KR20100091127A - Novel salts of adefovir dipivoxil and method for the preparation of the same - Google Patents

Abstract

PURPOSE: A novel salt of adefovir dipivoxil and a method for preparing the same are provided to ensure high bio-availability, low absorption, and high flowability. CONSTITUTION: An acid addition salt of adefovir dipivoxil is denoted by chemical formula 1. The crystalline of the addition salt if cocrystal. A pharmaceutical composition contains the acid addition salt of adefovir dipivoxil as an active ingredient and additionally contains diluents or carrier. The pharmaceutical composition is tablet or capsule for oral administration. A method for manufacturing the acid addition salt comprises: a step of dissolving adefovir dipivoxil in organic solvent to obtain a solution; a step of dissolving fatty acid selected from stearic acid, palmitate, lauric acid in organic solvent; and a step of crystallizing the addition salt formed by adding the solution.

Description

Novel salts of adefovir dipivoxil and method for the preparation of the same

The present invention relates to adefovir difficile novel salts and methods for their preparation.

Adefovir difficile is a prodrug of 9- [2-phosphonylmethoxyethyl] adenine (adefovir; PMEA) and is a medicine used for the treatment of infectious diseases caused by viruses. For example, adefovir is disclosed in European Patent 206459, US Patent 4808716, and adefovir difficile is disclosed in European Patent 481214, US Patent 5663159 and the like. In addition, the preparation method of adefovir difficile is described in Korean Patent No. 10-0700087, and Korean Patent No. 10-0618663 describes the crystal form and acid addition salt of adefovir difficile.

Adefovir difficile is known to be unstable in water and degrade into several products (Yuan et al., Pharmaceutical Research, Vol. 17, 1098-1103, 2000; U.S. Pat.No. 6635278). Therefore, dehumidifying agents such as silica gel or activated charcoal are required for packaging purposes (US Pat. No. 6635278), and in the case of Hepcera®, a product of Adefovir difficile, which is actually sold, Silica gel is used as a dehumidifying agent.

Adefovir difficile should satisfy solubility, good bioavailability, non-hygroscopicity, good powder flow, and ease of formulation in order to show sustained good efficacy. Adefovir difficile, which has been reported, has a strong hygroscopicity, low bioavailability of 59%, and does not satisfy the above because it has an inverse smell due to its material properties. According to US 2009/0247749, stability is improved by preparing acid addition salts or cocrystals (cocrystals) using nicotinamide, salicylicamide, saccharin in adefovir difficile.

In addition, it is known experimentally and empirically that the pKa values should show at least two differences in order for the acid-base pair to form a stable salt form. (Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry, page 319, etc.) The pKa value of adefovir difficile is about 4, and US Patent 2009/0247749 also mentioned salts with saccharin having a pKa value of 1.6 and 3.5 pKa value. Eggplants have been described as forming cocrystals (cocrystals) with nicotinamide.

US2009 / 0247749 Republic of Korea Patent 10-0618663

 Yuan et al., Pharmaceutical Research, Vol. 17, 1098-1103, 2000

It is an object of the present invention to prepare acid addition salts and / or cocrystals (cocrystals) of novel adefovir difficile using pharmacologically acceptable fatty acids to increase solubility, non-hygroscopicity, powder flowability, bioavailability, etc. We tried to improve the convenience and patient compliance in the manufacture of medicines by removing the adverse odor of adefovir difficile.

An aspect of the present invention,

(1) Acid addition salt of adefovir difficile compound represented by the following formula (1):

[Formula 1]

(Wherein n is 12, 14 or 16);

(2) The acid addition salt of adefovir difficile according to the above (1), wherein n is 16;

(3) The acid addition salt of adefovir difficile according to the above (1), wherein the crystalline form is cocrystal;

(4) The acid addition salt of adefovir difficile according to the above (3), wherein n is 16;

(5) A pharmaceutical composition containing the acid addition salt according to any one of (1) to (4) as an active ingredient, and further containing a pharmaceutically acceptable diluent or carrier;

(6) The pharmaceutical composition according to claim 5, which is a tablet or capsule for oral administration; And

(7) A method for producing an acid addition salt of adefovir difficile according to the above (1), characterized by comprising the following steps.

1) dissolving adefovir difficile in an organic solvent to prepare a solution,

2) dissolving a fatty acid selected from stearic acid, palmitic acid, and lauric acid in an organic solvent and then adding it to the solution prepared in step 1) to form an acid addition salt of adefovir difficile, and

3) crystallizing the acid addition salt of adefovir difficile formed in step 2), filtration, washing and drying to prepare the crystalline acid addition salt of adefovir difficile, represented by the formula (1) of claim 1 Method for producing an acid addition salt of adefovir difficile.

Acid addition salts of adefovir difficile according to the present invention exhibit high bioavailability, low hygroscopicity, high powder flowability, excellent aqueous solubility, ease of formulation, and the like compared to adefovir difficile.

Figure 1 shows the powder XRD analysis of adefovir difficile.
Figure 2 shows the results of powder XRD analysis of adefovir difficile stearate.
Figure 3 shows the DSC analysis of adefovir difficile stearate.
Figure 4 shows the NMR spectrum of adefovir difficile stearate.
5 shows the water solubility of adefovir difficile stearate and adefovir difficile.
6 shows the hygroscopicity of adefovir difficile stearate and adefovir difficile.
7 shows micrographs of adefovir difficile before preparation with salts.
8 shows a micrograph of adefovir difficile stearate prepared according to Example 1. FIG.

The present invention provides novel crystalline acid addition salts of adefovir difficile using fatty acids having high lipid affinity. As said fatty acid, stearic acid, palmitic acid, and lauric acid are preferable, and stearic acid is especially preferable.

Although there is no limitation to the crystalline form of the crystalline acid addition salt, it is most preferable that it is in a cocrystal form.

Specifically, the present invention provides an acid addition salt of adefovir difficile represented by the following formula (1).

[Formula 1]

In the above formula, n is 12, 14 or 16.

The acid addition salt of adefovir difficile is adefovir difficyl stearate when n is 16 in Formula 1, adefovir difficyl palmitate when n is 14, and adefovir difficyl laurate when n is 12.

The present invention also provides a co-crystal form of the acid addition salt of adefovir difficile represented by the formula (1).

The present invention also provides a pharmaceutical composition containing as an active ingredient a novel crystalline fatty acid salt of adefovir difficile. A pharmaceutical composition containing the novel crystalline fatty acid salt of adefovir difficile according to the present invention as an active ingredient may be tablets, capsules, etc. when formulated into a dosage form that can be easily administered orally. Tablets may be prepared by mixing the active ingredient with a carrier, diluent or excipient and the like followed by tableting, examples of suitable carriers, diluents or excipients used herein include sodium starch glycolate, crospovidone, starch, sugars, and mannitol Disintegrants such as; Fillers and extenders such as lactose, calcium phosphate and silicic acid derivatives; Binders such as polyvinyl pyrrolidone, carboxymethyl cellulose and other cellulose derivatives and gelatin; Pharmaceutically widely used excipients such as talc, lubricants such as calcium and magnesium stearate and solid polyethylene glycols. In addition, hard or soft gelatin capsules containing the active ingredient without or with the additives such as the above carriers, diluents or excipients can be prepared according to conventional methods. At this time, it is preferable that the active ingredient of the pharmaceutical composition contains 2 mg to 100 mg per dosage unit as the acid addition salt of adefovir difficile.

The present invention also provides a method for producing a novel crystalline acid addition salt of adefovir difficile using fatty acids having high lipid affinity.

The method for preparing acid addition salts of adefovir difficile according to the present invention comprises the steps of 1) dissolving adefovir difficile in an organic solvent to prepare a solution, 2) dissolving fatty acids in an organic solvent and then adding to the solution prepared in step 1). Forming an acid addition salt of adefovir difficile, 3) adding a poorly soluble solution to the reaction solution of step 2) to crystallize the acid addition salt of adefovir difficile, and 4) determining the acid addition salt of adefovir difficile Filtration, washing, and drying to obtain the crystalline acid addition salt of adefovir difficile.

If the method is described in detail step by step, the adefovir difficile acid of step 1) is preferably used 5 to 50% by weight, more preferably 10 to 30% by weight for efficient crystallization. In addition, the organic solvent used in step 1) may be used, such as ethanol, methanol, 2-propanol. The content of fatty acid used in step 2) is 0.1 to 5.0 equivalents, preferably 1.0 to 1.1 equivalents relative to adefovir difficile.

The following examples further illustrate the invention described herein and are not intended to limit the scope of the invention.

Powder XRD data of adefovir difficile before preparation with acid addition salt according to the present invention is shown in Figure 1, the novel acid addition salts of adefovir difficile prepared according to the present invention are powder XRD data (Fig. 2) and the adefovir diffi The crystal form was confirmed by comparative analysis with the powder XRD data of the compound, and DSC analysis (FIG. 3), and the structure was qualitatively confirmed using the NMR spectrum (FIG. 4).

Preparation of Adefovir difficile stearate

Adefovir difficile (10.0 g, 19.9 mmol) was dissolved in 30 ml of ethanol. Stearic acid (5.7 g, 19.9 mmol) was dissolved in 120 ml of ethanol, and then added to the adefovir difficile solution and stirred for 1 hour. 500 ml of purified water was added to the solution, and the mixture was cooled to 5-10 ° C., stirred for 2 hours, and the resulting solid was filtered, washed with 20 ml of ethanol and dried to obtain 14.8 g (yield 94.3%) of the title compound as white crystals.

¹ H NMR (CDCl ₃ ): δ (ppm) 8.30 (1H, s, H-8), 7.98 (1H, s, H-2), 6.57 (2H, br, NH ₂ ), 5.67 (4H, m, CH ₂ O-pivaloyl), 4.41 (2H, t, J = 5.10, H-1 '), 3.96 (2H, t, J = 5.10, H-2'), 3.86 (2H, d, J = 7.5, H -4 '), 2.37 (2H, t, J = 7.2, St-a), 1.67 (2H, m, St-b), 1.27 (28H, br, St-c), 1.22 (18H, C (CH ₃ ) _3- pivaloyl), 0.90 (3H, t, J = 6.3, St-d).

The figures on the powder XRD diagram of adefovir difficile before preparation with acid addition salts by Example 1 are shown in Table 1, and the figures on the powder XRD diagram of the stearate salt of adefovir difficile prepared according to Example 1 are shown in Table 2, respectively. It was.

Compared with the micrographs of adefovir difficile before preparation of acid addition salt by Example 1, it can be seen that adefovir difficile shows a needle-like shape as shown in FIG. 7, but the stear of adefovir difficile prepared according to Example 1 It was confirmed that the rate salt or cocrystal changed to a plate form as shown in FIG. 8.

Preparation of Adefovir difficile palmitate

Adefovir difficile (10.0 g, 19.9 mmol) was dissolved in 30 ml of ethanol. Palmitic acid (5.1 g, 19.9 mmol) was dissolved in 120 ml of ethanol, and then added to the adefovirdipicil solution and stirred for 1 hour. Crystallization, filtration, washing and drying were carried out in the same manner as in Example 1, to obtain 14.5 g (yield 96.0%) of the title compound as white crystals.

Preparation of Adefovir difficile laurate

Adefovir difficile (10.0 g, 19.9 mmol) was dissolved in 30 ml of ethanol. Lauric acid (3.99 g, 19.9 mmol) was dissolved in 120 ml of ethanol, and then added to the adefovir difficile solution and stirred for 1 hour. Crystallization, filtration, washing and drying were carried out in the same manner as in Example 1, to obtain 12.6 g (yield 90.0%) of the title compound as white crystals.

Tablet Preparation of Adefovirdiphyxyl Stearate

Adefovir difficyl stearate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and silicon dioxide of Example 1 were added to a mixer, mixed, and then combined in a mixer while adding purified water. The combined was dried in a fluid bed drier, sieved through a 50 mesh sieve, mixed with magnesium stearate and compressed to 100.0 mg by weight.

[Experimental Example]

Experimental Example 1: Measurement of the solubility of adefovir difficile acid addition salt

In order to confirm the water solubility of the active ingredient, the solubility test was carried out on the adefovir difficyl stearate and adefovir difficile prepared in Example 1 as follows.

Adefovir difficile stearate and adefovir difficile prepared in Example 1 above were sufficiently added to 30 ml of purified water at room temperature (20 ± 5 ° C.), respectively, and the sample was collected at a predetermined time to measure the content of adefovir difficile. The results are shown in Table 3 and FIG.

As can be seen from Table 3 and Figure 5, the adefovir difficile stearate prepared in Example 1 of the present invention was significantly higher solubility compared to adefovir difficile.

Experimental Example 2: Determination of hygroscopicity of adefovir difficile stearate

In order to measure the hygroscopicity of adefovir difficile stearate and adefovir difficile (AD) prepared in Example 1, the change in moisture (%) was measured while incubating in a 40 ° C./75% chamber for 4 days. The results are shown in Table 4 and FIG.

As can be seen in Table 4 and Figure 6, the adefovir difficile stearate of the present invention is expected to increase the stability of the formulation against moisture because the hygroscopicity is significantly lower than that of adefovir difficile.

Experimental Example 3: Bioavailability test of adefovir difficile stearate

Considering the bioavailability of the drug, the factor for biomembrane permeability is very important. Therefore, experiments on the biomembrane permeability of adefovir difficile stearate and adefovir difficile (AD) of Example 1 were conducted.

The experimental method was performed on the adefovir difficile stearate and adefovir difficile of Example 1 after the drug absorption evaluation test using the Caco-2 cell in vitro model, and the absorption direction (basal-basal) and the secretion direction (basal-) of the drug. Flux values of apical were quantified using HPLC. The value was considered statistically to evaluate the biomembrane permeability of the drug. The results are shown in Table 5.

Considering the above results statistically, the adefovir difficile stearate and adefovir difficile of Example 1 did not show a significant difference in the flux value in the absorption direction, but the adefovir dipy of Example 1 in the permeability in the secretion direction. Voxyl stearate was significantly lower than adefovir difficile (p <0.05).

As a result, the adefovir difficile stearate of Example 1 exhibits superior biomembrane permeability as compared to adefovir difficile. Therefore, bioavailability is expected to increase.

Experimental Example 4 Measurement of Powder Flow of Adefovir Difficile Stearate

In order to prepare the drug as a solid agent, the better the flowability of the powder, the lower the amount of excipient used and can be easily manipulated in various manufacturing processes. Therefore, the angle of repose, which is an index of powder flow properties of adefovir difficile stearate and adefovir difficile (AD) of Example 1, was measured.

D (Cm) Example 1 Adefovir difficile chamber (AD) 1.7 9 ° 16 °

From Table 6, the angles of repose of adefovir difficile stearate and adefovir difficile in Example 1 were 9 ° and 16 °, respectively, and the adefovir difficile stearate of Example 1 had a smaller repose angle than adefovir difficile, resulting in more powder flow. It can be seen that excellent. Therefore, the adefovir difficyl stearate of Example 1 can reduce the amount of excipient used, and the operation in the manufacturing process becomes easier.

Claims (7)

Acid addition salts of adefovir difficile represented by Formula 1 below:
[Formula 1]

(Wherein n is 12, 14 or 16). The acid addition salt of adefovir difficile according to claim 1, wherein n is 16. The acid addition salt of adefovir difficile according to claim 1, wherein the crystalline form is cocrystal. The acid addition salt of adefovir difficile according to claim 3, wherein n is 16. A pharmaceutical composition comprising the acid addition salt according to any one of claims 1 to 4 as an active ingredient and further containing a pharmaceutically acceptable diluent or carrier. The pharmaceutical composition according to claim 5, which is a tablet or capsule for oral administration. 1) dissolving adefovir difficile in an organic solvent to prepare a solution,
2) dissolving a fatty acid selected from stearic acid, palmitic acid, and lauric acid in an organic solvent and then adding it to the solution prepared in step (1) to form an acid addition salt of adefovir difficile, and
3) crystallizing the acid addition salt of adefovir difficile formed in step (2), and filtering, washing and drying to prepare the crystalline acid addition salt of adefovir difficile. The manufacturing method of acid addition salt of the adefovir difficile shown.

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