KR20210157692A - Pharmaceutical Composition For Oral Administration Comprising Dabigtran Etextilate - Google Patents

Abstract

A pharmaceutical composition for oral administration containing dabigatran according to the present invention is a multi-layer tablet formulation comprising an active component layer containing dabigatran as an active component and an organic acid layer containing an organic acid and a solubilizer. The pharmaceutical composition has excellent bioavailability compared to conventional formulations, and there is little variation between the administered subjects.

Description

Oral pharmaceutical composition comprising dabigatran etexilate {Pharmaceutical Composition For Oral Administration Comprising Dabigtran Etextilate}

The present invention relates to a pharmaceutical composition of an orally administered multi-layer tablet formulation comprising dabigatran etexilate.

Dabigatran is an oral direct thrombin inhibitor used to treat and prevent blood clotting and to prevent stroke in patients with atrial fibrillation. Dabigatran has a half-life of 14 to 17 hours, is excreted by the kidneys, and, unlike warfarin, which has a similar effect, INR It is advantageous in that it does not require inspection.

The oral pharmaceutical composition of dabigatran uses dabigatran etexilate, which is a double prodrug thereof, as an active ingredient, and is converted into dabigatran having pharmacological activity in the body when administered orally.

As a representative dabigatran formulation currently on the market, there is a product called Pradaxa Capsule of Boehringer Ingelheim Co., Ltd. as a capsule formulation containing dabigatran etexylate mesylate.

However, the pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof as an active ingredient is relatively well soluble in a low pH environment, whereas substantially no dissolution is achieved in an environment of pH 5 or higher. .

Therefore, in an environment with a high pH, the absorption rate in the body rapidly deteriorates, so it is generally used in a formulation with an organic acid to compensate for this problem. At this time, the organic acid provides a local acidic environment in the living body to locally lower the pH in various gastrointestinal tracts between patients to prevent drug absorption, thereby helping dabigatran etexilate to dissolve and absorb.

However, in the case of a general combination formulation containing dabigatran etexilate and an organic acid for pH control in a single formulation, there is a problem in that the stability of the drug is lowered due to the interaction between the two components. That is, since the acidic component of the organic acid affects the active ingredient, there is a disadvantage in that the active ingredient is denatured and related substances are rapidly generated.

In order to improve this point, registered Patent No. 10-1005716 (Pradaxa capsule) for commercially available Pradaxa capsules suggests a form of filling in the form of a large amount of pellets in the capsule, and the pellets surround the organic acid core and the core was spatially separated the active ingredients with the active ingredient layer to secure stability.

However, in the case of small pellets as above, since the active ingredient layer surrounds the organic acid, the organic acid inside can be eluted only when the active ingredient is eluted first. Since there is a case of passing, there is a problem that the bioavailability is low and the variability of the bioavailability is very large depending on the constitution of the patient.

According to the results of the clinical trial of NCT02044367, which tested the bioavailability of capsules, pellets, and solutions of dabigatran in healthy people, the bioavailability of dabigatran etexilate when administered in the form of a solution compared to the capsules As this increases, the variability decreases, which is also seen for the same reason as described above.

Therefore, the dabigatran preparations studied so far have limitations in improving malabsorption. Therefore, there is a need to develop a preparation that further reduces inter-individual variability while increasing bioavailability.

Korean Patent Registration No. 10-1005716

An object of the present invention is to provide an oral pharmaceutical composition of dabigatran having excellent stability while having high bioavailability and low inter-individual variability by improving the conventional pharmaceutical preparation of dabigatran having a low absorption rate in the body.

In order to achieve the above object, an oral multilayer tablet containing dabigatran according to the present invention includes an active ingredient layer containing dabigatran etexilate or a salt thereof as an active ingredient; and an organic acid layer containing an organic acid and a solubilizer.

The solubilizer is composed of a copolymer of ethylene oxide and propylene oxide monomer and is in a gel state at a temperature of 25° C., and preferably has a molecular weight of 9500 to 15000. More specifically, the solubilizing agent may be a poloxamer, and preferably, the content of ethylene oxide may be 71 to 75% by weight based on the total weight of the solubilizing agent.

The active ingredient is included in an amount of 20 to 70% by weight based on the combined weight of the organic acid and the solubilizing agent, and the organic acid and the solubilizing agent are 7:1 to 3:1, more preferably 6:1 to 4:1 by weight. It may be included as a percentage. The organic acid serves to temporarily lower the pH of the microenvironment around the active ingredient in an environment with high pH, and the solubilizer acts to increase the solubility of the active ingredient. However, the above-mentioned ratio of the active ingredient and the solubilizing agent is preferable, and if it is out of the above range, the solubility may be rather deteriorated.

Specifically, when the content ratio of the solubilizer is too low outside the above range, the solubilizing ability for the active ingredient may be reduced. On the other hand, even when the content ratio of the solubilizer is too high, interaction with the organic acid occurs to inhibit the organic acid elution, and accordingly, there is a problem in that the pH of the microenvironment around the active ingredient cannot be sufficiently lowered.

The active ingredient may be dabigatran etexylate mesylate, and the content of the active ingredient may be 10 to 40% by weight based on the total weight of the active ingredient layer.

Meanwhile, the organic acid may be one or more selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, and malic acid, and more preferably tartaric acid or fumaric acid.

The active ingredient layer may include 0.5 to 2% by weight of a binder and 2 to 6% by weight of a disintegrant based on the total weight of the active ingredient for rapid disintegration in the body. The binder and disintegrant are intended to achieve rapid disintegration and dissolution of the active ingredient after oral administration while maintaining formulation stability, and when out of the above range, stability may be reduced or pharmacological effect may be delayed.

In this case, the binder is hydroxypropyl cellulose, acacia, alginic acid, microcrystalline cellulose, copovidone, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methyl cellulose, hypromellose, maltodextrin, methyl cellulose, It may be one or two or more selected from the group consisting of polyethylene oxide, povidone, corn starch, potato starch, pregelatinized starch, and wheat starch.

The disintegrant is one or two kinds selected from the group consisting of crospovidone, sodium starch glycolate, polacrylline potassium, maltose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, alginic acid, microcrystalline cellulose, sodium hydrogen carbonate It may be more than

In addition to the above components, the multilayer tablet for oral administration containing dabigatran etexilate of the present invention may further include one or two or more pharmaceutically acceptable additives such as excipients and lubricants. The type of the additive is not particularly limited, and as long as it is pharmaceutically acceptable, such as described in the “Guidelines for Drug Additives” of the Korea Food and Drug Administration, the shape and size of the intended preparation, equipment used in the preparation, etc. An appropriate one can be selected and used according to the preparation conditions.

Orally administered multi-layer tablet containing dabigatran etexilate according to the present invention, according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test, at 37 ℃ temperature condition, the phase change of the active ingredient according to Equation 1 After 5 minutes, the dissolution rate is preferably 5% or more, more preferably 10% or more.

<Formula 1>

5 minutes after phase change Dissolution rate (%) = B / A * 100

(In Equation 2, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and B is the pH 1.2 eluate after 30 minutes in the environment, the pH of the eluate is adjusted to 6.8 in that state, and again 5 It means the dissolution rate of the active ingredient after minutes have passed)

In addition, the oral administration multi-layer tablet containing dabigatran etexilate according to the present invention, according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, at 37 ℃ temperature condition, the active ingredient according to the formula 2 It is characterized in that the dissolution rate for 30 minutes after the phase change is preferably 1.5% or more, more preferably 3% or more.

<Formula 2>

Dissolution rate (%) for 30 minutes after phase change = C / A * 100

(In Equation 1, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and C is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)

On the other hand, the orally administered multi-layer tablet of the present invention, according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, the dissolution rate of the active ingredient after 10 minutes in the pH 1.2 dissolution environment at 37 ° C. Preferably, it may be 90% or more.

The administration multi-layer tablet of the present invention is characterized in that the inter-individual variation in pharmacokinetic parameters is significantly lower than that of the reference drug (Pradaxa). Specifically, in a test on beagle dogs, the formulation of the present invention exhibited an inter-individual variation value (CV) of peak plasma concentration (Cmax) and area under the plasma concentration curve (AUC) of pharmacokinetic parameters, and Cmax was 45 % or less, AUC is characterized as 41% or less.

Dabigatran oral administration multi-layer tablet according to the present invention has excellent storage stability, and when stored for 6 weeks at 40°C and 75% RH, each related substance is 1.5% or less for active ingredients and total flexibility for active ingredients It is characterized in that the material is produced at 2.5% or less.

In addition, it is characterized in that when stored for 18 weeks at 25 ℃, 60%RH environment, each related substance for the active ingredient is 0.4% or less, and the total related substance for the active ingredient is 0.7% or less.

The pharmaceutical composition of the present invention has excellent bioavailability and inter-individual variability characteristics compared to conventional formulations, and thus, the active ingredient content is significantly reduced and pharmacological effects equivalent to those of conventional formulations appear. In particular, the pharmaceutical composition of the present invention is characterized in that there is little variation in pharmacological effects due to low inter-individual variability and significantly fewer side effects.

Specifically, as described above, the pharmaceutical composition of the present invention is composed of an active ingredient layer containing dabigatran etexilate as an active ingredient and an organic acid layer containing a solubilizer and an organic acid, and has a fast dissolution rate and inhibition of precipitation of the active ingredient This can increase bioavailability and reduce variability in plasma concentration patterns.

In addition, as the active ingredient is included in a layer separated from the organic acid and the solubilizer, it is possible to prevent denaturation due to physical contact between the active ingredient and the organic acid, so that the pharmacological activity can be maintained for a long time with product stability secured.

1 shows the results of primary screening for solubilizer candidates that can be included in the pharmaceutical preparation according to the present invention.
Figure 2 shows the results of evaluating solubility by injecting the solubilizer candidate group that can be included in the pharmaceutical formulation according to the present invention together with the active ingredient.
Figure 3 shows the results of dissolution testing in the pH 6.8 dissolution environment by preparing a tablet containing an additional solubilizer group that can be included in the pharmaceutical formulation according to the present invention.
4 is a graph showing the results of the dissolution test in water for Examples 1, 2, 3 and the control drug (Pradaxa) of the present invention.
5 is a graph showing the pharmacokinetic parameters of Examples 1, 2, Comparative Example 1 and the control drug (Pradaxa) of the present invention.
6 is a graph showing the pharmacokinetic parameters of Example 3 of the present invention and the control drug (Pradaxa).
7 is a graph showing the individual variation in bioavailability of Examples 1, 2, Comparative Example 1 and a control drug of the present invention.

After oral administration, the solubility of dabigatran decreases as the pH increases while the active ingredient moves along the gastrointestinal tract. Due to this decrease in solubility, the already eluted dabigatran is precipitated again. As a result, most of the active ingredients that are not absorbed after passing through the stomach are precipitated as they are.

Accordingly, commercially available Pradaxa capsules (110 mg) also have a large variation in bioavailability depending on the constitution of the patient, and thus there is a problem in that side effects also increase. However, a formulation that solves the problem of individual deviation has not been presented so far,

The present applicant can suppress the precipitation of dabigatran due to a rise in pH, thereby increasing the bioavailability of dabigatran, thereby achieving the same pharmacological effect as the conventional formulation even with a relatively small amount of active ingredient. It was expected that side effects could be further reduced by reducing the effect deviation according to the constitution of the patient, and after repeated research, the present invention was completed.

As a method of increasing bioavailability of a conventional dabigatran formulation, a method of administering dabigatran and an organic acid in combination is suggested. However, even in the case of a commercially available combination formulation containing an organic acid, there are cases in which side effects occur due to the low bioavailability. On the other hand, there are documents that describe that a solubilizing agent can be added to the dabigatran formulation as needed, but it does not specifically mention what kind of effect difference appears when which solubilizer is added to the formulation by any method.

Accordingly, the present applicant, after repeated research and experimentation, elutes the active ingredient and organic acid into the body as quickly as possible, and when a solubilizer is included in a specific content, it is possible to suppress the precipitation of the active ingredient for a pH increase, and this pH phase It was found that the inhibition of precipitation according to the change appeared as an effect of increasing bioavailability in the body and reducing individual variation.

Therefore, the pharmaceutical composition of the present invention is a multi-layered tablet in which an active ingredient layer and an organic acid layer are bonded, and each layer rapidly disintegrates and then elutes when administered orally. At this time, since the organic acid layer contains a solubilizing agent, dissolution occurs as quickly as possible in an acidic environment such as the stomach, and at the same time, a lower pH environment is provided so that the active ingredient can be completely dissolved. Thereafter, even when exposed to a high pH environment, the solubilizer prevents precipitation and precipitation of the active ingredient, thereby remarkably increasing the bioavailability even in an intestinal environment with a higher pH than the stomach, and reducing inter-individual variability.

In the present specification, the ability to inhibit precipitation of the active ingredient according to the pH phase change is expressed as “dissolution ratio after phase change”. The dissolution rate after phase change is determined by first measuring the dissolution rate in the pH 1.2 dissolution solution based on 30 minutes, which is the time for disintegration and dissolution of the immediate-release formulation of the conventional tablet formulation, and then in the phase-changed dissolution solution to pH 6.8. The dissolution rate after passing was additionally measured and expressed as a relative ratio.

For example, “5 min dissolution rate after phase change” refers to adding the tablet to the pH 1.2 eluate, measuring the dissolution rate of the active ingredient after 30 minutes (A), and adding a basic substance to adjust the pH. After changing the phase by adjusting to 6.8, the dissolution rate was measured again after 5 minutes (B), indicating that these measured values were expressed as a relative ratio (B/A).

Specifically, in the present invention, the dissolution rate for 5 minutes after the phase change of the active ingredient can be expressed by Equation 1 below.

<Formula 1>

5 minutes after phase change Dissolution rate (%) = B / A * 100

(In Equation 1, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and B is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)

First, the test formulation is put into the pH 1.2 dissolution solution and eluted for 30 minutes, and then the A value, which is the dissolution rate of the active ingredient in the pH 1.2 dissolution solution environment, is calculated. Thereafter, a basic material is added to the pH 1.2 eluate to adjust the pH to 6.8. When the eluate is adjusted to pH 6.8, the active ingredient is eluted again for 5 minutes, and then the dissolution rate B value of the active ingredient after the phase change to the pH 6.8 eluate environment is obtained.

At this time, the dissolution rates A and B are both measured at 37° C. temperature according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method. By dividing the B value by the A value, the phase change dissolution rate of the present invention can be obtained.

In the same way, the dissolution rate for 30 minutes after the phase change of the active ingredient can be expressed by Equation 2 below.

<Formula 2>

Dissolution rate (%) for 30 minutes after phase change = C / A * 100

(In Equation 1, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and C is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)

However, since the solubilizer component rapidly induces denaturation upon contact with the active ingredient, formulation stability may be greatly reduced. Therefore, the pharmaceutical composition of the present invention includes a solubilizing agent in a separate layer separated from the active ingredient, so that the amount of related substances produced for the active ingredient is small even after long-term storage.

Below. The oral administration pharmaceutical composition containing dabigatran of the present invention will be described in detail through Examples and Comparative Examples.

The double tablet of the present invention can be prepared through the following steps.

a) preparing granules of dabigatran etexilate using pharmaceutically acceptable additives and solvents;

b) mixing an organic acid and a solubilizer with a pharmaceutically acceptable additive or preparing granules using a solvent;

c) tabletting the granules prepared in steps a) and b) into a two-layer tablet or a multi-layer tablet in a separated state;

<Solubilizer screening>

Solubilizer screening

First, among commercially available excipients, candidates for solubilizers expected to increase the solubility of dabigatran etexilate were selected, and primary screening was performed on them. Fig. 1 shows the degree of solubility increase when dabigatran etexilate and each solubilizer candidate were added together with reference to 100 when dabigatran etexilate was administered alone. Considering the degree of solubility increase and formulation suitability, solubilizer candidates were selected as Tween 20 (or Tween 80), Brij O20, and Transcutol P.

Selection of 1st candidate for solubilizer

Additional solubility tests were performed on Tween 20, Tween 80, Brij O20 and Transcutol P according to the results of the primary screening. The solubility change was observed by changing the concentration of the solubilizer together with dabigatran etexylate mesylate, and the results are shown in FIG. 2 .

As a result of the experiment, Tween 20, Tween 80, and Brij O 20 showed excellent solubilizing ability, but Brij O20 was an excipient whose safety was not sufficiently verified, so Tween 20 and Tween 80 were selected as candidates. Tween 20 was selected as a solubilizing agent candidate because it had excellent flowability and thus less tableting failure occurred.

Additional Solubilizer Screening

In addition to the solubilizers screened in the process of selecting the primary solubilizing agent candidates, a screening test was performed on additional solubilizing agent candidates. In the process of selecting the primary solubilizing agent candidate, dabigatran etexilate is affected by the hydrophilic-lipophilic balance (HLB) value of the solubilizing agent, and in the manufacturing process, the productivity varies depending on the liquid or solid phase. found Based on this, a group of solubilizer candidates having different HLB values and different states at room temperature were additionally derived. Additional solubilizer candidates are shown in Table 1 below.

product name substance name HLB appearance
(25℃) Labrafil M 2125 CS Linoleoyl Macrogol-6 Glyceride 9 Liquid Laurogolycol 90 polypropylene glycol monolaurate 3 Liquid Poloxamer 407 Poloxamer 407 22 solid Labrasol Caprylocaprioyl Polyoxyglycerides 12 Liquid Precirol ATO 5 Glyceryl Distearate 2 solid Compritol 888 ATO glyceryl behenate One solid

Selection of 2nd candidate for solubilizer

In order to test formulation stability and solubility against the additional candidate group in Table 1 above, 69.3 mg of dabigatran etexylate mesylate as an active ingredient and a test tablet containing a solubilizer, excipient, disintegrant, and lubricant were prepared. The dissolution rate in the pH 6.8 dissolution solution, which is a condition for the active ingredient to precipitate, was measured, and the results are shown in FIG. 3 .

According to the result of FIG. 3, the dissolution rate was the best when 35 mg of poloxamer 407 containing 71 to 75 wt% of ethylene oxide as a copolymer of ethylene oxide and propylene oxide monomer was administered. Poloxamer 407 has a molecular weight of 9,500 to 15,000, and has excellent formulation flowability and fluidity, and is expected to have a desirable effect, so it was selected as a secondary solubilizer candidate.

<Examples 1, 2, 3 and Comparative Example 1> Preparation of a two-layer tablet comprising an active ingredient layer and an organic acid layer

According to the composition shown in Table 2 below, granules of the active ingredient layer and the organic acid layer were prepared, respectively, and then tableted into a double-layer tablet. In Examples 1, 2, and 3, the solubilizer selected in the first and second steps was included in the organic acid layer, respectively, and the type and content of the excipient were adjusted according to the characteristics of the solubilizer. On the other hand, the formulation of Comparative Example 1 did not include a solubilizer.

division Usage Ingredient name Example 1 Example 2 Example 3 Comparative Example 1 active ingredient layer active ingredient Dabigatran etexylate mesylate 69.3 69.3 57.75 69.3 lubricant colloidal silicon dioxide 70.0 70.0 70.0 70.0 binder Hydroxypropyl Cellulose 2.0 2.0 2.0 2.0 excipient Lactose hydrate (premix) 70.0 70.0 70.0 70.0 disintegrant sodium bicarbonate 3.0 3.0 3.0 3.0 excipient Lactose hydrate (post-mix) 45.7 45.7 47.25 45.7 disintegrant crospovidone 10.0 10.0 10.0 10.0 lubricant Sodium Stearyl Fumarate 10.0 10.0 5.0 10.0 Total weight of active ingredient layer 280.0 280.0 265.0 280.0 organic acid layer organic acid tartaric acid 135.0 135.0 115.0 135.0 solubilizer Twin 20 20.0 - - solubilizer Poloxamer 407 - 25.0 25.0 - excipient colloidal silicon dioxide 20.0 - 10.0 - excipient Microcrystalline Cellulose 52.0 - - excipient pregelatinized starch - 60.0 80.0 - excipient Silica Microcrystalline Cellulose 70.0 62.5 70.0 64.5 binder crospovidone 15.0 30.0 30.0 8.0 lubricant Sodium Stearyl Fumarate 3.0 2.5 8.0 2.5 Total weight of organic acid layer 315.0 315.0 338.0 210.0 tablet total weight 595.0 595.0 603.0 490.0

Preparation of active ingredient layer granules

In the active ingredient layer composition shown in Table 2, hydroxypropyl cellulose in a mixture of dabigatran etexylate mesylate, colloidal silicon dioxide, and lactose hydrate in powder form was dissolved in ethanol as a binding solution for wet granulation. After sizing with a 20 mesh, it was dried (40° C., 3 hours). Sodium bicarbonate, crospovidone, lactose hydrate, and sodium stearyl fumarate were mixed with this dried product, and then granules of the active ingredient layer including the active ingredient were prepared.

Preparation of organic acid layer granules (Example 1)

A solution obtained by dissolving a solubilizing agent in ethanol was used as a binding solution, followed by wet granulation and drying. The remaining organic acid, other excipients, and binder lubricant were mixed with the dried product and granulated.

Preparation of organic acid layer powder (Example 2, Example 3, Comparative Example 1)

According to the organic acid layer composition of Examples 2 and 3 and Comparative Example 1 shown in Table 2, each component was mixed in a powder form.

manufacture of tablets

The active ingredient layer and the organic acid layer granules or powders of Examples 1, 2. 3 and Comparative Example 1 were put into a double-layer tablet press and compressed to prepare a double-layer tablet.

<Test Example 1>: dissolution test in water

The dissolution test was conducted according to the dissolution test method in the General Test Method of the Korean Pharmacopoeia. Put the Pradaxa capsules prepared as the double-layer tablets of Examples 1, 2, and 3 above and the reference drug in a container, and use 900 mL of water at 37°C according to the second method (paddle method) of the dissolution test method, and rotate 50 times per minute. was tested with

After the start of the dissolution test, take 10 mL of each eluate from each eluate, filter it with a suitable membrane filter (0.45 μm, PVDF or PTFE filter is preferable), discard the first 4 mL, and collect the remaining filtrate. 3 mL of the eluent was added to 2 mL of the filtrate to obtain a sample solution. With the above sample solution, UV absorbance was measured at 325 nm using an ultraviolet absorptiometer, and the measured dissolution profile is shown in Table 3 and FIG. 4 below.

hours (minutes) Example 1 Example 2 Example 3 Control drug (Pradaxa) 5 70.1 ± 7.1 60.7 ± 4.8 63.4 ± 6.1 Dissolution below the limit of quantitation 10 89.1 ± 4.2 88.5 ± 1.8 85.2 ± 5.2 8.4 ± 4.5 15 94.4 ± 3.7 97.3 ± 1.0 91.5 ± 2.7 43.4 ± 11.5 30 102.3 ± 2.6 103.5 ± 1.2 97.9 ± 1.6 87.4 ± 9.0

As a result of measuring the dissolution rate, the dissolution of the example was faster than the dissolution pattern of the reference drug capsule. Compared to the control drug (Pradaxa), which takes time for the organic acid in the core layer to create an acidic environment after the capsule is melted, Examples 1, 2, and 3 according to the formulation of the present invention dissolve the drug well through the rapid dissolution of the organic acid layer. By quickly creating an environment that allows the drug to be rapidly released from the formulation.

<Test Example 2> Precipitation test by two-phase dissolution

Next, when the pH of the eluate is adjusted to a high level after most of the active ingredient is eluted in an eluate environment with a low pH, Examples 1, 2, 3 and the control drug (Pradaxa) was tested against.

Test conditions except for the eluate were performed under the same conditions as the dissolution test of Test Example 1. First, as shown in Table 4 below, a dissolution test was performed under the condition of 750 mL of 0.1N HCl for 30 minutes so that all of the tablets and reference drug capsules of Examples 1, 2, and 3 could be dissolved.

eluate hours (minutes) Example 1 Example 2 Example 3 Control drug (Pradaxa) Acid stage
(pH 1.2, 0.1 N HCL 750 mL) 10 92.1 ± 2.4 96.8 ± 1.9 91.6.5 ± 4.7 30.5 ± 30.5 30 94.2 ± 1.6 98.3 ± 1.4 100.1 ± 1.3 100.2 ± 3.3

Next, 250 mL of 0.2M tribasic sodium phosphate solution was added to each container, the pH was adjusted to 6.8, and the total solution was 1000 mL. The dissolution rate was obtained by measuring the UV absorbance by taking the eluate at each predetermined time, and the results are shown in Table 5 below.

eluate hours (minutes) Example 1 Example 2 Example 3 Control drug (Pradaxa) pH 6.8 1000 mL 5 2.8 ± 0.1 16.4 ± 3.2 7.0 ± 0.2 1.4 ± 0.2 10 2.8 ± 0.1 5.8 ± 1.6 5.2 ± 0.5 1.2 ± 0.1 15 3.0 ± 0.3 4.5 ± 0.4 - 1.0 ± 0.1 30 3.5 ± 0.2 3.2 ± 0.1 4.7 ± 0.0 1.0 ± 0.2

First, according to the results of Table 4, at the time point 10 minutes after each formulation is added to the pH 1.2 eluate, in the case of Examples 1, 2, and 3 formulations of the present invention, 80% or more, more preferably 85% or more, , in particular, in the case of the formulation of Example 2, the initial dissolution rate was the best at 90% or more. On the other hand, the reference drug (Pradaxa) showed no dissolution at all or even at the maximum dissolution rate of less than 61%, and the dissolution deviation was also more than 30%. Therefore, the preparation of the present invention in an acidic environment in the human body at the initial stage of oral administration can expect rapid dissolution of the active ingredient and rapid pharmacological effect compared to the reference drug (Pradaxa).

On the other hand, according to the results in Table 5, as a result of raising the pH from a state in which all dabigatran is dissolved in an acidic environment of pH 1.2 to a pH of 6.8 in which dabigatran is practically hardly dissolved, in Examples 2 and 3, Specifically, the result showed that the precipitation was delayed against the rise of pH from the beginning. In particular, when looking at the initial dissolution in the environment changed to the pH 6.8 eluate of Examples 2 and 3, a significantly higher value than that of Example 1 appears. Therefore, in Examples 1, 2 and 3, the ability to inhibit precipitation is expected to be expressed in the intestinal environment in which the pH gradually rises after passing through the stomach. It was expected that the bioavailability or individual variation would be even better because the inhibitory ability was very good.

That is, in Examples 1, 2, and 3, since the gastric solubilizer is added in a state in which the active ingredient and the organic acid are rapidly eluted, the main ingredient is inhibited from precipitating due to the change in pH during passage through the gastrointestinal tract compared to the reference drug, and absorption It was determined that the defect could be reduced and the bioavailability could also be increased, and in particular, in the case of Example 2, this precipitation inhibitory effect was estimated to be more excellent than that of Example 1.

On the other hand, for Examples 1, 2, 3 and the reference drug (Pradaxa), based on the dissolution results in Tables 4 and 5, the 5-minute dissolution ratio showing the precipitation inhibiting ability at the beginning after the phase change by Equation 1 was calculated. , the results are shown in Table 6 below.

<Formula 1>

5 minutes after phase change Dissolution rate (%) = B / A * 100

(In Equation 1, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and B is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)

In addition, in order to compare whether the precipitation inhibiting ability at the beginning of the phase change is maintained for a considerable time, the dissolution rate at 30 minutes after the phase change according to Equation 2 below was measured, and the dissolution rate of 10 minutes and 15 minutes was also calculated in the same way. , are shown in Table 6 below.

<Formula 2>

Dissolution rate (%) for 30 minutes after phase change = C / A * 100

(In Equation 2, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and C is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)

Phase change dissolution rate Example 1 Example 2 Example 3 Control drug (pradaxa) 5 minutes later 3.0 ± 0.2 16.7 ± 3.5 7.0 ± 0.2 1.5 ± 0.3 after 10 minutes 3.0 ± 0.2 5.9 ± 1.7 5.1 ± 0.5 1.2 ± 0.1 after 15 minutes 3.2 ± 0.4 4.6 ± 0.5 - 1.0 ± 0.1 30 minutes later 3.7 ± 0.3 3.3 ± 0.2 4.6 ± 0.0 1.0 ± 0.2

As shown in Table 6, when comparing the dissolution rate 5 minutes after the phase change, Example 2 has a significantly higher value compared to Examples 1 and 3 as well as the control drug (Pradaxa). For this reason, the formulation of Example 2 was expected to have the best ability to inhibit precipitation in the initial stage after a phase change from pH 1.2 to pH 6.8. In the case of the formulations of Examples 2 and 3, the dissolution rate for 5 minutes after the phase change according to Equation 1 may be preferably 5% or more, and in Example 2, where the most desirable effect is expected, it may be 10% or more.

On the other hand, the dissolution rate 30 minutes after the phase change was less than 1.5% in the case of the reference drug (pradaxa) formulation, whereas Examples 1, 2, and 3 showed 3.0% or more. Therefore, from the above results, the formulation of the present invention has a phase change dissolution rate of the active ingredient of 1.5% or more, preferably 3.0% or more, and because the gastric solubilizer is added in a state in which the active ingredient and the organic acid are rapidly eluted, the gastrointestinal tract It can be expected that the precipitation of the active ingredient due to the change in pH made during passage will be suppressed. Due to this precipitation inhibiting ability, the formulation of the present invention can reduce malabsorption and is expected to exhibit high bioavailability.

<Test Example 3> Bioavailability comparison test for beagle dogs

In the above Test Example 2, the embodiment of the present invention was expected to obtain improved bioavailability and relatively small individual variation compared to the reference drug (Pradaxa) through an in vitro dissolution test. The effect was confirmed. The test was conducted independently over the first and second rounds, and the beagle dog population was different according to each order.

The test conditions are as follows.

- Test type: parallel test/8 subjects per group

- Test animal: beagle dog

- Test Example 3 - 1 (1st test): After oral administration of Example 1, Example 2, Comparative Example 1, and the control drug (Pradaxa) for each group once, the blood concentration profile was observed for 24 hours

- Test Example 3 - 2 (Secondary Test): After oral administration of Example 3 and the reference drug (Pradaxa) for each group once, the blood concentration profile was observed for 24 hours

The peak plasma concentration (Cmax) and the area under the plasma concentration curve (AUC) among the pharmacokinetic parameters measured for each group are shown in Tables 7 (Test Example 3-1) to 8 (Test Example 3-2) below.

PK parameter Example 1 Example 2 Comparative Example 1 reference drug Cmax 39.8 ± 21.8 50.8 ± 22.7 46.6 ± 46.7 34.8 ± 20.4 AUC 206.1 ± 91.7 249.3 ± 93.4 226.2 ± 187.2 198.4 ± 107.5

PK parameter Example 3 reference drug Cmax 62.6 ± 26.7 82.147 ± 103.021 AUC 305.5 ± 122.8 426.9 ± 520.1

The CV (%) values, which are individual deviations for the pharmacokinetic parameters of Tables 7 and 8, are shown in Tables 9 and 10 below.

PK parameter Example 1 Example 2 Comparative Example 1 reference drug Cmax 54.7 44.7 100.3 58.5 AUC 44.5 37.5 82.7 54.2

PK parameter Example 3 reference drug Cmax 42.6 125.4 AUC 40.2 121.8

As shown in Tables 7 and 9 above, the active ingredient content of Examples 1 and 2 (60 mg as dabigatran etexilate) was about 0.55 compared to the reference drug (Pradaxa, 110 mg as dabigatran etexilate) Even with pears, the pharmacological effect is the same as that of the reference drug, and the variation (CV) between individuals is also less than that of the reference drug, which is more excellent. In particular, in the case of Example 2, the individual deviation of Cmax was 45% or less, and the individual deviation of AUC was 40% or less, so the difference in the degree of expression of the pharmacological effect according to the constitution of the patient was expected to be small, and it was expected that there would be few side effects.

In addition, in the results of Tables 8 and 10, Example 3 with an active ingredient content of 50 mg as dabigatran etexilate also showed the same bioavailability as the reference drug, and the individual variation in Cmax was 43% or less, and the individual variation in AUC was It showed a significantly smaller inter-individual variation (CV) compared to the reference drug at 41% or less. In particular, looking at the individual deviation results for the reference drug in Table 10, it was found that the deviation was wider than the results in Table 8. Combining the above results, it can be seen that this formulation shows equivalent bioavailability despite containing relatively few active ingredients compared to the reference drug and reduces the variation between individuals during actual in vivo administration.

<Test Example 4> Formulation stability test

Since the solubilizer is denatured to generate related substances when in contact with the active ingredient, a stability test was performed to determine whether the solubilizer included in the organic acid layer flows into the active ingredient layer to additionally generate related substances.

Stability tests were performed under accelerated conditions and long-term storage conditions as described below to evaluate the degree of production of related substances in dabigatran etexilate.

Storage conditions

- Acceleration conditions: 40℃, 75%RH, 6 weeks

- Long-term storage conditions: 25℃, 60%RH, 18 weeks

The stability test results according to the above conditions are shown in Tables 11 and 12 below.

accelerated test BIBR 951 BIBR 1154 BIBR 1087 the first Comparative Example 1 0.06 0.09 0.09 Example 1 0.06 0.09 0.09 Example 2 0.06 0.09 0.09 2 weeks Comparative Example 1 0.27 0.43 0.10 Example 1 0.28 0.46 0.10 Example 2 0.28 0.53 0.10 4 weeks Comparative Example 1 0.43 0.76 0.10 Example 1 0.45 0.84 0.11 Example 2 0.47 0.92 0.11 6 weeks Comparative Example 1 0.60 1.09 0.11 Example 1 0.62 1.20 0.12 Example 2 0.64 1.30 0.11

long-term preservation test BIBR 951 BIBR 1154 BIBR 1087 the first Comparative Example 1 0.06 0.09 0.09 Example 1 0.06 0.09 0.09 Example 2 0.06 0.09 0.09 6 weeks Comparative Example 1 0.11 0.16 0.09 Example 1 0.11 0.16 0.10 Example 2 0.11 0.16 0.10 12 weeks Comparative Example 1 0.07 0.17 0.08 Example 1 0.08 0.22 0.07 Example 2 0.08 0.23 0.07 18 weeks Comparative Example 1 0.10 0.26 0.11 Example 1 0.12 0.33 0.10 Example 2 0.11 0.32 0.10

As shown in Tables 11 and 12, the formulations of Examples 1 and 2 contained 1.5% or less of individual related substances for active ingredients and total related substances with respect to active ingredients when stored at 40° C. and 75% RH for 6 weeks. It was found to be produced at less than 2.5%.

In addition, when stored for 18 weeks at 25°C and 60%RH environment, each related substance for the active ingredient is produced at 0.4% or less and the total related substance for the active ingredient is 0.7% or less, which is evaluated as suitable for long-term stability.

In addition, it can be seen that since the production amount of related substances is substantially the same as that of Comparative Example 1, the solubilizer of the organic acid layer does not flow into the active ingredient layer, and the organic acid and the solubilizer are maintained in a state in which they do not contact.

As a result, both Examples 1 and 2 showed excellent formulation stability. Among them, in the case of Example 2 using poloxamer 407, a copolymer of ethylene oxide and propylene oxide monomer, the ability to inhibit the initial precipitation of the active ingredient during pH phase change was significantly higher than that of Example 1, and thus individual variation was also low low, which gave excellent results. As a result, the formulation of Example 2 improved the bioavailability of dabigatran etexylate mesylate, while also having the lowest individual variation, which is expected to greatly reduce side effects.

Claims (15)

an active ingredient layer containing dabigatran etexilate or a salt thereof as an active ingredient;
As a two-layer tablet comprising; an organic acid layer containing an organic acid and a solubilizer,
The solubilizer is composed of a copolymer of ethylene oxide and propylene oxide monomer and is in a gel state at a temperature of 25 ° C.
The active ingredient is included in an amount of 20 to 70% by weight based on the combined weight of the organic acid and the solubilizer,
The organic acid and the solubilizing agent 7 : 1 to 3 : Orally administered multi-layer tablet that is contained in a weight ratio of 1.
The method of claim 1,
The solubilizer is an oral multilayer tablet having a molecular weight of 9500 to 15000.
The method of claim 1,
The content of ethylene oxide in the solubilizer is 71 to 75% by weight based on the total weight of the solubilizer.
The method of claim 1,
The active ingredient is dabigatran etexylate mesylate oral administration multi-layer tablet.
The method of claim 1,
The content of the active ingredient is 10 to 40% by weight based on the total weight of the active ingredient layer, oral administration multi-layer tablet.
The method of claim 1,
The organic acid is one or more selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, and malic acid.
The method of claim 1,
The active ingredient layer is an orally administered multi-layer tablet comprising 0.5 to 2% by weight of a binder and 2 to 6% by weight of a disintegrant based on the total weight of the active ingredient layer.
8. The method of claim 7,
The binder is hydroxypropyl cellulose, acacia, alginic acid, microcrystalline cellulose, copovidone, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methyl cellulose, hypromellose, maltodextrin, methyl cellulose, polyethylene oxide , povidone, corn starch, potato starch, pregelatinized starch, wheat starch, one or more types selected from the group consisting of orally administered multi-layered tablet.
8. The method of claim 7,
The disintegrant is one or two kinds selected from the group consisting of crospovidone, sodium starch glycolate, polacrylline potassium, maltose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, alginic acid, microcrystalline cellulose, sodium hydrogen carbonate Orally administered multi-layered tablet of more than one.
According to claim 1,
The oral administration multi-layer tablet,
According to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, at 37°C temperature condition,
An orally administered multilayer tablet having a dissolution rate of 5% or more for 5 minutes after a phase change of the active ingredient according to Equation 1 below.
<Formula 1>
5 minutes after phase change Dissolution rate (%) = B / A * 100
(In Equation 2, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and B is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)
According to claim 1,
The oral administration multi-layer tablet,
According to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, at 37°C temperature condition,
An orally administered multilayer tablet having a dissolution rate of 1.5% or more for 30 minutes after the phase change of the active ingredient according to the following formula (2).
<Formula 2>
Dissolution rate (%) for 30 minutes after phase change = C / A * 100
(In Equation 1, A means the dissolution rate of the active ingredient after 30 minutes in the pH 1.2 eluate environment, and C is the pH 1.2 eluate after 30 minutes in the eluate environment. It means the dissolution rate of the active ingredient after minutes have passed)

According to claim 1,
The oral administration multi-layer tablet,
According to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, at 37°C temperature condition,
Orally administered multi-layer tablet in which the dissolution rate of the active ingredient after 10 minutes in the pH 1.2 dissolution environment is 80% or more.
The method of claim 1,
The oral administration multi-layer tablet,
The inter-individual deviation (CV) of peak plasma concentration (Cmax) and area under the plasma concentration curve (AUC) in pharmacokinetic parameters for beagle dogs,
Cmax is 45% or less, AUC is 41% or less orally administered multi-layer tablet.
The method of claim 1,
The oral administration multi-layer tablet is
When stored for 6 weeks at 40℃, 75%RH,
1.5% or less of individual related substances for active ingredients;
Orally administered multi-layered tablet in which the total amount of related substances for the active ingredient is produced in 2.5% or less.
The method of claim 1,
The oral administration multi-layer tablet is
When stored for 18 weeks at 25℃, 60%RH,
Each related substance for the active ingredient is 0.4% or less,
Orally administered multi-layered tablet in which the total amount of related substances for the active ingredient is 0.7% or less.

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