WO2015130083A1

WO2015130083A1 - Pharmaceutical composition with improved usage containing entecavir

Info

Publication number: WO2015130083A1
Application number: PCT/KR2015/001839
Authority: WO
Inventors: 김순회; 손미원; 장선우; 박찬웅; 김정수; 마경완; 이상진
Original assignee: 동아에스티 주식회사
Priority date: 2014-02-25
Filing date: 2015-02-25
Publication date: 2015-09-03

Abstract

The present invention relates to a pharmaceutical composition containing entecavir as an active ingredient and a dietary effect remover. The pharmaceutical composition according to the present invention exhibits a stable in vivo behavior regardless of food intake, by minimizing a dietary effect shown when taking entecavir, that is, the decrease in bioavailability, which occurs when taking entecavir with meals. Therefore, the present invention can maximize the bioavailability of entecavir regardless of food intake and improve the medication compliance of chronic hepatitis B patients taking entecavir, and thus the improvement in the therapeutic effect can be anticipated.

Description

Pharmaceutical composition containing entecavir with improved usage

The present invention relates to a pharmaceutical composition containing entecavir, and relates to a composition containing entecavir by maximizing bioavailability and enabling patients to take entecavir with or without meals.

Entecavir is [1S- (1α, 3α, 4β)]-2-amino-1,9-dihydro-9- [4-hydroxy-3- (hydroxymethyl) -2- of Formula 1 Methylenecyclopentyl] -6H-purin-6-one, a guanosine nucleoside analog approved in March 2005 by the US FDA, and through animal and human mechanisms that inhibit the three-step process of viral replication. It is used as a treatment for chronic hepatitis B by showing antiviral activity in.

Formula 1

Entercavir is described in US Pat. No. 5,206,244 for the use of a therapeutic agent for hepatitis B virus, wherein the patent assumes an effective dosage of an antiviral agent for oral or parenteral administration in the range of about 1.0 to 50 mg / kg body weight, with preferred administration. Amounts and appropriate intervals are disclosed.

Korean Patent No. 10-0757155 discloses a composition containing a low dose of entercavir administered daily to treat hepatitis B virus infection and co-infection. The patent also provides formulations for oral administration of low doses of entercavir.

BARACLUDE ^® tablet is manufactured, marketed in accordance with the Republic of Korea Patent (Baraclude information ^®, Bristol-Myers Squibb) is a widely used product for the treatment of chronic hepatitis B. However, the dosage and dosage of the barracrud tablets is limited to fasting (2 hours after meal or at least 2 hours before) administration, causing a lot of discomfort in patients with chronic hepatitis B who need to take a long time.

According to US FDA-approved data for barracuda tablets, Cmax is reduced by about 44% and AUC by about 20% when taken with low-fat meals, while Cmax is about 46% when taken with high-fat meals, and AUC. Is indicated to be reduced by about 18%. In fact, a study published in the journal Arzneimittelforschung in 2010 compared the fasting and post-entak entecavir bioavailability in 12 Chinese subjects. Reported a decrease of about 22%.

Thus, for the same reason, the administration of entecavir is limited to fasting doses, and this limited dosage regimen may reduce the compliance of entecavir and cause incomplete treatment effects.

The present inventors conducted various studies to identify the cause and solve the problem of the problem of the pharmaceutical composition containing entecavir, in particular, to reduce the bioavailability when taken with meals. As a result, by minimizing the dietary effect of entecavir, a pharmaceutical composition containing entecavir, which exhibits stable bioavailability regardless of food intake, has been invented.

The present invention is to provide an enticavir-containing pharmaceutical composition exhibiting a stable bioavailability regardless of food intake by minimizing the dietary effect of entecavir when taking an enticavir-containing preparation with a meal.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising entecavir and a dietary effect remover.

In the present invention, the dietary effect remover is a substance selected from the group consisting of the heavy chain fatty acids and salts thereof, the heavy chain fatty acid derivatives, the organic acids, and the cationic polymers described below, and the role of enticavir in the active ingredient enticavir is increased and It plays a role of increasing the time to stay in the urinary tract at high concentration, and when entecavir-containing preparation is taken with a meal, it means that it shows stable bioavailability regardless of food intake by minimizing the dietary effect of entecavir.

As a dietary effect remover according to the present invention, medium chain fatty acids and salts thereof are salts of medium chain fatty acids and medium chain fatty acids having a carbon chain length of 6 to 20 carbon atoms, and the medium chain fatty acid derivatives are glyceryl caprylate / caprate. , Glyceryl Dicaprylate / Dicaprate, Caprylocapryl Polyoxy-8 Glyceride, Propylene Glycol Dicaprylate / Dicaprate, Propylene Glycol Monolaurate, Propylene Glycol Monocaprylate, Polyethylene Glycol 15-Hydroxy Stearates, organic acids are lactinic acid, maleic acid, citric acid, phytic acid, cationic polymers may include chitosan, dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, one of them The above can be selected.

The present invention provides a method for preparing entericavir tablets comprising the steps of preparing a particle comprising the active ingredient enticavir and a dietary scavenger, preparing a tablet by mixing a pharmaceutically acceptable excipient and coating the tablet. It can manufacture.

The pharmaceutical composition comprising enticavir and a dietary effect remover of the present invention can maximize the bioavailability stably regardless of food intake by minimizing the dietary effect of entecavir, and the dietary effect of reducing the bioavailability when taken with meals. This can solve the problem causing discomfort in the patient when taking, and improve the patient's compliance with the medication.

Figure 1 shows the results of the dissolution test of the tablets of Examples 4, 5 and 6 of the present invention and the commercial formulation of Comparative Example 1 according to the USP dissolution test method 2 (paddle method).

Figure 2 shows the results of the dissolution test of the enteric coated tablets prepared in Examples 7, 8 and 9 of the present invention according to the USP dissolution test method 2 (paddle method).

Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, these Examples and Experimental Examples illustrate the present invention, and the scope of the present invention is not limited to these Examples and Test Examples.

<실시예 1> <Example 1> 입자의 제조 (1)Preparation of particles (1)

1.06 mg of entecavir monohydrate (1 mg as enticavir) and 24 mg of citric acid are added to 1 g of distilled water and dissolved therein, and 60 mg of dimethylaminoethyl methacrylate copolymer is added to dissolve completely. To the solution was added 35 mg of caprylocapryl polyoxy-8 glyceride, 50 mg of glyceryl dicaprate / dikiprilate and 5 mg of sodium lauryl sulfate, followed by stirring and dispersing 40 mg of calcium silicate and 100 mg of lactose. Let's do it. The obtained solution was spray-dried (inlet temperature 115-125 degreeC, outlet temperature 65-75 degreeC) using the spray dryer, and solid particle | grains were manufactured.

<실시예 2> <Example 2> 입자의 제조 (2)Preparation of particles (2)

1.06 mg of entecavir monohydrate (1 mg as entecavir) and 24 mg of citric acid are added to 1 g of distilled water and dissolved, and 60 mg of polyvinyl acetal diethylaminoacetate is added to dissolve completely. To the solution was added 35 mg of caprylocapryl polyoxy-8 glyceride, 50 mg of glyceryl dicaprate / dikiprilate and 5 mg of sodium lauryl sulfate, followed by stirring and dispersing 40 mg of calcium silicate and 100 mg of lactose. Let's do it. The obtained solution was spray-dried (inlet temperature 115-125 degreeC, outlet temperature 65-75 degreeC) using the spray dryer, and solid particle | grains were manufactured.

<실시예 3> <Example 3> 입자의 제조 (3)Preparation of particles (3)

1.06 mg of entecavir monohydrate (1 mg as entecavir) and 40 mg of citric acid are added to 1 g of distilled water and dissolved, and 100 mg of polyvinyl acetal diethylamino acetate is added to dissolve completely. To the solution was added 35 mg of caprylocapryl polyoxy-8 glyceride, 50 mg of glyceryl dicaprate / dikiprilate and 5 mg of sodium lauryl sulfate, followed by stirring and dispersing 40 mg of calcium silicate and 100 mg of lactose. Let's do it. The obtained solution was spray-dried (inlet temperature 115-125 degreeC, outlet temperature 65-75 degreeC) using the spray dryer, and solid particle | grains were manufactured.

<실시예 4> <Example 4> 정제의 제조 (1)Preparation of tablets (1)

315.06 mg of the particles prepared in Example 1 were mixed with 60 mg of crospovidone, 60 mg of croscarmellose sodium, 50 mg of colloidal silicon dioxide, and 3 mg of magnesium stearate, followed by tableting with a single tableting machine to prepare tablets containing 1 mg of entacavir. It was.

<실시예 5> Example 5 정제의 제조 (2)Preparation of tablets (2)

315.06 mg of the particles prepared in Example 2 were mixed with 60 mg of crospovidone, 60 mg of croscarmellose sodium, 50 mg of colloidal silicon dioxide, and 3 mg of magnesium stearate, followed by tableting with a single tableting machine to prepare tablets containing 1 mg of entacavir. It was.

<실시예 6> <Example 6> 정제의 제조 (3)Preparation of tablets (3)

371.06 mg of the particles prepared in Example 3 were mixed with 60 mg of crospovidone, 60 mg of croscarmellose sodium, 50 mg of colloidal silicon dioxide, and 3 mg of magnesium stearate, followed by tableting with a single tableting machine to prepare tablets containing 1 mg of entacavir. It was.

<실시예 7> <Example 7> 장용코팅제의 제조 (1)Preparation of Enteric Coatings (1)

The tablets prepared in Example 4 were sprayed with a 7% hydroxypropylmethylcellulose ethanol solution using a coater to prepare tablets subcoated with about 3% HPMC. 20% of the enteric coating solution (methacrylate copolymer solution) was sprayed onto the obtained tablet to prepare a tablet coated with about 10% of the enteric base.

<실시예 8> <Example 8> 장용코팅제의 제조 (2)Preparation of Enteric Coatings (2)

The tablets prepared in Example 5 were sprayed with 7% hydroxypropylmethylcellulose ethanol solution using a coater to prepare tablets subcoated with about 3% HPMC. 20% of the enteric coating solution (methacrylate copolymer solution) was sprayed onto the obtained tablet to prepare a tablet coated with about 10% of the enteric base.

<실시예 9> Example 9 장용코팅제의 제조 (3)Preparation of Enteric Coatings (2006.01)

Tablets prepared in Example 6 were sprayed with 7% hydroxypropylmethylcellulose ethanol solution using a coater to prepare tablets subcoated with about 3% HPMC. 20% of the enteric coating solution (methacrylate copolymer solution) was sprayed onto the obtained tablet to prepare a tablet coated with about 10% of the enteric base.

<비교예 1> Comparative Example 1 시판제제Commercially available

Comparative Example in International Patent Application Publication No. 2001/64221 commercially available formulation of BARACLUDE 1mg tablet ^® based on the number (Bristol-Mayers Squibb Co., Lot No.: 3H66321A) was used.

<실험예 1> Experimental Example 1 정제의 용출시험Tablet Dissolution Test

The tablets prepared in Examples 4, 5 and 6 and the commercially available formulations of Comparative Example 1 were subjected to a dissolution test in accordance with USP Dissolution Test Method 2 (paddle method). The dissolution test solution was 900 ml of the first solution, the temperature of the test solution was set to 37 ± 0.5 ℃, the paddle rotation speed was set to 50 rpm. 5, 10, 15, 30, 45, and 60 minutes after the start of the test, 5 ml of the elution test solution was taken out and filtered through a 0.45 μm syringe filter. The filtrate was analyzed by HPLC and the results are shown in FIG. 1.

As can be seen in Figure 1, the dissolution evaluation results of the tablet prepared in Examples 4, 5 and 6 according to the present invention and Comparative Example 1 which is a commercial formulation, all of the entercavir elution within 60 minutes after the start of the dissolution test in the first liquid This is done.

<실험예 2> Experimental Example 2 장용코팅제의 용출시험Dissolution test of enteric coating

The tablets prepared in Examples 7, 8 and 9 were subjected to dissolution test in accordance with USP Dissolution Test Method 2 (paddle method). In order to confirm the dissolution in an acidic state, 750 ml of 0.1N hydrochloric acid was used as an acidic test solution, and after 2 hours, 250 ml of 0.2M sodium triphosphate solution was added to pH 6.8 test solution to convert the pH of the eluate to pH 6.8. The temperature of the test solution was set at 37 ± 0.5 ° C., and the paddle rotation speed was 50 rpm. After starting the test, 5 ml of the elution test solution was taken at 60, 120 minutes in the acidic test solution and 5, 10, 15, 30, 45, 60 minutes after the acidic test solution was converted to pH 6.8 and filtered with a 0.45 μm syringe filter. After that, the filtrate was analyzed by HPLC and the results are shown in FIG. 2.

As can be seen in Figure 2, the tablets prepared in Examples 7, 8 and 9 according to the present invention as a result of dissolution evaluation, the conditions that did not elute entecavir for 2 hours under acidic conditions, pH conversion to pH 6.8 test solution Enterecavir elution was completed within 60 minutes at, indicating that enteric coating was performed properly.

<실험예 3> Experimental Example 3 비교예 제제인 정제의 비글견에서의 식이효과 확인 평가Confirmation and Evaluation of Dietary Effect in Beagle Dogs of Tablets of Comparative Examples

In order to confirm the dietary effect of the formulation of Comparative Example 1, the bioavailability was evaluated in the fasted and fed state using a beagle dog. The formulation of Comparative Example 1 used a commercially available barracrud 1 mg tablet ^® (Bristol-Mayers Squibb). The fasting group was orally administered to five beagle dogs fasted for 12 hours at fasting, and the feeding group was orally administered 200 ml of diet to 5 beagle dogs fasting for 12 hours and orally after 30 minutes. After administration, blood was drawn with a heparinized syringe after 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours. The collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis. The concentration of entecavir in plasma was quantified using LC / MS, and the PK parameters obtained from the blood concentration profile are shown in Table 1 below.

Table 1

Based on the results of Table 1, commercially available Barracrud 1 mg tablets ^® (Bristol-Mayers Squibb) based on the fasting state, AUC and Cmax in the fed state about 10% compared to AUC and Cmax in the fasted state , Cmax was found to decrease by about 60%. This is similar to the results in the aforementioned US FDA data and clinical papers.

Therefore, from the test, Comparative Example 1 (Baraclude 1mg tablet ^® ), which is a commercially available product, can be confirmed that the bioavailability is reduced when taken with a diet.

<실험예 4> Experimental Example 4 본 발명에 따른 정제의 비글견에서의 식이효과 제거 확인 평가Evaluation of elimination of dietary effects in beagle dogs of tablets according to the present invention

Bioavailability of the tablets prepared in Examples 4, 5, and 6 according to the present invention was evaluated using beagle dogs. Comparative evaluation with a commercially available formulation of BARACLUDE 1mg tablet ^® (Bristol-Mayers Squibb Co.) was orally administered to the fasting beagles targeting the 5 weight of about 8kg were fasted for 12 hours. As a test evaluation, the tablets prepared in Examples 4, 5 and 6 were orally administered to fasting groups of 5 beagle dogs fasted for 12 hours, and the feeding group of 5 beagle dogs fasted for 12 hours. 200 ml of diet was forced orally and 30 minutes later. After administration, the fasting group of the comparative evaluation group and the test evaluation group had 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours later, and the feeding group of the test evaluation group had 1, 1.5, 2 , 2.5, 3, 3.5, 4, 5, 6, 8, 12 hours later, blood was collected with a heparinized syringe. The collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis. The concentration of entecavir in plasma was quantified using LC / MS, and the PK parameters obtained from the blood concentration profile are shown in Table 2 below.

TABLE 2

From the results of Table 2, the tablets prepared by Examples 4, 5, 6 of the present invention, based on the fasting state of Comparative Example 1, the average ratio of AUC and Cmax in the fasting and feeding state is shown to be 0.889 to 1.157 It can be seen that the PK change due to the diet does not appear.

Therefore, the tablet according to the present invention exhibited a similar degree to AUC and Cmax in fasting state of Comparative Example 1 (Baraclude 1mg tablet ^® ) in fasting and wet state, which is commercially available, so that the entecavir-containing formulation is taken with the meal. It can be seen that by minimizing the dietary effect of entecavir shows a stable bioavailability regardless of food intake.

<실험예 5> Experimental Example 5 본 발명에 따른 코팅제의 비글견에서의 식이효과 제거 확인 평가Evaluation of elimination of dietary effects in beagle dogs of the coating agent according to the present invention

The bioavailability of the coatings prepared in Examples 7, 8, and 9 according to the present invention was evaluated using beagle dogs. Comparative evaluation with a commercially available formulation of BARACLUDE 1mg tablet ^® (Bristol-Mayers Squibb Co.) was orally administered to the fasting beagles targeting the 5 weight of about 8kg were fasted for 12 hours. In the evaluation of the test, the coatings prepared in Examples 7, 8 and 9 were orally administered to fasting groups of 5 beagle dogs fasted for 12 hours, and the feeding group of 5 beagle dogs fasting for 12 hours. 200 ml of diet was forced orally and 30 minutes later. After administration, the fasting group of the comparative evaluation group and the test evaluation group had 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours later, and the feeding group of the test evaluation group had 1, 1.5, 2 , 2.5, 3, 3.5, 4, 5, 6, 8, 12 hours later, blood was collected with a heparinized syringe. The collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis. The concentration of entecavir in plasma was quantified using LC / MS, and the PK parameters obtained from the blood concentration profile are shown in Table 3 below.

TABLE 3

From the results of Table 3, the tablets prepared by Examples 7, 8, and 9 of the present invention, based on the fasting state of Comparative Example 1, the average ratio of AUC and Cmax in the fasting and feeding state is shown to be between 0.805 and 1.169 It can be seen that the PK change due to the diet does not appear.

Therefore, the enteric coating agent according to the present invention exhibits a similar degree to AUC and Cmax in the fasting state of Comparative Example 1 (Baraclude 1mg tablet ^® ) in the fasting and wet state of commercially available preparations, so that the preparation containing entecavir with a meal When taken, it can be seen that it shows stable bioavailability regardless of food intake by minimizing the dietary effect of entecavir.

In the commercial formulation of Comparative Example 1 (Baraclude 1mg tablets ^® ), AUC and Cmax in the fed state was reduced by about 10% and C60 was reduced by about 60% compared to AUC and Cmax in the fasting state, but the bioavailability was lowered. Tablets and enteric coatings of the present invention exhibit a high bioavailability even in the fed state, it is possible to take the formulation containing entecavir regardless of the meal to improve the patient's ease of taking.

Claims

A pharmaceutical composition comprising enticavir as an active ingredient and comprising a dietary effect remover selected from the group consisting of medium chain fatty acids or salts thereof, medium chain fatty acid derivatives, organic acids and cationic polymers.
The pharmaceutical composition according to claim 1, wherein the heavy chain fatty acid or a salt thereof as a dietary effect remover is selected from fatty acids having a carbon chain length of 6 to 20 carbon atoms or a pharmaceutically acceptable salt thereof.
The medium chain fatty acid derivative of claim 1, wherein the heavy chain fatty acid derivative is a dietary effect remover is glyceryl caprylate / caprate, glyceryl dicaprylate / dicaprate, caprylocapryl polyoxy-8 glyceride, propylene glycol dicaprylate / dica Pharmaceutical composition, characterized in that it is selected from the group consisting of acrylate, propylene glycol monolaurate, propylene glycol monocaprylate or polyethylene glycol 15- hydroxycystearate.
The pharmaceutical composition of claim 1, wherein the organic acid that is a dietary eliminator is selected from the group consisting of lactic acid, maleic acid, citric acid or phytic acid.
2. The pharmaceutical composition of claim 1, wherein the cationic polymer that is a dietary effect remover is selected from the group consisting of chitosan, dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate.