient and a disintegrant. The pharmaceutical composition of claim 8, wherein the excipient is selected from the group consisting of microcrystalline cellulose, anhydrous lactose and lactose hydrate. The pharmaceutical composition of claim 8, wherein the disintegrant is selected from the group consisting of sodium croscarmellose, crospovidone, and sodium starch glyconate. A pharmaceutical formulation wherein the pharmaceutical composition according to claim 1 is formulated into a tablet. The pharmaceutical formulation according to claim 11, wherein the friability of the tablet is 0.5 or less. 13. The pharmaceutical formulation of claim 12, wherein the friability of the tablet is 0.3 or less. Preparing a granule by adding tenofovir disoproxyl or a pharmaceutically acceptable salt thereof, Starch 1500 and PA5;
Further mixing an additive with the granules to produce a final mixture; And
Tableting the final mixture;
As a method for producing a tablet comprising tenofovir disoproxyl or a pharmaceutically acceptable salt thereof,
The tablet is a method of producing a tablet, characterized in that containing starch 1500 and PA5 in a weight ratio of 1: 0.5 to 1: 2.

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